What is the deadliest mosquito-born disease?

Plasmodium falciparum is a unicellular protozoan parasite of humans, and the deadliest species of "Plasmodium" that cause malaria in humans. It is transmitted through the bite of a female "Anopheles" mosquito. It is responsible for roughly 50% of all malaria cases. It causes the disease's most dangerous form called falciparum malaria. It is therefore regarded as the deadliest parasite in humans, causing 435,000 deaths in 2017. It is also associated with the development of blood cancer (Burkitt's lymphoma) and is classified as Group 2A carcinogen.

Plasmodium falciparum

The species originated from the malarial parasite "Laverania" found in gorillas, around 10,000 years ago. Alphonse Laveran was the first to identify the parasite in 1880, and named it "Oscillaria malariae". Ronald Ross discovered its transmission by mosquito in 1897. Giovanni Battista Grassi elucidated the complete transmission from a female anopheline mosquito to humans in 1898. In 1897, William H. Welch created the name "Plasmodium falciparum", which ICZN formally adopted in 1954. "P. falciparum" assumes several different forms during its life cycle. The human-infective stage are sporozoites from the salivary gland of a mosquito. The sporozoites grow and multiply in the liver to become merozoites. These merozoites invade the erythrocytes (RBCs) to form trophozoites, schizonts and gametocytes, during which the symptoms of malaria are produced. In the mosquito, the gametocytes undergo sexual reproduction to a zygote, which turns into ookinete. Ookinete forms oocyts from which sporozoites are formed.

As of the latest "World Malaria Report" of the World Health Organization, there were 219 million cases of malaria worldwide in 2017, up from 216 million cases in 2016. This resulted in an estimated 435,000 deaths. Almost every malarial death is caused by "P. falciparum", and 93% of death occurs in Africa. Children under five years of age are most affected, accounting for 61% of the total deaths. In Sub-Saharan Africa, over 75% of cases were due to "P. falciparum", whereas in most other malarial countries, other, less virulent plasmodial species predominate.

Falciparum malaria was familiar to the ancient Greeks, who gave the general name "pyretós" "fever". Hippocrates (c. 460-370 BCE) gave several descriptions on tertian fever and quartan fever. It was prevalent throughout the ancient Egyptian and Roman civilizations. It was the Romans who named the disease "malaria"—"mala" for bad, and "aria" for air, as they believed that the disease was spread by contaminated air, or miasma.

A German physician, Johann Friedrich Meckel, must have been the first to see "P. falciparum" but not knowing what it was. In 1847 he reported the presence of black pigment granules from the blood and spleen of a patient who died of malaria. The French Army physician Charles Louis Alphonse Laveran, while working at Bône Hospital (now Annaba in Algeria), correctly identified the parasite as a causative pathogen of malaria in 1880. He presented his discovery before the French Academy of Medicine in Paris, and published it in "The Lancet", in 1881. He gave the scientific name "Oscillaria malariae". But his discovery was received with skepticism mainly because by that time leading physicians such as Theodor Albrecht Edwin Klebs and Corrado Tommasi-Crudeli claimed that they had discovered a bacterium (which they called "Bacillus malariae") as the pathogen of malaria. Laveran's discovery was widely accepted only after five years when Camillo Golgi confirmed the parasite using better microscope and staining technique. Laveran was awarded the Nobel Prize in Physiology or Medicine in 1907 for his work. In 1900, the Italian zoologist Giovanni Battista Grassi categorized "Plasmodium" species based on the timing of fever in the patient; malignant tertian malaria was caused by "Laverania malariae" (now "P. falciparum"), benign tertian malaria by "Haemamoeba vivax" (now "P. vivax"), and quartan malaria by "Haemamoeba malariae" (now "P. malariae").

The British physician Patrick Manson formulated the mosquito-malaria theory in 1894; until that time, malarial parasites were believed to be spread in air as miasma, a Greek word for pollution. His colleague Ronald Ross, a British Army surgeon, travelled to India to test the theory. Ross discovered in 1897 that malarial parasite lived in certain mosquitoes. The next year, he demonstrated that a malarial parasite of birds could be transmitted by mosquitoes from one bird to another. Around the same time, Grassi demonstrated that "P. falciparum" was transmitted in humans only by female anopheline mosquito (in his case "Anopheles claviger"). Ross, Manson and Grassi were nominated for the Nobel Prize in Physiology or Medicine in 1902. Under controversial circumstances, only Ronald Ross was selected for the award.

There was a long debate on the taxonomy. It was only in 1954 the International Commission on Zoological Nomenclature officially approved the binominal "Plasmodium falciparum". The valid genus "Plasmodium" was created by two Italian physicians Ettore Marchiafava and Angelo Celli in 1885. The species name was introduced by an American physician William Henry Welch in 1897. It is derived from the Latin "falx", meaning "sickle" and "parum" meaning "like or equal to another".

"P. falciparum" is now generally accepted to have evolved from "Laverania" (a subgenus of "Plasmodium" found in apes) species present in gorilla in Western Africa. Genetic diversity indicates that the human protozoan emerged around 10,000 years ago. The closest relative of "P. falciparum" is "P. praefalciparum", a parasite of gorillas, as supported by mitochondrial, apicoplastic and nuclear DNA sequences. These two species are closely related to the chimpanzee parasite "P. reichenowi", which was previously thought to be the closest relative of "P. falciparum". "P. falciparum" was also once thought to originate from a parasite of birds.

Levels of genetic polymorphism are extremely low within the "P. falciparum" genome compared to that of closely related, ape infecting species of "Plasmodium" (including "P. praefalciparum")"." This suggests that the origin of "P. falciparum" in humans is recent, as a single "P. praefalciparum" strain became capable of infecting humans. The genetic information of "Plasmodium falciparum" has signaled a recent expansion that coincides with the agricultural revolution. It is likely that the development of extensive agriculture increased mosquito population densities by giving rise to more breeding sites, which may have triggered the evolution and expansion of "Plasmodium falciparum".

"P. falciparum" does not have a fixed structure but undergoes continuous change during the course of its life cycle. A sporozoite is spindle-shaped and 10-15 μm long. In the liver it grows into an ovoid schizont of 30-70 μm in diameter. Each schizont produces merozoites, each of which is roughly 1.5 μm in length and 1 μm in diameter. In the erythrocyte the merozoite form a ring-like structure, becoming a trophozoite. A trophozoites feed on the haemoglobin and forms a granular pigment called haemozoin. Unlike those of other "Plasmodium" species, the gametocytes of "P. falciparum" are elongated and crescent-shaped, by which they are sometimes identified. A mature gametocyte is 8-12 μm long and 3-6 μm wide. The ookinete is also elongated measuring about 18-24 μm. An oocyst is rounded and can grow up to 80 μm in diameter. Microscopic examination of a blood film reveals only early (ring-form) trophozoites and gametocytes that are in the peripheral blood. Mature trophozoites or schizonts in peripheral blood smears, as these are usually sequestered in the tissues. On occasion, faint, comma-shaped, red dots are seen on the erythrocyte surface. These dots are Maurer's cleft and are secretory organelles that produce proteins and enzymes essential for nutrient uptake and immune evasion processes.

The apical complex, which is actually a combination of organelles, is an important structure. It contains secretory organelles called rhoptries and micronemes, which are vital for mobility, adhesion, host cell invasion, and parasitophorous vacuole formation. As an apicomplexan, it harbours a plastid, an apicoplast, similar to plant chloroplasts, which they probably acquired by engulfing (or being invaded by) a eukaryotic alga and retaining the algal plastid as a distinctive organelle encased within four membranes. The apicoplast is involved in the synthesis of lipids and several other compounds and provides an attractive drug target. During the asexual blood stage of infection, an essential function of the apicoplast is to produce the isoprenoid precursors isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) via the MEP (non-mevalonate) pathway.

In 1995 the Malaria Genome Project was set up to sequence the genome of "P. falciparum". The genome of its mitochondrion was reported in 1995, that of the nonphotosynthetic plastid known as the apicoplast in 1996, and the sequence of the first nuclear chromosome (chromosome 2) in 1998. The sequence of chromosome 3 was reported in 1999 and the entire genome was reported on 3 October 2002. The roughly 24-megabase genome is extremely AT-rich (about 80%) and is organised into 14 chromosomes. Just over 5,300 genes were described. Many genes involved in antigenic variation are located in the subtelomeric regions of the chromosomes. These are divided into the "var", "rif", and "stevor" families. Within the genome, there exist 59 "var", 149 "rif", and 28 "stevor" genes, along with multiple pseudogenes and truncations. It is estimated that 551, or roughly 10%, of the predicted nuclear-encoded proteins are targeted to the apicoplast, while 4.7% of the proteome is targeted to the mitochondria.

Humans are the intermediate hosts in which asexual reproduction occurs, and female anopheline mosquitos are the definitive hosts harbouring the sexual reproduction stage.

Infection in humans begins with the bite of an infected female "Anopheles" mosquito. Out of about 460 species of "Anopheles" mosquito, more than 70 species transmit falciparum malaria. "Anopheles gambiae" is one of the best known and most prevalent vectors, particularly in Africa.

The infective stage called sporozoites released from the salivary glands through the proboscis of the mosquito enter the bloodstream during feeding. The mosquito saliva contains antihemostatic and anti-inflammatory enzymes that disrupt blood clotting and inhibit the pain reaction. Typically, each infected bite contains 20-200 sporozoites. The immune system clears the sporozoites from the circulation within 30 minutes. But a few escape and quickly invade liver cells (hepatocytes). The sporozoites move in the blood stream by gliding, which is driven by motor made up of proteins actin and myosin beneath their plasma membrane.

Entering the hepatocytes, the parasite loses its apical complex and surface coat, and transforms into a trophozoite. Within the parasitophorous vacuole of the hepatocyte, it undergoes 13-14 rounds of mitosis and meiosis which produce a syncytial cell (coenocyte) called a schizont. This process is called schizogony. A schizont contains tens of thousands of nuclei. From the surface of the schizont, tens of thousands of haploid (1n) daughter cells called merozoites emerge. The liver stage can produce up to 90,000 merozoites, which are eventually released into the bloodstream in parasite-filled vesicles called merosomes.

Merozoites use the apicomplexan invasion organelles (apical complex, pellicle and surface coat) to recognize and enter the host erythrocyte (red blood cell). The parasite first binds to the erythrocyte in a random orientation. It then reorients such that the apical complex is in proximity to the erythrocyte membrane. The parasite forms a parasitophorous vacuole, to allow for its development inside the erythrocyte. This infection cycle occurs in a highly synchronous fashion, with roughly all of the parasites throughout the blood in the same stage of development. This precise clocking mechanism has been shown to be dependent on the human host's own circadian rhythm.

Within the erythrocyte, the parasite metabolism depends on the digestion of hemoglobin. The clinical symptoms of malaria such as fever, anemia, and neurological disorder are produced during the blood stage.

The parasite can also alter the morphology of the erythrocyte, causing knobs on the erythrocyte membrane. Infected erythrocytes are often sequestered in various human tissues or organs, such as the heart, liver and brain. This is caused by parasite-derived cell surface proteins being present on the erythrocyte membrane, and it is these proteins that bind to receptors on human cells. Sequestration in the brain causes cerebral malaria, a very severe form of the disease, which increases the victim's likelihood of death.

After invading the erythrocyte, the parasite loses its specific invasion organelles (apical complex and surface coat) and de-differentiates into a round trophozoite located within a parasitophorous vacuole. The young trophozoite (or "ring" stage, because of its morphology on stained blood films) grows substantially before undergoing schizogony.

At the schizont stage, the parasite replicates its DNA multiple times and multiple mitotic divisions occur asynchronously. Each schizont forms 16-18 merozoites. The red blood cells are ruptured by the merozoites. The liberated merozoites invade fresh erythrocytes. A free merozoite is in the bloodstream for roughly 60 seconds before it enters another erythrocyte.

The duration of each blood stage is approximately 48 hours. This gives rise to the characteristic clinical manifestations of falciparum malaria, such as fever and chills, corresponding to the synchronous rupture of the infected erythrocytes.

Not all of the merozoites divide into schizonts; some get differentiated into sexual forms, male and female gametocytes. These gametocytes take roughly 7–15 days to reach full maturity, through the process called gametocytogenesis. These gametocytes are taken up by a female "Anopheles" mosquito during a blood meal.

The time of appearance of the symptoms from infection (called incubation period) is shortest for "P. falciparum" among "Plasmodium" species. An average incubation period is 11 days, but may range from 9 to 30 days. In isolated cases, prolonged incubation period as long as 2, 3 or even 8 years have been recorded. Pregnancy and co-infection with HIV are important conditions for delayed symptoms. Parasites can be detected from blood samples by the 10th day after infection (pre-patent period).

Within the mosquito midgut, the female gamete maturation process entails slight morphological changes, becoming more enlarged and spherical. The male gametocyte undergoes a rapid nuclear division within 15 minutes, producing eight flagellated microgametes by a process called exflagellation. The flagellated microgamete fertilizes the female macrogamete to produce a diploid cell called a zygote. The zygote then develops into an ookinete. The ookinete is a motile cell, capable of invading other organs of the mosquito. It traverses the peritrophic membrane of the mosquito midgut and crosses the midgut epithelium. Once through the epithelium, the ookinete enters the basal lamina, and settles to an immotile oocyst. For several days, the oocyst undergoes 10 to 11 rounds of cell division to create a syncytial cell (sporoblast) containing thousands of nuclei. Meiosis takes place inside the sporoblast to produce over 3,000 haploid daughter cells called sporozoites on the surface of the mother cell. Immature sporozoites break through the oocyst wall into the haemolymph. They migrate to the mosquito salivary glands where they undergo further development and become infective to humans.

A single anopheline mosquito can transmit hundreds of "P. falciparum" sporozoites in a single bite under experimental conditions. But in nature the number is generally less than 80. The sporozoites do not enter the blood stream directly and remain in the skin tissue for 2 to 3 hours. About 15–20% sporozoites enter the lymphatic system where they activate dendritic cells, which send them for destruction by T lymphocytes (CD8+ T cells). At 48 hours after infection, "Plasmodium"-specific CD8+ T cells can be detected in the lymph nodes connected to the skin cells. Most of the sporozites remaining in the skin tissue are subsequently killed by the innate immune system. The sporozoite glycoprotein specifically activates mast cells. The mast cells then produce signalling molecules such as TNFα and MIP-2, which activate cell eaters (professional phagocytes) such as neutrophils and macrophages.

Only a small number (0.5-5%) of sporozoites enter the blood stream into the liver. In the liver, the activated CD8+ T cells from the lymph bind the sporozoites through the circumsporozoite protein (CSP). Antigen presentation by dendritic cells in the skin tissue to T cells is also a crucial process. From this stage onward the parasites produce different proteins that help in suppressing communication of the immune cells. Even at the height of the infection when RBCs are ruptured, the immune signals are not strong enough to activate macrophages or natural killer cells.

Although "P. falciparum" is easily recognized by human immune system while in the bloodstream, it evades immunity by producing over 2,000 cell membrane antigens The initial infective stage sporozoites produce circumsporozoite protein (CSP), which binds to hepatocytes. Binding to and entry into the hepatocytes is aided by another protein, thrombospondin-related anonymous protein (TRAP). TRAP and other secretory proteins (including sporozoite microneme protein essential for cell traversal 1, SPECT1 and SPECT2) from microneme allow the sporozoite to move through the blood, avoiding immune cells and penetrating hepatocytes.

During erythrocyte invasion, merozoites release merozoite cap protein-1 (MCP1), apical membrane antigen 1 (AMA1), erythrocyte-binding antigens (EBA), myosin A tail domain interacting protein (MTIP), and merozoite surface proteins (MSPs). Of these MSPs, MSP1 and MSP2 are primarily responsible for avoiding immune cells. The virulence of "P. falciparum" is mediated by erythrocyte membrane proteins, which are produced by the schizonts and trophozoites inside the erythrocytes and are displayed on the erythrocyte membrane. PfEMP1 is the most important, capable of acting as both an antigen and an adhesion molecule.

The clinical symptoms of falciparum malaria are produced by the rupture of schizont and destruction of erythrocytes. Most of the patients experience fever (>92% of cases), chills (79%), headaches (70%), and sweating (64%). Dizziness, malaise, muscle pain, abdominal pain, nausea, vomiting, mild diarrhea, and dry cough are also generally associated. High heartrate, jaundice, pallor, orthostatic hypotension, enlarged liver, and enlarged spleen are also diagnosed.

"P. falciparum" works via sequestration, a distinctive property not shared by few other "Plasmodiae". The mature schizonts change the surface properties of infected erythrocytes, causing them to stick to blood vessel walls (cytoadherence). This leads to obstruction of the microcirculation and results in dysfunction of multiple organs, such as the brain in cerebral malaria.

"P. falciparum" is responsible for (almost) all severe human illnesses and deaths due to malaria, in a condition called complicated or severe malaria. Complicated malaria occurs more commonly in children under age 5, and sometimes in pregnant women (a condition specifically called pregnancy-associated malaria). Women become susceptible to severe malaria during their first pregnancy. Susceptibility to severe malaria is reduced in subsequent pregnancies due to increased antibody levels against variant surface antigens that appear on infected erythrocytes. But increased immunity in mother increases susceptibility to malaria in newborn babies.

"P. falciparum" is found in all continents except Europe. According to the WHO "World Malaria Report 2018", 219 million people suffered from malaria in 2017, an increase from 216 million in 2016. 435,000 people died from it. The infection is most prevalent in Africa, where 92% of malaria deaths occr. Children under five years of age are most affected and 61% of malaria deaths occurred in this age group. 80% of the infection is found in Sub-Saharan Africa, 7% in the South-East Asia, and 2% in the Eastern Mediterranean. Nigeria has the highest incidence with 27% of the total global cases. Outside Africa, India has the highest incidence with 4.5% of the global burden. Europe is regarded as a malaria-free region. Historically, the parasite and its disease had been most well known in Europe. But medical programmes, such as insecticide spraying, drug therapy and environmental engineering since the early 20th century resulted in complete eradication in the 1970s. It is estimated that approximately 2.4 billion people are at constant risk of infection.

In 1640, Huan del Vego first employed the tincture of the cinchona bark for treating malaria; the native Indians of Peru and Ecuador had been using it even earlier for treating fevers. Thompson (1650) introduced this "Jesuits' bark" to England. Its first recorded use there was by John Metford of Northampton in 1656. Morton (1696) presented the first detailed description of the clinical picture of malaria and of its treatment with cinchona. Gize (1816) studied the extraction of crystalline quinine from the cinchona bark and Pelletier and Caventou (1820) in France extracted pure quinine alkaloids, which they named quinine and cinchonine. The total synthesis of quinine was achieved by American chemists R.B. Woodward and W.E. Doering in 1944. Woodward received the Nobel Prize in Chemistry in 1965.

Attempts to make synthetic antimalarials began in 1891. Atabrine, developed in 1933, was used widely throughout the Pacific in World War II, but was unpopular because of its adverse effects. In the late 1930s, the Germans developed chloroquine, which went into use in the North African campaigns. Creating a secret military project called Project 523, Mao Zedong encouraged Chinese scientists to find new antimalarials after seeing the casualties in the Vietnam War. Tu Youyou discovered artemisinin in the 1970s from sweet wormwood ("Artemisia annua"). This drug became known to Western scientists in the late 1980s and early 1990s and is now a standard treatment. Tu won the Nobel Prize in Physiology or Medicine in 2015.

According to WHO guidelines 2010, artemisinin-based combination therapies (ACTs) are the recommended first-line antimalarial treatments for uncomplicated malaria caused by "P. falciparum". WHO recommends combinations such as artemether/lumefantrine, artesunate/amodiaquine, artesunate/mefloquine, artesunate/sulfadoxine-pyrimethamine, and dihydroartemisinin/piperaquine.

The choice of ACT is based on the level of resistance to the constituents in the combination. Artemisinin and its derivatives are not appropriate for monotherapy. As second-line antimalarial treatment, when initial treatment does not work, an alternative ACT known to be effective in the region is recommended, such as artesunate plus tetracycline or doxycycline or clindamycin, and quinine plus tetracycline or doxycycline or clindamycin. Any of these combinations is to be given for 7 days. For pregnant women, the recommended first-line treatment during the first trimester is quinine plus clindamycin for 7 days. Artesunate plus clindamycin for 7 days is indicated if this treatment fails. For travellers returning to nonendemic countries, atovaquone/proguanil, artemether/lumefantrineany and quinine plus doxycycline or clindamycin are recommended.

For adults, intravenous (IV) or intramuscular (IM) artesunate is recommended. Quinine is an acceptable alternative if parenteral artesunate is not available.

For children, especially in the malaria-endemic areas of Africa, artesunate IV or IM, quinine (IV infusion or divided IM injection), and artemether IM are recommended.

Parenteral antimalarials should be administered for a minimum of 24 hours, irrespective of the patient's ability to tolerate oral medication earlier. Thereafter, complete treatment is recommended including complete course of ACT or quinine plus clindamycin or doxycycline.

RTS,S is the only candidate as malaria vaccine to have gone through clinical trials. Analysis of the results of the phase III trial (conducted between 2011 and 2016) revealed a rather low efficacy (20-39% depending on age, with up to 50% in 5–17-month aged babies), indicating that the vaccine will not lead to full protection and eradication.

The International Agency for Research on Cancer (IARC) has classified malaria due to "P. falciparum" as Group 2A carcinogen, meaning that the parasite is probably a cancer-causing agent in humans. Its association with a blood cell (lymphocyte) cancer called Burkitt's lymphoma is established. Burkit's lymphoma was discovered by Denis Burkitt in 1958 from African children, and he later speculated that the cancer was likely due to certain infectious diseases. In 1964, a virus, later called Eppstein-Barr virus (EBV) after the discoverers, was identified from the cancer cells. The virus was subsequently proved to be the direct cancer agent, and is now classified as Group 1 carcinogen. In 1989, it was realised that EBV requires other infections such as with malaria to cause lymphocyte transformation. It was reported that the incidence of Burkitt's lymphoma decreased with effective treatment of malaria over several years. The actual role played by "P. falciparum" remained unclear for the next two-and-half decades. EBV had been known to induce lymphocytes to become cancerous using its viral proteins (antigens such as EBNA-1, EBNA-2, LMP-1, and LMP2A). From 2014, it became clear that "P. falciparum" contributes to the development of the lymphoma. "P. falciparum"-infected erythrocytes directly bind to B lymphocytes through the CIDR1α domain of PfEMP1. This binding activates toll-like receptors (TLR7 and TLR10) causing continuous activation of lymphocytes to undergo proliferation and differentiation into plasma cells, thereby increasing the secretion of IgM and cytokines. This in turn activates an enzyme called activation-induced cytidine deaminase (AID), which tends to cause mutation in the DNA (by double-strand break) of an EBV-infected lymphocytes. The damaged DNA undergoes uncontrolled replication, thus making the cell cancerous.

The high mortality and morbidity caused by "P. falciparum" has placed great selective pressure on the human genome. Several genetic factors provide some resistance to "Plasmodium" infection, including sickle cell trait, thalassaemia traits, glucose-6-phosphate dehydrogenase deficiency, and the absence of Duffy antigens on red blood cells. The presence of "P. falciparum" in human populations has exerted selective pressure on the human genome. E. A. Beet, a doctor working in Southern Rhodesia (now Zimbabwe) had observed in 1948 that sickle-cell disease was related to lower rate of malaria infection. This suggestion was reiterated by J. B. S. Haldane in 1948, who suggested that thalassaemia could provide similar protection. This hypothesis has since been confirmed and extended to hemoglobin E, hemoglobin C and Hemoglobin S.

Mosquito-borne diseases are currently most prevalent in East Africa, Latin America,  Southeast Asia, and India; however, emergence of vector-borne diseases in Europe have recently been observed. A weighted risk analysis demonstrated associations to climate for 49% of infectious diseases in Europe including all transmission routes. One statistical model predicts by 2030, the climate of southern Great Britain will be climatically-suitable for malaria transmission "Plasmodium vivax" malaria for 2 months of the year. By 2080 it is predicted that the same will be true for southern Scotland.

Mosquito

Mosquitoes (alternate spelling "mosquitos") are a group of about 3500 species of small insects that are a type of fly (order Diptera). Within that order they constitute the family Culicidae (from the Latin "culex" meaning "gnat"). The word "mosquito" (formed by "mosca" and diminutive "-ito") is Spanish for "little fly". Mosquitoes have a slender segmented body, a pair of wings, three pairs of long hair-like legs, feathery antennae, and elongated mouthparts.

Mosquitoes diverged from other insects about 226 million years ago. Fossils of primitive mosquitoes have been found that are over 90 million years old; fossils similar to modern mosquitoes, 79 million years old; fossils identical to modern mosquitoes, 46 million years old. The life cycle consists of the egg, larva, pupa, and adult. Eggs are laid on the water surface; they hatch into motile larvae which feed on aquatic algae and organic material; pupae are breathing non-flying primitive adults.

Females of most species have tube-like mouthparts (called a proboscis) which can pierce the skin of the host (colloquially but incorrectly referred to as a "bite") in order to extract blood, which contains protein and iron needed to produce eggs. Thousands of mosquito species feed on the blood of various hosts — vertebrates, including mammals, birds, reptiles, amphibians, and some fish; and some invertebrates, primarily other arthropods. This loss of blood is seldom of any importance to the host.

The saliva of the mosquito transmitted to the host with the bite can cause itching and a rash. In addition, many species of mosquitoes inject or ingest (or both) disease-causing organisms with the bite and are thus a vector for the transmission of diseases such as malaria, yellow fever, Chikungunya, West Nile virus, dengue fever, filariasis, Zika virus and other arboviruses. Mosquitoes kill more people than any other animal: over 700,000 each year.

The oldest known mosquito with an anatomy similar to modern species was found in 79-million-year-old Canadian amber from the Cretaceous. An older sister species with more primitive features was found in Burmese amber that is 90 to 100 million years old. Two mosquito fossils have been found that show very little morphological change in modern mosquitoes against their counterpart from 46 million years ago. These fossils are also the oldest ever found to have blood preserved within their abdomens. Despite no fossils being found earlier than the Cretaceous, recent studies suggest that the earliest divergence of mosquitoes between the lineages leading to Anophelinae and Culicinae occurred 226 million years ago.

The mosquito "Anopheles gambiae" is currently undergoing speciation into the M(opti) and S(avanah) molecular forms. Consequently, some pesticides that work on the M form no longer work on the S form.
Over 3,500 species of the Culicidae have already been described. They are generally divided into two subfamilies which in turn comprise some 43 genera. These figures are subject to continual change, as more species are discovered, and as DNA studies compel rearrangement of the taxonomy of the family. The two main subfamilies are the Anophelinae and Culicinae, with their genera as shown in the subsection below. The distinction is of great practical importance because the two subfamilies tend to differ in their significance as vectors of different classes of diseases. Roughly speaking, arboviral diseases such as yellow fever and dengue fever tend to be transmitted by Culicine species, not necessarily in the genus "Culex". Some transmit various species of avian malaria, but it is not clear that they ever transmit any form of human malaria. Some species do however transmit various forms of filariasis, much as many Simuliidae do.

Mosquitoes are members of a family of nematocerid flies: the Culicidae (from the Latin, genitive, meaning "midge" or "gnat"). Superficially, mosquitoes resemble crane flies (family Tipulidae) and chironomid flies (family Chironomidae).

Over 3,500 species of mosquitoes have thus far been described in the scientific literature.

Like all flies, mosquitoes go through four stages in their lifecycles: egg, larva, pupa, and adult or imago. The first three stages—egg, larva, and pupa—are largely aquatic. These stages typically last 5 to 14 days, depending on the species and the ambient temperature, but there are important exceptions. Mosquitoes living in regions where some seasons are freezing or waterless spend part of the year in "diapause"; they delay their development, typically for months, and carry on with life only when there is enough water or warmth for their needs. For instance, "Wyeomyia" larvae typically get frozen into solid lumps of ice during winter and only complete their development in spring. The eggs of some species of "Aedes" remain unharmed in diapause if they dry out, and hatch later when they are covered by water.

Eggs hatch to become larvae, which grow until they are able to change into pupae. The adult mosquito emerges from the mature pupa as it floats at the water surface. Bloodsucking mosquitoes, depending on species, sex, and weather conditions, have potential adult lifespans ranging from as short as a week to as long as several months. Some species can overwinter as adults in diapause.

In most species, adult females lay their eggs in stagnant water: some lay near the water's edge while others attach their eggs to aquatic plants. Each species selects the situation of the water into which it lays its eggs and does so according to its own ecological adaptations. Some are generalists and are not very fussy. Some breed in lakes, some in temporary puddles. Some breed in marshes, some in salt-marshes. Among those that breed in salt water, some are equally at home in fresh and salt water up to about one-third the concentration of seawater, whereas others must acclimatize themselves to the salinity. Such differences are important because certain ecological preferences keep mosquitoes away from most humans, whereas other preferences bring them right into houses at night.

Some species of mosquitoes prefer to breed in phytotelmata (natural reservoirs on plants), such as rainwater accumulated in holes in tree trunks, or in the leaf-axils of bromeliads. Some specialize in the liquid in pitchers of particular species of pitcher plants, their larvae feeding on decaying insects that had drowned there or on the associated bacteria; the genus "Wyeomyia" provides such examples — the harmless "Wyeomyia smithii" breeds only in the pitchers of "Sarracenia purpurea".

However, some of the species of mosquitoes that are adapted to breeding in phytotelmata are dangerous disease vectors. In nature, they might occupy anything from a hollow tree trunk to a cupped leaf. Such species typically take readily to breeding in artificial water containers. Such casual puddles are important breeding places for some of the most serious disease vectors, such as species of "Aedes" that transmit dengue and yellow fever. Some with such breeding habits are disproportionately important vectors because they are well-placed to pick up pathogens from humans and pass them on. In contrast, no matter how voracious, mosquitoes that breed and feed mainly in remote wetlands and salt marshes may well remain uninfected, and if they do happen to become infected with a relevant pathogen, might seldom encounter humans to infect, in turn.

Mosquito habits of oviposition, the ways in which they lay their eggs, vary considerably between species, and the morphologies of the eggs vary accordingly. The simplest procedure is that followed by many species of "Anopheles"; like many other gracile species of aquatic insects, females just fly over the water, bobbing up and down to the water surface and dropping eggs more or less singly. The bobbing behavior occurs among some other aquatic insects as well, for example mayflies and dragonflies; it is sometimes called "dapping". The eggs of "Anopheles" species are roughly cigar-shaped and have floats down their sides. Females of many common species can lay 100–200 eggs during the course of the adult phase of their lifecycles. Even with high egg and intergenerational mortality, over a period of several weeks, a single successful breeding pair can create a population of thousands.

Some other species, for example members of the genus "Mansonia", lay their eggs in arrays, attached usually to the under-surfaces of waterlily pads. Their close relatives, the genus "Coquillettidia", lay their eggs similarly, but not attached to plants. Instead, the eggs form layers called "rafts" that float on the water. This is a common mode of oviposition, and most species of "Culex" are known for the habit, which also occurs in some other genera, such as "Culiseta" and "Uranotaenia". "Anopheles" eggs may on occasion cluster together on the water, too, but the clusters do not generally look much like compactly glued rafts of eggs.

In species that lay their eggs in rafts, rafts do not form adventitiously; the female "Culex" settles carefully on still water with its hind legs crossed, and as it lays the eggs one by one, it twitches to arrange them into a head-down array that sticks together to form the raft.

"Aedes" females generally drop their eggs singly, much as "Anopheles" do, but not as a rule into water. Instead, they lay their eggs on damp mud or other surfaces near the water's edge. Such an oviposition site commonly is the wall of a cavity such as a hollow stump or a container such as a bucket or a discarded vehicle tire. The eggs generally do not hatch until they are flooded, and they may have to withstand considerable desiccation before that happens. They are not resistant to desiccation straight after oviposition, but must develop to a suitable degree first. Once they have achieved that, however, they can enter diapause for several months if they dry out. Clutches of eggs of the majority of mosquito species hatch as soon as possible, and all the eggs in the clutch hatch at much the same time. In contrast, a batch of "Aedes" eggs in diapause tends to hatch irregularly over an extended period of time. This makes it much more difficult to control such species than those mosquitoes whose larvae can be killed all together as they hatch. Some "Anopheles" species do also behave in such a manner, though not to the same degree of sophistication.

The mosquito larva has a well-developed head with mouth brushes used for feeding, a large thorax with no legs, and a segmented abdomen.

Larvae breathe through spiracles located on their eighth abdominal segments, or through a siphon, so must come to the surface frequently. The larvae spend most of their time feeding on algae, bacteria, and other microbes in the surface microlayer.

They dive below the surface only when disturbed. Larvae swim either through propulsion with their mouth brushes, or by jerky movements of their entire bodies, giving them the common name of "wigglers" or "wrigglers".

Larvae develop through four stages, or instars, after which they metamorphose into pupae. At the end of each instar, the larvae molt, shedding their skins to allow for further growth.

As seen in its lateral aspect, the mosquito pupa is comma-shaped. The head and thorax are merged into a cephalothorax, with the abdomen curving around underneath. The pupa can swim actively by flipping its abdomen, and it is commonly called a "tumbler" because of its swimming action. As with the larva, the pupa of most species must come to the surface frequently to breathe, which they do through a pair of respiratory trumpets on their cephalothoraxes. However, pupae do not feed during this stage; typically they pass their time hanging from the surface of the water by their respiratory trumpets. If alarmed, say by a passing shadow, they nimbly swim downwards by flipping their abdomens in much the same way as the larvae do. If undisturbed, they soon float up again.

After a few days or longer, depending on the temperature and other circumstances, the pupa rises to the water surface, the dorsal surface of its cephalothorax splits, and the adult mosquito emerges. The pupa is less active than the larva because it does not feed, whereas the larva feeds constantly.

The period of development from egg to adult varies among species and is strongly influenced by ambient temperature. Some species of mosquitoes can develop from egg to adult in as few as five days, but a more typical period of development in tropical conditions would be some 40 days or more for most species. The variation of the body size in adult mosquitoes depends on the density of the larval population and food supply within the breeding water.

Adult mosquitoes usually mate within a few days after emerging from the pupal stage. In most species, the males form large swarms, usually around dusk, and the females fly into the swarms to mate.

Males typically live for about 5–7 days, feeding on nectar and other sources of sugar. After obtaining a full blood meal, the female will rest for a few days while the blood is digested and eggs are developed. This process depends on the temperature, but usually takes two to three days in tropical conditions. Once the eggs are fully developed, the female lays them and resumes host-seeking.

The cycle repeats itself until the female dies. While females can live longer than a month in captivity, most do not live longer than one to two weeks in nature. Their lifespans depend on temperature, humidity, and their ability to successfully obtain a blood meal while avoiding host defenses and predators.

The length of the adult is typically between 3mm and 6mm. The smallest known mosquitoes are around, and the largest around. Mosquitoes typically weigh around 5 mg. All mosquitoes have slender bodies with three segments: a head, a thorax and an abdomen.

The head is specialized for receiving sensory information and for feeding. It has eyes and a pair of long, many-segmented antennae. The antennae are important for detecting host odors, as well as odors of breeding sites where females lay eggs. In all mosquito species, the antennae of the males in comparison to the females are noticeably bushier and contain auditory receptors to detect the characteristic whine of the females.
The compound eyes are distinctly separated from one another. Their larvae only possess a pit-eye ocellus. The compound eyes of adults develop in a separate region of the head. New ommatidia are added in semicircular rows at the rear of the eye. During the first phase of growth, this leads to individual ommatidia being square, but later in development they become hexagonal. The hexagonal pattern will only become visible when the carapace of the stage with square eyes is molted.

The head also has an elongated, forward-projecting, stinger-like proboscis used for feeding, and two sensory palps. The maxillary palps of the males are longer than their proboscises, whereas the females’ maxillary palps are much shorter. In typical bloodsucking species, the female has an elongated proboscis.

The thorax is specialized for locomotion. Three pairs of legs and a pair of wings are attached to the thorax. The insect wing is an outgrowth of the exoskeleton. The "Anopheles" mosquito can fly for up to four hours continuously at, traveling up to in a night. Males beat their wings between 450 and 600 times per second.

The abdomen is specialized for food digestion and egg development; the abdomen of a mosquito can hold three times its own weight in blood. This segment expands considerably when a female takes a blood meal. The blood is digested over time, serving as a source of protein for the production of eggs, which gradually fill the abdomen.

Typically, both male and female mosquitoes feed on nectar and plant juices, but in many species the mouthparts of the females are adapted for piercing the skin of animal hosts and sucking their blood as ectoparasites. In many species, the female needs to obtain nutrients from a blood meal before it can produce eggs, whereas in many other species, it can produce more eggs after a blood meal. A mosquito has a variety of ways of finding its prey, including chemical, visual, and heat sensors. Both plant materials and blood are useful sources of energy in the form of sugars, and blood also supplies more concentrated nutrients, such as lipids, but the most important function of blood meals is to obtain proteins as materials for egg production.

Among humans, the feeding preferences of mosquitoes typically include those with type O blood, those who are heavy breathers, those with an abundance of skin bacteria, those with high body heat, and pregnant women. Individuals' attractiveness to mosquitoes also has a heritable, genetically-controlled component.

When a female reproduces without such parasitic meals, it is said to practice autogenous reproduction, as in "Toxorhynchites"; otherwise, the reproduction may be termed anautogenous, as occurs in mosquito species that serve as disease vectors, particularly "Anopheles" and some of the most important disease vectors in the genus "Aedes". In contrast, some mosquitoes, for example, many "Culex", are partially anautogenous: they do not need a blood meal for their first cycle of egg production, which they produce autogenously; however, subsequent clutches of eggs are produced anautogenously, at which point their disease vectoring activity becomes operative.

Female mosquitoes hunt their blood host by detecting organic substances such as carbon dioxide (CO) and 1-octen-3-ol ("mushroom alcohol", found in exhaled breath) produced from the host, and through visual recognition. Mosquitoes prefer some people over others. The preferred victim's sweat smells more attractive than others' because of the proportions of the carbon dioxide, octenol, and other compounds that make up body odor. The most powerful semiochemical that triggers the keen sense of smell of "Culex quinquefasciatus" is nonanal. Another compound identified in human blood that attracts mosquitoes is sulcatone or 6-methyl-5-hepten-2-one, especially for "Aedes aegypti" mosquitoes with the odor receptor gene Or4. A large part of the mosquito’s sense of smell, or olfactory system, is devoted to sniffing out blood sources. Of 72 types of odor receptors on its antennae, at least 27 are tuned to detect chemicals found in perspiration. In "Aedes", the search for a host takes place in two phases. First, the mosquito exhibits a nonspecific searching behavior until the perception of a host's stimulants, then it follows a targeted approach.

Most mosquito species are crepuscular (dawn or dusk) feeders. During the heat of the day, most mosquitoes rest in a cool place and wait for the evenings, although they may still bite if disturbed. Some species, such as the Asian tiger mosquito, are known to fly and feed during daytime.

Prior to and during blood feeding, blood-sucking mosquitoes inject saliva into the bodies of their source(s) of blood. This saliva serves as an anticoagulant; without it the female mosquito's proboscis might become clogged with blood clots. The saliva also is the main route by which mosquito physiology offers passenger pathogens access to the hosts' bloodstream. The salivary glands are a major target to most pathogens, whence they find their way into the host via the saliva.

A mosquito bite often leaves an itchy weal, a raised bump, on the victim's skin, which is caused by histamines trying to fight off the protein left by the attacking insect.

Mosquitoes of the genus "Toxorhynchites" never drink blood. This genus includes the largest extant mosquitoes, the larvae of which prey on the larvae of other mosquitoes. These mosquito eaters have been used in the past as mosquito control agents, with varying success.

Many, if not all, blood-sucking species of mosquitoes are fairly selective feeders that specialise in particular host species, though they often relax their selectivity when they experience severe competition for food, defensive activity on the part of the hosts, or starvation. Some species feed selectively on monkeys, while others prefer particular kinds of birds, but they become less selective as conditions become more difficult. For example, "Culiseta melanura" sucks the blood of passerine birds for preference, and such birds are typically the main reservoir of the Eastern equine encephalitis virus in North America. Early in the season while mosquito numbers are low, they concentrate on passerine hosts, but as mosquito numbers rise and the birds are forced to defend themselves more vigorously, the mosquitoes become less selective of hosts. Soon the mosquitoes begin attacking mammals more readily, thereby becoming the major vector of the virus, and causing epidemics of the disease, most conspicuously in humans and horses.

Even more dramatically, in most of its range in North America, the main vector for the Western equine encephalitis virus is "Culex tarsalis", because it is known to feed variously on mammals, birds, reptiles, and amphibians. Even fish may be attacked by some mosquito species if they expose themselves above water level, as mudskippers do.

Some species of blood-sucking flies, such as many of the Ceratopogonidae, will attack large, live insects and suck their haemolymph and others, such as the so-called "jackal flies" (Milichiidae), will attack the recently dead prey of say, crab spiders (Thomisidae). In 1969 it was reported that some species of anautogenous mosquitoes would feed on the haemolymph of caterpillars. Other observations include mosquitoes feeding on cicadas and mantids. In 2014 it was shown that malaria-transmitting mosquitoes actively seek out some species of caterpillars and feed on their haemolymph, and do so to the caterpillar's apparent physical detriment.

Mosquito mouthparts are very specialized, particularly those of the females, which in most species are adapted to piercing skin and then sucking blood. Apart from bloodsucking, the females generally also drink assorted fluids rich in dissolved sugar, such as nectar and honeydew, to obtain the energy they need. For this, their blood-sucking mouthparts are perfectly adequate. In contrast, male mosquitoes are not bloodsuckers; they only drink sugary fluids. Accordingly, their mouthparts do not require the same degree of specialization as those of females.

Externally, the most obvious feeding structure of the mosquito is the proboscis. More specifically, the visible part of the proboscis is the labium, which forms the sheath enclosing the rest of the mouthparts. When the mosquito first lands on a potential host, its mouthparts are enclosed entirely in this sheath, and it will touch the tip of the labium to the skin in various places. Sometimes, it will begin to bite almost straight away, while other times, it will prod around, apparently looking for a suitable place. Occasionally, it will wander for a considerable time, and eventually fly away without biting. Presumably, this probing is a search for a place with easily accessible blood vessels, but the exact mechanism is not known. It is known that there are two taste receptors at the tip of the labium which may well play a role.

The female mosquito does not insert its labium into the skin; it bends back into a bow when the mosquito begins to bite. The tip of the labium remains in contact with the skin of the victim, acting as a guide for the other mouthparts. In total, there are six mouthparts besides the labium: two mandibles, two maxillae, the hypopharynx, and the labrum.

The mandibles and the maxillae are used for piercing the skin. The mandibles are pointed, while the maxillae end in flat, toothed "blades". To force these into the skin, the mosquito moves its head backwards and forwards. On one movement, the maxillae are moved as far forward as possible. On the opposite movement, the mandibles are pushed deeper into the skin by levering against the maxillae. The maxillae do not slip back because the toothed blades grip the skin.

The hypopharynx and the labrum are both hollow. Saliva with anticoagulant is pumped down the hypopharynx to prevent clotting, and blood is drawn up the labrum.

To understand the mosquito mouthparts, it is helpful to draw a comparison with an insect that chews food, such as a dragonfly. A dragonfly has two mandibles, which are used for chewing, and two maxillae, which are used to hold the food in place as it is chewed. The labium forms the floor of the dragonfly's mouth, the labrum forms the top, while the hypopharynx is inside the mouth and is used in swallowing. Conceptually, then, the mosquito's proboscis is an adaptation of the mouthparts that occur in other insects. The labium still lies beneath the other mouthparts, but also enfolds them, and it has been extended into a proboscis. The maxillae still "grip" the "food" while the mandibles "bite" it. The top of the mouth, the labrum, has developed into a channeled blade the length of the proboscis, with a cross-section like an inverted "U". Finally, the hypopharynx has extended into a tube that can deliver saliva at the end of the proboscis. Its upper surface is somewhat flattened so, when the lower part of the hypopharynx is pressed against it, the labrum forms a closed tube for conveying blood from the victim.

For the mosquito to obtain a blood meal, it must circumvent the vertebrate's physiological responses. The mosquito, as with all blood-feeding arthropods, has mechanisms to effectively block the hemostasis system with their saliva, which contains a mixture of secreted proteins. Mosquito saliva acts to reduce vascular constriction, blood clotting, platelet aggregation, angiogenesis and immunity, and creates inflammation. Universally, hematophagous arthropod saliva contains at least one anti-clotting, one anti-platelet, and one vasodilatory substance. Mosquito saliva also contains enzymes that aid in sugar feeding, and antimicrobial agents to control bacterial growth in the sugar meal. The composition of mosquito saliva is relatively simple, as it usually contains fewer than 20 dominant proteins., scientists still were unable to ascribe functions to more than half of the molecules found in arthropod saliva. One promising application of components of mosquito saliva is the development of anti-clotting drugs, such as clotting inhibitors and capillary dilators, that could be useful for cardiovascular disease.

It is now well recognized that feeding ticks, sandflies, and, more recently, mosquitoes, have an ability to modulate the immune response of the animals (hosts) on which they feed. The presence of this activity in vector saliva is a reflection of the inherent overlapping and interconnected nature of the host hemostatic and inflammatory/immunological responses and the intrinsic need to prevent these host defenses from disrupting successful feeding. The mechanism for mosquito saliva-induced alteration of the host immune response is unclear, but the data have become increasingly convincing that such an effect occurs. Early work described a factor in saliva that directly suppresses TNF-α release, but not antigen-induced histamine secretion, from activated mast cells. Experiments by Cross et al. (1994) demonstrated that the inclusion of "Ae. aegypti" mosquito saliva into naïve cultures led to a suppression of interleukin (IL)-2 and IFN-γ production, while the cytokines IL-4 and IL-5 are unaffected. Cellular proliferation in response to IL-2 is clearly reduced by prior treatment of cells with mosquito salivary gland extract. Correspondingly, activated splenocytes isolated from mice fed upon by either "Ae. aegypti" or "Cx. pipiens" mosquitoes produce markedly higher levels of IL-4 and IL-10 concurrent with suppressed IFN-γ production. Unexpectedly, this shift in cytokine expression is observed in splenocytes up to 10 days after mosquito exposure, suggesting natural feeding of mosquitoes can have a profound, enduring, and systemic effect on the immune response.

T cell populations are decidedly susceptible to the suppressive effect of mosquito saliva, showing increased mortality and decreased division rates. Parallel work by Wasserman et al. (2004) demonstrated that T and B cell proliferation was inhibited in a dose dependent manner with concentrations as low as 1/7 of the saliva in a single mosquito. Depinay et al. (2005) observed a suppression of antibody-specific T cell responses mediated by mosquito saliva and dependent on mast cells and IL-10 expression.

A 2006 study suggests mosquito saliva can also decrease expression of interferon−α/β during early mosquito-borne virus infection. The contribution of type I interferons (IFN) in recovery from infection with viruses has been demonstrated "in vivo" by the therapeutic and prophylactic effects of administration of IFN inducers or IFN itself, and different research suggests mosquito saliva exacerbates West Nile virus infection, as well as other mosquito-transmitted viruses.

Studies in humanized mice bearing a reconstituted human immune system have suggested potential impact of mosquito saliva in humans. Work published in 2018 from the Baylor College of Medicine using such humanized mice came to several conclusions, among them being that mosquito saliva led to an increase in natural killer T cells in peripheral blood; to an overall decrease in "ex vivo" cytokine production by peripheral blood mononuclear cells (PBMCs); changes to proportions of subsets of PBMCs; changes in the prevalence of T cell subtypes across organs; and changes to circulating levels of cytokines.

Female mosquitoes use two very different food sources. They need sugar for energy, which is taken from sources such as nectar, and they need blood as a source of protein for egg development. Because biting is risky and suitable hosts may be difficult to find, mosquitoes take as much blood as possible when they have the opportunity. Digesting large volumes of blood takes time, requiring the use of energy from sugars during the feeding process. To avoid this problem, mosquitoes possess a digestive system which can store both food types, giving access to both as needed. When the mosquito drinks a sugar solution, it is directed to a crop. The crop can release sugar into the stomach as it is required. At the same time, the stomach never becomes full of sugar solution, which would prevent the mosquito taking a blood meal. Blood is directed straight into the mosquito's stomach. In species that feed on mammalian or avian blood, hosts whose blood pressure is high, the mosquito feeds selectively from active blood vessels, where the pressure assists in filling the gut rapidly.

Upon completion of feeding, the mosquito will withdraw her proboscis, and as the gut fills up, the stomach lining secretes a peritrophic membrane that surrounds the blood. This membrane keeps the blood separate from anything else in the stomach. However, like certain other insects that survive on dilute, purely liquid diets, notably many of the Hemiptera, many adult mosquitoes must excrete unwanted aqueous fractions even as they feed. (See the photograph of a feeding "Anopheles stephensi": Note that the excreted droplet patently is not whole blood, being far more dilute). As long as they are not disturbed, this permits mosquitoes to continue feeding until they have accumulated a full meal of nutrient solids. As a result, a mosquito replete with blood can continue to absorb sugar, even as the blood meal is slowly digested over a period of several days. Once blood is in the stomach, the midgut of the female synthesizes proteolytic enzymes that hydrolyze the blood proteins into free amino acids. These are used as building blocks for the synthesis of egg yolk proteins.

In the mosquito "Anopheles stephensi", trypsin activity is restricted entirely to the posterior midgut lumen. No trypsin activity occurs before the blood meal, but activity increases continuously up to 30 hours after feeding, and subsequently returns to baseline levels by 60 hours. Aminopeptidase is active in the anterior and posterior midgut regions before and after feeding. In the whole midgut, activity rises from a baseline of approximately three enzyme units (EU) per midgut to a maximum of 12 EU at 30 hours after the blood meal, subsequently falling to baseline levels by 60 hours. A similar cycle of activity occurs in the posterior midgut and posterior midgut lumen, whereas aminopeptidase in the posterior midgut epithelium decreases in activity during digestion. Aminopeptidase in the anterior midgut is maintained at a constant, low level, showing no significant variation with time after feeding. Alpha-glucosidase is active in anterior and posterior midguts before and at all times after feeding. In whole midgut homogenates, alpha-glucosidase activity increases slowly up to 18 hours after the blood meal, then rises rapidly to a maximum at 30 hours after the blood meal, whereas the subsequent decline in activity is less predictable. All posterior midgut activity is restricted to the posterior midgut lumen. Depending on the time after feeding, greater than 25% of the total midgut activity of alpha-glucosidase is located in the anterior midgut. After blood meal ingestion, proteases are active only in the posterior midgut. Trypsin is the major primary hydrolytic protease and is secreted into the posterior midgut lumen without activation in the posterior midgut epithelium. Aminopeptidase activity is also luminal in the posterior midgut, but cellular aminopeptidases are required for peptide processing in both anterior and posterior midguts. Alpha-glucosidase activity is elevated in the posterior midgut after feeding in response to the blood meal, whereas activity in the anterior midgut is consistent with a nectar-processing role for this midgut region.

Mosquitoes are cosmopolitan (world-wide): they are in every land region except Antarctica and a few islands with polar or subpolar climates. Iceland is such an island, being essentially free of mosquitoes.

The absence of mosquitoes from Iceland and similar regions is probably because of quirks of their climate, which differs in some respects from mainland regions. At the start of the uninterrupted continental winter of Greenland and the northern regions of Eurasia and America, the pupa enters diapause under the ice that covers sufficiently deep water. The imago ecloses only after the ice breaks in late spring. In Iceland however, the weather is less predictable. In mid-winter it frequently warms up suddenly, causing the ice to break, but then to freeze again after a few days. By that time the mosquitoes will have emerged from their pupae, but the new freeze sets in before they can complete their life cycle. Any anautogenous adult mosquito would need a host to supply a blood meal before it could lay viable eggs; it would need time to mate, mature the eggs and oviposit in suitable wetlands. These requirements would not be realistic in Iceland and in fact the absence of mosquitoes from such subpolar islands is in line with the islands' low biodiversity; Iceland has fewer than 1,500 described species of insects, many of them probably accidentally introduced by human agency. In Iceland most ectoparasitic insects live in sheltered conditions or actually on mammals; examples include lice, fleas and bedbugs, in whose living conditions freezing is no concern, and most of which were introduced inadvertently by humans.

Some other aquatic Diptera, such as Simuliidae, do survive in Iceland, but their habits and adaptations differ from those of mosquitoes; Simuliidae for example, though they, like mosquitoes, are bloodsuckers, generally inhabit stones under running water that does not readily freeze and which is totally unsuited to mosquitoes; mosquitoes are generally not adapted to running water.

Eggs of species of mosquitoes from the temperate zones are more tolerant of cold than the eggs of species indigenous to warmer regions. Many even tolerate subzero temperatures. In addition, adults of some species can survive the winter by taking shelter in suitable microhabitats such as buildings or hollow trees.

In warm and humid tropical regions, some mosquito species are active for the entire year, but in temperate and cold regions they hibernate or enter diapause. Arctic or subarctic mosquitoes, like some other arctic midges in families such as Simuliidae and Ceratopogonidae may be active for only a few weeks annually as melt-water pools form on the permafrost. During that time, though, they emerge in huge numbers in some regions and may take up to 300 ml of blood per day from each animal in a caribou herd.

Worldwide introduction of various mosquito species over large distances into regions where they are not indigenous has occurred through human agencies, primarily on sea routes, in which the eggs, larvae, and pupae inhabiting water-filled used tires and cut flowers are transported. However, apart from sea transport, mosquitoes have been effectively carried by personal vehicles, delivery trucks, trains, and aircraft. Man-made areas such as storm water retention basins, or storm drains also provide sprawling sanctuaries. Sufficient quarantine measures have proven difficult to implement. In addition, outdoor pool areas make a perfect place for them to grow.

In order for a mosquito to transmit a disease to the host there must be favorable conditions, referred to as "transmission seasonality". Seasonal factors that impact the prevalence of mosquitos and mosquito-borne diseases are primarily humidity, temperature, and precipitation. A positive correlation between malaria outbreaks and these climatic variables has been demonstrated in China; and El Niño has been shown to impact the location and number of outbreaks of mosquito-borne diseases observed in East Africa, Latin America, Southeast Asia and India. Climate change impacts each of these seasonal factors and in turn impacts the dispersal of mosquitos.

Climatology and the study of mosquito-borne disease have been developed only over the past 100 years; however historical records of weather patterns and distinct symptoms associated with mosquito-borne diseases can be utilized to trace the prevalence of these diseases in relation to the climate over longer time periods. Further, statistical models are being created to predict the impact of climate change on vector-borne diseases using these past records, and these models can be utilized in the field of public health in order to create interventions to reduce the impact of these predicted outcomes.

Two types of models are used to predict mosquito-borne disease spread in relation to climate: correlative models and mechanistic models. "Correlative models" focus primarily on vector distribution, and generally function in 3 steps. First, data is collected regarding geographical location of a target mosquito species. Next, a multivariate regression model establishes the conditions under which the target species can survive. Finally, the model determines the likelihood of the mosquito species to become established in a new location based on similar living conditions. The model can further predict future distributions based on environmental emissions data. "Mechanistic models" tend to be broader and include the pathogens and hosts in the analysis. These models have been used to recreate past outbreaks as well as predict the potential risk of a vector-borne disease based on an areas forecasted climate.

Mosquito-borne diseases are currently most prevalent in East Africa, Latin America,  Southeast Asia, and India; however, emergence of vector-borne diseases in Europe have recently been observed. A weighted risk analysis demonstrated associations to climate for 49% of infectious diseases in Europe including all transmission routes. One statistical model predicts by 2030, the climate of southern Great Britain will be climatically-suitable for malaria transmission "Plasmodium vivax" malaria for 2 months of the year. By 2080 it is predicted that the same will be true for southern Scotland.

Mosquitoes can act as vectors for many disease-causing viruses and parasites. Infected mosquitoes carry these organisms from person to person without exhibiting symptoms themselves. Mosquito-borne diseases include:

Potential transmission of HIV was originally a public health concern, but practical considerations and detailed studies of epidemiological patterns suggest that any transmission of the HIV virus by mosquitoes is at worst extremely unlikely.

Various species of mosquitoes are estimated to transmit various types of disease to more than 700 million people annually in Africa, South America, Central America, Mexico, Russia, and much of Asia, with millions of resultant deaths. At least two million people annually die of these diseases, and the morbidity rates are many times higher still.

Methods used to prevent the spread of disease, or to protect individuals in areas where disease is endemic, include:

Since most such diseases are carried by "elderly" female mosquitoes, some scientists have suggested focusing on these to avoid the evolution of resistance.

Many measures have been tried for mosquito control, including the elimination of breeding places, exclusion via window screens and mosquito nets, biological control with parasites such as fungi and nematodes, or predators such as fish, copepods, dragonfly nymphs and adults, and some species of lizard and gecko. Another approach is to introduce large numbers of sterile males. Genetic methods including cytoplasmic incompatibility, chromosomal translocations, sex distortion and gene replacement have been explored. They are cheaper and not subject to vector resistance.

According to an article in "Nature" discussing the idea of totally eradicating mosquitoes, "Ultimately, there seem to be few things that mosquitoes do that other organisms can’t do just as well — except perhaps for one. They are lethally efficient at sucking blood from one individual and mainlining it into another, providing an ideal route for the spread of pathogenic microbes.” The eradication of mosquitoes may now be possible using gene drives.

Insect repellents are applied on skin and give short-term protection against mosquito bites. The chemical DEET repels some mosquitoes and other insects. Some CDC-recommended repellents are picaridin, eucalyptus oil (PMD) and ethyl butylacetylaminopropionate (IR3535). Others are indalone, dimethyl phthalate, dimethyl carbate, and ethyl hexanediol.

There are also electronic insect repellent devices which produce ultrasounds that were developed to keep away insects (and mosquitoes). However, no scientific research based on the EPA's as well as the many universities' studies has ever provided evidence that these devices prevent a human from being bitten by a mosquito.

Mosquito bites lead to a variety of mild, serious, and, rarely, life-threatening allergic reactions. These include ordinary wheal and flare reactions and mosquito bite allergies (MBA). The MBA, also termed hypersensitivity to mosquito bites (HMB), are excessive reactions to mosquito bites that are not caused by any toxin or pathogen in the saliva injected by a mosquito at the time it takes its blood-meal. Rather, they are allergic hypersensitivity reactions caused by the non-toxic allergenic proteins contained in the mosquito's saliva. Studies have shown or suggest that numerous species of mosquitoes can trigger ordinary reactions as well as MBA. These include "Aedes aegypti, Aedes vexans, Aedes albopictus, Anopheles sinensis, Culex pipiens", "Aedes communis, Anopheles stephensi", "Culex quinquefasciatus, Ochlerotatus triseriatus", and "Culex tritaeniorhynchus". Furthermore, there is considerable cross-reactivity between the salivary proteins of mosquitoes in the same family and, to a lesser extent, different families. It is therefore assumed that these allergic responses may be caused by virtually any mosquito species (or other biting insect).

The mosquito bite allergies are informally classified as 1) the Skeeter syndrome, i.e. severe local skin reactions sometimes associated with low-grade fever; 2) systemic reactions that range from high-grade fever, lymphadenopathy, abdominal pain, and/or diarrhea to, very rarely, life-threatening symptoms of anaphylaxis; and 3) severe and often systmeic reactions occurring in individuals that have an Epstein-Barr virus-associated lymphoproliferative disease, Epstein-Barr virus-negative lymphoid malignancy, or another predisposing condition such as Eosinophilic cellulitis or chronic lymphocytic leukemia.

Visible, irritating bites are due to an immune response from the binding of IgG and IgE antibodies to antigens in the mosquito's saliva. Some of the sensitizing antigens are common to all mosquito species, whereas others are specific to certain species. There are both immediate hypersensitivity reactions (types I and III) and delayed hypersensitivity reactions (type IV) to mosquito bites. Both reactions result in itching, redness and swelling. Immediate reactions develop within a few minutes of the bite and last for a few hours. Delayed reactions take around a day to develop, and last for up to a week.

Several anti-itch medications are commercially available, including those taken orally, such as diphenhydramine, or topically applied antihistamines and, for more severe cases, corticosteroids, such as hydrocortisone and triamcinolone. A common topical remedy in camping gear is aqueous ammonia.

Both topical heat and cool may be useful to treat mosquito bites.

Ancient Greek beast fables including "The Elephant and the Mosquito" and "The Bull and the Mosquito", with the general moral that the large beast does not even notice the small one, derive ultimately from Mesopotamia.

The peoples of Siberia have origin myths surrounding the mosquito - one Ostiak myth tells of a man eating giant, "Punegusse", who is killed by a hero but will not stay dead, the hero eventually burns the giant, but the ashes of the fire become mosquitos that continue to plague mankind.

Other myths from the Yakuts, Goldes (Nanai people), and Samoyed have the insect arising from the ashes or fragments of some giant creature or demon. Similar tales are found in North American Indian myth, with the mosquito arising from the ashes of a man-eater - suggesting a common origin. The Tatars of the Altai had a similar myth, though to be of Indian origin, involving the fragments of the dead giant "Andalma-Muus", becoming mosquitos and other insects.

Winsor McCay's 1912 film "How a Mosquito Operates" was one of the earliest works of animation, far ahead of its time in technical quality. It depicts a giant mosquito tormenting a sleeping man. The de Havilland Mosquito was a high-speed aircraft manufactured between 1940 and 1950, and used in many roles.

Plasmodium vivax is a protozoal parasite and a human pathogen. This parasite is the most frequent and widely distributed cause of recurring (Benign tertian) malaria, "P. vivax" is one of the five species of malaria parasites that commonly infect humans. Although it is less virulent than "Plasmodium falciparum", the deadliest of the five human malaria parasites, "P. vivax" malaria infections can lead to severe disease and death, often due to splenomegaly (a pathologically enlarged spleen). "P. vivax" is carried by the female "Anopheles" mosquito; the males do not bite.

Plasmodium vivax

"Plasmodium vivax" is found mainly in Asia, Latin America, and in some parts of Africa. "P. vivax" is believed to have originated in Asia, but latest studies have shown that wild chimpanzees and gorillas throughout central Africa are endemically infected with parasites that are closely related to human "P. vivax." These findings indicate that human P. vivax is of African origin". Plasmodium vivax" accounts for 65% of malaria cases in Asia and South America. Unlike "Plasmodium falciparum", "Plasmodium vivax" is capable of undergoing sporogonic development in the mosquito at lower temperatures. It has been estimated that 2.5 billion people are at risk of infection with this organism.

Although the Americas contribute 22% of the global area at risk, high endemic areas are generally sparsely populated and the region contributes only 6% to the total population at risk. In Africa, the widespread lack of the Duffy antigen in the population has ensured that stable transmission is constrained to Madagascar and parts of the Horn of Africa. It contributes 3.5% of global population at risk. Central Asia is responsible for 82% of global population at risk with high endemic areas coinciding with dense populations particularly in India and Myanmar. South East Asia has areas of high endemicity in Indonesia and Papua New Guinea and overall contributes 9% of global population at risk.

P. vivax is carried by at least 71 mosquito species. Many vivax vectors live happily in temperate climates—as far north as Finland. Some prefer to bite outdoors or during the daytime, hampering the effectiveness of indoor insecticide and bed nets. Several key vector species have yet to be grown in the lab for closer study, and insecticide resistance is unquantified.

Pathogenesis results from rupture of infected red blood cells, leading to fever. Infected red blood cells may also stick to each other and to walls of capillaries. Vessels plug up and deprive tissues of oxygen. Infection may also cause the spleen to enlarge.
Unlike "P. falciparum", "P. vivax" can populate the bloodstream with sexual-stage parasites—the form picked up by mosquitoes on their way to the next victim—even before a patient shows symptoms. Consequently, prompt treatment of symptomatic patients doesn't necessarily help stop an outbreak, as it does with falciparum malaria, in which fevers occur as sexual stages develop. Even when symptoms appear, because they are usually not immediately fatal, the parasite continues to multiply.

The parasite can go dormant in the liver for days to years, causing no symptoms and remaining undetectable in blood tests. They form what are called hypnozoites, a small stage that nestles inside an individual liver cell. This name derives from “sleeping organisms”. The hypnozoites allow the parasite to survive in more temperate zones, where mosquitoes bite only part of the year.

A single infectious bite can trigger six or more relapses a year, leaving sufferers more vulnerable to other diseases. Other infectious diseases, including falciparum malaria, appear to trigger relapses.

Serious complications for malaria are dormant liver stage parasites, organ failures such as acute kidney failure. More complications of leprosy can also be impairment of consciousness, neurological abnormalities, hypoglycemia and low blood pressures caused by cardiovascular collapse, clinical jaundice and or other vital organ dysfunctions and coagulation defects. The most serious complication ultimately being death.
The main way to prevent malaria is through vector control. There are mostly three main forms that the vector can be controlled: (1) insecticide-treated mosquito nets, (2) indoor residual spraying and (3) antimalarial drugs. Long-lasting insecticidal nets (LLNs) are the preferred method of control because it is the most cost effective. The WHO is currently strategizing how to ensure that the net is properly maintained to protect people at risk. The second option is indoor residual spraying and has been proven effective if at least 80% of the homes are sprayed. However, such method is only effective for 3-6months. A drawback to these two methods, unfortunately, is that mosquito resistance against these insecticides has risen. National malaria control efforts are undergoing rapid changes to ensure the people are given the most effective method of vector control. Lastly, antimalarial drugs can also be used to prevent infection from developing into a clinical disease. However, there has also been an increase resistance to antimalarial medicine.

In 2015 the World Health Organization (WHO) drew up a plan to address vivax malaria, as part of their Global Technical Strategy for Malaria.

"P. vivax" and "P. ovale" that has been sitting in EDTA for more than 30 minutes before the blood film is made will look very similar in appearance to "P. malariae", which is an important reason to warn the laboratory immediately when the blood sample is drawn so they can process the sample as soon as it arrives. Blood films are preferably made within 30 minutes of the blood draw and must certainly be made within an hour of the blood being drawn. Diagnosis can be done with the strip fast test of antibodies.

Chloroquine remains the treatment of choice for "vivax" malaria, except in Indonesia's Irian Jaya (Western New Guinea) region and the geographically contiguous Papua New Guinea, where chloroquine resistance is common (up to 20% resistance). Chloroquine resistance is an increasing problem in other parts of the world, such as Korea and India.

When chloroquine resistance is common or when chloroquine is contraindicated, then artesunate is the drug of choice, except in the U.S., where it is not approved for use. Where an artemisinin-based combination therapy has been adopted as the first-line treatment for "P. falciparum" malaria, it may also be used for P. vivax malaria in combination with primaquine for radical cure. An exception is artesunate plus sulfadoxine-pyrimethamine (AS+SP), which is not effective against P. vivax in many places. Mefloquine is a good alternative and in some countries is more readily available. Atovaquone-proguanil is an effective alternative in patients unable to tolerate chloroquine. Quinine may be used to treat "vivax" malaria but is associated with inferior outcomes.

32–100% of patients will relapse following successful treatment of "P. vivax" infection if a radical cure (eradication of liver stages) is not given.

Eradication of the liver stages is achieved by giving primaquine. Patients with glucose-6-phosphate dehydrogenase deficiency risk haemolysis. G6PD is an enzyme important for blood chemistry. No field-ready test is available. Recently, this point has taken particular importance for the increased incidence of vivax malaria among travelers. At least a 14-day course of primaquine is required for the radical treatment of "P. vivax".

In 2013 a Phase IIb trial was completed that studied a single-dose alternative drug named tafenoquine. It is an 8-aminoquinoline, of the same family as primaquine, developed by researchers at the Walter Reed Army Institute of Research in the 1970s and tested in safety trials. It languished, however, until the push for malaria elimination sparked new interest in primaquine alternatives.

Among patients who received a 600-mg dose, 91% were relapse-free after 6 months. Among patients who received primaquine, 24% relapsed within 6 months. "The data are absolutely spectacular," Wells says. Ideally, he says, researchers will be able to combine the safety data from the Army's earlier trials with the new study in a submission to the U.S. Food and Drug Administration for approval. Like primaquine, tafenoquine causes hemolysis in people who are G6PD deficient.

In 2013 researchers produced cultured human "microlivers" that supported liver stages of both "P. falciparum" and "P. vivax" and may have also created hypnozoites.

Mass-treating populations with a primaquine can kill the hypnozoites, exempting those with G6PD deficiency. However, the standard regimen requires a daily pill for 14 days across an asymptomatic population.

"P. vivax" is the only indigenous malaria parasite on the Korean peninsula. In the years following the Korean War (1950–53), malaria-eradication campaigns successfully reduced the number of new cases of the disease in North Korea and South Korea. In 1979, World Health Organization declared the Korean peninsula vivax malaria-free, but the disease unexpectedly re-emerged in the late 1990s and still persists today. Several factors contributed to the re-emergence of the disease, including reduced emphasis on malaria control after 1979, floods and famine in North Korea, emergence of drug resistance and possibly global warming. Most cases are identified along the Korean Demilitarized Zone. As such, vivax malaria offers the two Koreas an opportunity to work together on an important health problem that affects both countries.

Like all malaria parasites, "P. vivax" has a complex life cycle. It infects a definitive insect host, where sexual reproduction occurs, and an intermediate vertebrate host, where asexual amplification occurs. In "P. vivax", the definitive hosts are Anopheles mosquitoes (also known as the vector), while humans are the intermediate asexual hosts. During its life cycle, "P. vivax" assumes many different physical forms.

Asexual forms:Sexual forms:"P. vivax" human infection occurs when an infected mosquito feeds on a human. During feeding, the mosquito injects saliva to prevent blood clotting (along with sporozoites), thousands of sporozoites are inoculated into human blood; within a half-hour the sporozoites reach the liver. There they enter hepatic cells, transform into the trophozoite form and feed on hepatic cells, and reproduce asexually. This process gives rise to thousands of merozoites (plasmodium daughter cells) in the circulatory system and the liver.

The incubation period of human infection usually ranges from ten to seventeen days and sometimes up to a year. Persistent liver stages allow relapse up to five years after elimination of red blood cell stages and clinical cure.

The "P. vivax" sporozoite enters a hepatocyte and begins its exoerythrocytic schizogony stage. This is characterized by multiple rounds of nuclear division without cellular segmentation. After a certain number of nuclear divisions, the parasite cell will segment and merozoites are formed.

There are situations where some of the sporozoites do not immediately start to grow and divide after entering the hepatocyte, but remain in a dormant, hypnozoite stage for weeks or months. The duration of latency is thought to be variable from one hypnozoite to another and the factors that will eventually trigger growth are not known; this might explain how a single infection can be responsible for a series of waves of parasitaemia or "relapses". It has been assumed that different strains of "P. vivax" have their own characteristic relapse pattern and timing. However, such recurrent parasitaemia is probably being over-attributed to hypnozoite activation. One newly recognized, non-hypnozoite, possible contributing source to recurrent peripheral "P. vivax" parasitaemia is erythrocytic forms in bone marrow.

"P. vivax" preferentially penetrates young red blood cells (reticulocytes), unlike "Plasmodium falciparum" which can invade erythrocytes. In order to achieve this, merozoites have two proteins at their apical pole (PvRBP-1 and PvRBP-2). The parasite uses the Duffy blood group antigens (Fy6) to penetrate red blood cells. This antigen does not occur in the majority of humans in West Africa [phenotype Fy (a-b-)]. As a result, "P. vivax" occurs less frequently in West Africa.

The parasitised red blood cell is up to twice as large as a normal red cell and Schüffner's dots (also known as Schüffner's stippling or Schüffner's granules) are seen on the infected cell's surface. Schüffner's dots have a spotted appearance, varying in color from light pink, to red, to red-yellow, as coloured with Romanovsky stains. The parasite within it is often wildly irregular in shape (described as "amoeboid"). Schizonts of "P. vivax" have up to twenty merozoites within them. It is rare to see cells with more than one parasite within them. Merozoites will only attach to immature blood cell (reticulocytes) and therefore it is unusual to see more than 3% of all circulating erythrocytes parasitised.

Parasite life cycle in mosquitoes includes all stages of
sexual reproduction:When a female Anopheles mosquito bites an infected person, gametocytes and other stages of the parasite are transferred to the mosquito stomach.
Gametocytes ultimately develop into gametes, a process known as gametogony.

Microgametocytes become very active, and their nuclei undergo fission (i.e. amitosis) to each give 6-8 daughter nuclei, which becomes arranged at the periphery. The cytoplasm develops long thin flagella like projections, then a nucleus enter into each one of these extensions. These cytoplasmic extensions later break off as mature male gametes (microgametes). This process of formation of flagella-like microgametes or male gametes is known as exflagellation.
Macrogametocytes show very little change. They develop a cone of reception at one side and becomes mature as macrogametocytes (female gametes).

Male gametes move actively in the stomach of mosquitoes in search of female gametes. Male gametes then enter into female gametes through the cone of reception. The complete fusion of 2 gametes results in the formation of zygote. Here, fusion of 2 dissimilar gametes occurs, known as anisogamy.

The zygote remains inactive for sometime but it soon elongates, becomes vermiform (worm-like) and motile. It is now known as ookinete. The pointed ends of ookinete penetrate the stomach wall and come to lie below its outer epithelial layer. Here the zygote becomes spherical and develops a cyst wall around itself. The cyst wall is derived partly from the stomach tissues and partly produced by the zygote itself. At this stage, the zygote is known as an oocyst. The oocyst absorbs nourishment and grows in size. Oocysts protrude from the surface of stomach, giving it a blistered appearance. In a highly infected mosquito, as many as 1000 oocysts may be seen.

The oocyst nucleus divides repeatedly to form large number of daughter nuclei. At the same time, the cytoplasm develops large vacuoles and forms numerous cytoplasmic masses. These cytoplasmic masses then elongate and a daughter nuclei migrates into each mass. The resulting sickle-shaped bodies are known as sporozoites. This phase of asexual multiplication is known as sporogony and is completed in about 10–21 days. The oocyst then bursts and sporozoites are released into the body cavity of mosquito. Sporozoites eventually reach the salivary glands of mosquito via its hemolymph. The mosquito now becomes infectious. Salivary glands of a single infected mosquito may contain as many as 200,000 sporozoites.
When the mosquito bites a healthy person, thousands of sporozoites are infected into the blood along with the saliva and the cycle starts again.

"P. vivax" can be divided into two clades one that appears to have origins in the Old World and a second that originated in the New World. The distinction can be made on the basis of the structure of the A and S forms of the rRNA. A rearrangement of these genes appears to have occurred in the New World strains. It appears that a gene conversion occurred in an Old World strain and this strain gave rise to the New World strains. The timing of this event has yet to be established.

At present both types of "P. vivax" circulate in the Americas. The monkey parasite - "Plasmodium simium" - is related to the Old World strains rather than to the New World strains.

A specific name - "Plasmodium collinsi" - has been proposed for the New World strains but this suggestion has not been accepted to date.

It has been suggested that P. vivax has horizontally acquired genetic material from humans.
Plasmodium vivax is not known to have a particular gram stain (negative vs. positive) and may appear as either.

"P. vivax" was used between 1917 and the 1940s for malariotherapy, that is, to create very high fevers to combat certain diseases such as tertiary syphilis. In 1917, the inventor of this technique, Julius Wagner-Jauregg, received the Nobel Prize in Physiology or Medicine for his discoveries. However, the technique was dangerous, killing about 15% of patients, so it is no longer in use.

Mosquito-borne diseases or mosquito-borne illnesses are diseases caused by bacteria, viruses or parasites transmitted by mosquitoes. They can transmit disease without being affected themselves. Nearly 700 million people get a mosquito-borne illness each year resulting in over one million deaths.

Mosquito-borne disease

Diseases transmitted by mosquitoes include: malaria, dengue, West Nile virus, chikungunya, yellow fever, filariasis, tularemia, dirofilariasis, Japanese encephalitis, Saint Louis encephalitis, Western equine encephalitis, Eastern equine encephalitis, Venezuelan equine encephalitis, Ross River fever, Barmah Forest fever, La Crosse encephalitis, and Zika fever. as well as newly detected Keystone virus.

The female mosquito of the genus "Anopheles" carry the malaria parasite. Four different species of protozoa cause malaria "Plasmodium falciparum", "Plasmodium malariae", "Plasmodium" ovale and "Plasmodium" vivax. (see "Plasmodium"). Worldwide, malaria is a leading cause of premature mortality, particularly in children under the age of five, with an estimated 207 million cases and more than half a million deaths in 2012, according to the World Malaria Report 2013 published by WHO. The death toll increased to one million as of 2018 according to the American Mosquito Control Association.

Botflies are known to parazitise humans or other mammalians thus causing myiasis and to use mosquitoes as intermediate vector agents to deposit eggs on a host. The human botfly "Dermatobia hominis" attaches its eggs to the underside of a mosquito, and when the mosquito takes a blood meal from a human or an animal, the body heat of the mammalian host induces hatching of larvae.

Some species of mosquito can carry the filariasis worm, a parasite that causes a disfiguring condition (often referred to as elephantiasis) characterized by a great swelling of several parts of the body; worldwide, around 40 million people are living with a filariasis disability.

The viral diseases yellow fever, dengue fever, Zika fever and chikungunya are transmitted mostly by "Aedes aegypti" mosquitoes.

Other viral diseases like epidemic polyarthritis, Rift Valley fever, Ross River fever, St. Louis encephalitis, West Nile fever, Japanese encephalitis, La Crosse encephalitis and several other encephalitic diseases are carried by several different mosquitoes. Eastern equine encephalitis (EEE) and Western equine encephalitis (WEE) occurs in the United States where it causes disease in humans, horses, and some bird species. Because of the high mortality rate, EEE and WEE are regarded as two of the most serious mosquito-borne diseases in the United States. Symptoms range from mild flu-like illness to encephalitis, coma and death.

Viruses carried by arthropods such as mosquitoes or ticks are known collectively as arboviruses. West Nile virus was accidentally introduced into the United States in 1999 and by 2003 had spread to almost every state with over 3,000 cases in 2006.

Other species of "Aedes" as well as "Culex" and "Culiseta" are also involved in the transmission of disease.

A mosquito's period of feeding is often undetected; the bite only becomes apparent because of the immune reaction it provokes. When a mosquito bites a human, it injects saliva and anti-coagulants. For any given individual, with the initial bite there is no reaction but with subsequent bites the body's immune system develops antibodies and a bite becomes inflamed and itchy within 24 hours. This is the usual reaction in young children. With more bites, the sensitivity of the human immune system increases, and an itchy red hive appears in minutes where the immune response has broken capillary blood vessels and fluid has collected under the skin. This type of reaction is common in older children and adults. Some adults can become desensitized to mosquitoes and have little or no reaction to their bites, while others can become hyper-sensitive with bites causing blistering, bruising, and large inflammatory reactions, a response known as skeeter syndrome.

Mosquitoes carrying such arboviruses stay healthy because their immune systems recognizes the virions as foreign particles and "chop off" the virus's genetic coding, rendering it inert. Human infection with a mosquito-borne virus occurs when a female mosquito bites someone while its immune system is still in the process of destroying the virus's harmful coding. It is not completely known how mosquitoes handle eukaryotic parasites to carry them without being harmed. Data has shown that the malaria parasite "Plasmodium falciparum" alters the mosquito vector's feeding behavior by increasing frequency of biting in infected mosquitoes, thus increasing the chance of transmitting the parasite.

The mechanism of transmission of this disease starts with the injection of the parasite into the victim's blood when malaria-infected female "Anopheles" mosquitoes bite into a human being. The parasite uses human liver cells as hosts for maturation where it will continue to replicate and grow, moving into other areas of the body via the bloodstream. The spread of this infection cycle then continues when other mosquitoes bite the same victim. The result will cause that mosquito to ingest the parasite and allow it to transmit the Malaria disease into another person through the same mode of bite injection.

Other viral transmission for Flaviviridae diseases include West Nile virus, yellow fever virus and hepatitis B and C, via vectors like mosquitoes consists of a single stranded, positive-sense RNA virus that is enveloped membranous in a protein coat. Once inside the host's body, the virus will attach itself to a cell's surface through receptor-mediated endocytosis. This essentially means that the proteins and DNA material of the virus are ingested into the host cell. The viral RNA material will undergo several changes and processes inside the host's cell so that it can release more viral RNA that can then be replicated and assembled to infect neighboring host cells.

Currently, there are no specific vaccine therapies for West Nile virus approved for humans; however, vaccines are available and some show promising for animals, as a means to intervene with the mechanism of spreading such pathogens.

Symptoms of illness are specific to the type of viral infection and vary on severity, based on the individuals infected.

Symptoms vary on severity, from mild unnoticeable symptoms to more common symptoms like fever, rash, headache, achy muscle and joints, and conjunctivitis. Symptoms can last several days to weeks, but death resulting from this infection is rare.

Most people infected with the West Nile virus usually do not develop symptoms. However, some individuals can develop cases of severe fatigue, weakness, headaches, body aches, joint and muscle pain, vomiting, diarrhea, and rash, which can last for weeks or months. More serious symptoms have a greater risk of appearing in people over 60 years of age, or those suffering from cancer, diabetes, hypertension, and kidney disease.

Dengue fever is mostly characterized by high fever, headaches, joint pain, and rash. However, more severe instances can lead to hemorrhagic fever, internal bleeding, and breathing difficulty, which can be fatal.

People infected with this virus can develop sudden onset fever along with debilitating joint and muscle pain, rash, headache, nausea, and fatigue. Symptoms can last a few days or be prolonged to weeks and months. Although patients can recover completely, there have been cases in which joint pain has persisted for several months and can extend beyond that for years. Other people can develop heart complications, eye problems, and even neurological complications.

There is a re-emergence of mosquito vector viruses (arthropod-borne viruses) called arboviruses carried by the "Aedes aegypti" mosquito. Examples are the Zika virus, chikungunya virus, yellow fever and dengue fever. The re-emergence of the viruses has been at a faster rate, and over a wider geographic area, than in the past. The rapid re-emergence is due to expanding global transportation networks, the mosquito's increasing ability to adapt to urban settings, the disruption of traditional land use and the inability to control expanding mosquito populations. Like malaria, other arboviruses do not have a vaccine. The only exception is yellow fever. Prevention is focused on reducing the adult mosquito populations, controlling mosquito larvae and protecting individuals from mosquito bites. Depending on the mosquito vector, and the affected community, a variety of prevention methods may be deployed at one time.

The use of insecticide treated mosquito nets (ITNs) are at the forefront of preventing mosquito bites that cause malaria. The prevalence of ITNs in sub-Saharan Africa has grown from 3% of households to 50% of households from 2000 to 2010 with over 254 million insecticide treated nets distributed throughout sub-Saharan Africa for use against the mosquito vectors "Anopheles gambiae" and "Anopheles funestus" which carry malaria. Because the "Anopheles gambiae" feeds indoors (endophagic) and rests indoors after feeding (endophilic), insecticide treated nets (ITNs) interrupt the mosquito's feeding pattern. The ITNs continue to offer protection, even after there are holes in the nets, because of their excito-repellency properties which reduce the number of mosquitoes that enter the home. The World Health Organization (WHO) recommends treating ITNs with the pyrethroid class of insecticides. There is an emerging concern of mosquito resistance to insecticides used in ITNs. Twenty-seven (27) sub-Saharan African countries have reported "Anopheles" vector resistance to pyrethroid insecticides.

Indoor spraying of insecticides is another prevention method widely used to control mosquito vectors. To help control the "Aedes aegypti" mosquito, homes are sprayed indoors with residual insecticide applications. Indoor residual spraying (IRS) reduces the female mosquito population and mitigates the risk of dengue virus transmission. Indoor residual spraying is completed usually once or twice a year. Mosquitoes rest on walls and ceilings after feeding and are killed by the insecticide. Indoor spraying can be combined with spraying the exterior of the building to help reduce the number of mosquito larvae and subsequently, the number of adult mosquitoes.

There are other methods that an individual can use to protect themselves from mosquito bites. Limiting exposure to mosquitoes from dusk to dawn when the majority of mosquitoes are active and wearing long sleeves and long pants during the period mosquitoes are most active. Placing screens on windows and doors is a simple and effective means of reducing the number of mosquitoes indoors. Anticipating mosquito contact and using a topical mosquito repellant with DEET or icaridin is also recommended. Draining or covering water receptacles, both indoor and outdoors, is also a simple but effective prevention method. Removing debris and tires, cleaning drains, and cleaning gutters help larval control and reduce the number of adult mosquitoes.

There is a vaccine for yellow fever which was developed in the 1930s, the yellow 17D vaccine, and it is still in use today. The initial yellow fever vaccination provides lifelong protection for most people and provides immunity within 30 days of the vaccine. Reactions to the yellow fever vaccine have included mild headache and fever, and muscle aches. There are rare cases of individuals presenting with symptoms that mirror the disease itself. The risk of complications from the vaccine are greater for individuals over 60 years of age. In addition, the vaccine is not usually administered to babies under nine months of age, pregnant women, people with allergies to egg protein, and individuals living with AIDS/HIV. The World Health Organization (WHO) reports that 105 million people have been vaccinated for yellow fever in West Africa from 2000 to 2015.

To date, there are relatively few vaccines against mosquito-borne diseases. The National Institute of Allergy and Infectious Disease (NIAID) began Phase 1 clinical trials of a new vaccine that would be nearly universal in protecting against the majority of mosquito-borne diseases.

The arboviruses have expanded their geographic range and infected populations that had no recent community knowledge of the diseases carried by the "Aedes aegypti" mosquito. Education and community awareness campaigns are necessary for prevention to be effective. Communities are educated on how the disease is spread, how they can protect themselves from infection and the symptoms of infection. Community health education programs can identify and address the social/economic and cultural issues that can hinder preventative measures. Community outreach and education programs can identify which preventative measures a community is most likely to employ. Leading to a targeted prevention method that has a higher chance of success in that particular community. Community outreach and education includes engaging community health workers and local healthcare providers, local schools and community organizations to educate the public on mosquito vector control and disease prevention.

Mosquito-borne diseases, such as dengue fever and malaria, typically affect third world countries and areas with tropical climates. Mosquito vectors are sensitive to climate changes and tend to follow seasonal patterns. Between years there are often dramatic shifts in incidence rates. The occurrence of this phenomenon in endemic areas makes mosquito-borne viruses difficult to treat.

Dengue fever is caused by infection through viruses of the family Flaviviridae. The illness is most commonly transmitted by Aedes aegypti mosquitoes in tropical and subtropical regions. Dengue virus has four different serotypes, each of which are antigenically related but have limited cross-immunity to reinfection.

Although dengue fever has a global incidence of 50-100 million cases, only several hundreds of thousands of these cases are life-threatening. The geographic prevalence of the disease can be examined by the spread of the Aedes aegypti. Over the last twenty years, there has been a geographic spread of the disease. Dengue incidence rates have risen sharply within urban areas which have recently become endemic hot spots for the disease. The recent spread of Dengue can also be attributed to rapid population growth, increased coagulation in urban areas, and global travel. Without sufficient vector control, the dengue virus has evolved rapidly over time, posing challenges to both government and public health officials.

Malaria is caused by a protozoan called Plasmodium falciparum. P. falciparum parasites are transmitted mainly by the Anopheles gambiae complex in rural Africa. In just this area, P. falciparum infections comprise an estimated 200 million clinical cases and 1 million annual deaths. 75% of individuals afflicted in this region are children. As with dengue, changing environmental conditions have led to novel disease characteristics. Due to increased illness severity, treatment complications, and mortality rates, many public health officials concede that malaria patterns are rapidly transforming in Africa. Scarcity of health services, rising instances of drug resistance, and changing vector migration patterns are factors that public health officials believe contribute to malaria’s dissemination.

Climate heavily affects mosquito vectors of malaria and dengue. Climate patterns influence the lifespan of mosquitos as well as the rate and frequency of reproduction. Climate change impacts have been of great interest to those studying these diseases and their vectors. Additionally, climate impacts mosquito blood feeding patterns as well as extrinsic incubation periods. Climate consistency gives researchers an ability to accurately predict annual cycling of the disease but recent climate unpredictability has eroded researchers’ ability to track the disease with such precision.

In many insect species, such as "Drosophila melanogaster", researchers found that a natural infection with the bacteria strain "Wolbachia" "pipientis" increases the fitness of the host by increasing resistance to RNA viral infections. Robert L. Glaser and Mark A. Meola investigated "Wolbachia"-induced resistance to West Nile virus (WNV) in "Drosophila melanogaster" (fruit flies). Two groups of fruit flies were naturally infected with "Wolbachia." Glaser and Meola then cured one group of fruit flies of "Wolbachia using" tetracycline. Both the infected group and the cured groups were then infected with WNV.  Flies infected with "Wolbachia" were found to have a changed phenotype that caused resistance to WNV. The phenotype was found to be caused by a “dominant, maternally transmitted, cytoplasmic factor”. The WNV-resistance phenotype was then reversed by curing the fruit flies of "Wolbachia." Since "Wolbachia" is also maternally transmitted, it was found that the WNV-resistant phenotype is directly related to the "Wolbachia" infection. West Nile virus is transmitted to humans and animals through the Southern house mosquito, "Culex quinquefasciatus." Glaser and Meola knew vector compatibility could be reduced through "Wolbachia" infection due to studies done with other species of mosquitoes, mainly, "Aedes aegypti". Their goal was to transfer WNV resistance to "Cx. quinquefasciatus" by inoculating the embryos of the mosquito with the same strain of "Wolbachia" that naturally occurred in the fruit flies. Upon infection, "Cx. quinquefasciatus" showed an increased resistance to WNV that was transferable to offspring. The ability to genetically modify mosquitoes in the lab and then have the infected mosquitoes transmit it to their offspring showed that it was possible to transmit the bacteria to wild populations to decrease human infections.

In 2011, Ary Hoffmann and associates produced the first case of "Wolbachia"-induced arbovirus resistance in wild populations of "Aedes aegypti" through a small project called Eliminate Dengue: Our Challenge. This was made possible by an engineered strain of "Wolbachia" termed "w"Mel that came from "D. melanogaster". The transfer of "w"Mel from "D. melanogaster" into field-caged populations of the mosquito "Aedes aegypti" induced resistance to dengue, yellow fever, and chikungunya viruses. Although other strains of Wolbachia also reduced susceptibility to dengue infection, they also put a greater demand on the fitness of "Ae. aegypti. w"Mel was different in that it was thought to only cost the organism a small portion of its fitness. "w"Mel-infected "Ae. aegypti" were released into two residential areas in the city of Cairns, Australia over a 14-week period. Hoffmann and associates, released a total of 141,600 infected adult mosquitoes in Yorkeys Knob suburb and 157,300 in Gordonvale suburb. After release, the populations were monitored for three years to record the spread of "w"Mel. Population monitoring was gauged by measuring larvae laid in traps. At the beginning of the monitoring period but still within the release period, it was found that "w"Mel-infected "Ae. aegypti" had doubled in Yorkeys Knob and increased 1.5-fold in Gordonvale. Uninfected "Ae. aegypti" populations were in decline. By the end of the three years, "w"Mel-infected "Ae. aegypti" had stable populations of about 90%. However, these populations were isolated to the Yorkeys Knob and Gordonvale suburbs due to unsuitable habitat surrounding the neighborhoods.

Although populations flourished in these areas with nearly 100% transmission, no signs of spread were noted, proving disappointing for some. Following this experiment, Tom L. Schmidt and his colleagues conducted an experiment releasing "Wolbachia"-infected "Aedes aegypti" using different site selection methods occurred in different areas of Cairns during 2013. The release sites were monitored over two years. This time the release was done in urban areas that were adjacent to adequate habitat to encourage mosquito dispersal. Over the two years, the population doubled, and spatial spread was also increased, unlike the first release, giving ample satisfactory results. By increasing the spread of the "Wolbachia"-infected mosquitoes, the researchers were able to establish that population of a large city was possible if the mosquitoes were given adequate habitat to spread into upon release in different local locations throughout the city. An important detail in both of these studies is that no adverse effects on public health or the natural ecosystem occurred. This made it an extremely attractive alternative to traditional insecticide methods given the increased pesticide resistance occurring from heavy use.

From the success seen in Australia, the researchers were able to begin operating in more threatened portions of the world. The Eliminate Dengue program spread to 10 countries throughout Asia, Latin America, and the Western Pacific blooming into the non-profit organization, World Mosquito Program, as of September 2017. They still use the same technique of infecting wild populations of "Ae. aegypti" as they did in Australia, but this time their target disease has shifted to include Zika and chikungunya on top of dengue. Although not alone in their efforts to use "Wolbachia-"infected mosquitoes to reduce mosquito-borne disease, the World Mosquito Program method is praised for being self-sustaining in that it causes permanent phenotype change rather than reducing mosquito populations through cytoplasmic incompatibility through male-only dispersal.

Doctors can typically identify a mosquito bite by sight.

A doctor will perform a physical examination and ask about medical history as well as any travel history. Be ready to give details on any international trips, including the dates you were traveling, the countries you visited and any contact you had with mosquitoes.

Diagnosing dengue fever can be difficult, its symptoms often overlap with many other diseases such as malaria and typhoid fever. Laboratory tests can detect evidence of the dengue viruses, however the results often come back too late to assist in directing treatment.

Medical testing can confirm the presence of West Nile fever or a West Nile-related illness, such as meningitis or encephalitis. If infected, a blood test may show a rising level of antibodies to the West Nile virus. A lumbar puncture (spinal tap) is the most common way to diagnose meningitis, by analyzing the cerebrospinal fluid surrounding your brain and spinal cord. The fluid sample may show an elevated white cell count and antibodies to the West Nile virus if you were exposed. In some cases, an electroencephalography (EEG) or magnetic resonance imaging (MRI) scan can help detect brain inflammation.

A Zika virus infection might be suspected if symptoms are present and an individual has traveled to an area with known Zika virus transmission. Zika virus can only be confirmed by a laboratory test of body fluids, such as urine or saliva, or by blood test.

Laboratory blood tests can identify evidence of chikungunya or other similar viruses such as dengue and Zika. Blood test may confirm the presence of IgM and IgG anti-chikungunya antibodies. IgM antibodies are highest 3 to 5 weeks after the beginning of symptoms and will continue be present for about 2 months.

Numerous drugs have been used to treat yellow fever disease with minimal satisfaction to date. Patients with multisystem organ involvement will require critical care support such as possible hemodialysis or mechanical ventilation. Rest, fluids, and acetaminophen are also known to relieve milder symptoms of fever and muscle pain. Due to hemorrhagic complications, aspirin should be avoided. Infected individuals should avoid mosquito exposure by staying indoors or using a mosquito net.

Dengue infection's therapeutic management is simple, cost effective and successful in saving lives by adequately performing timely institutionalized interventions. Treatment options are restricted, while no effective antiviral drugs for this infection have been accessible to date. Patients in the early phase of the dengue virus may recover without hospitalization. However, ongoing clinical research is in the works to find specific anti-dengue drugs.

Zika virus vaccine clinical trials are to be conducted and established. There are efforts being put toward advancing antiviral therapeutics against zika virus for swift control. Present day Zika virus treatment is symptomatic through antipyretics and analgesics. Currently there are no publications regarding viral drug screening. Nevertheless, therapeutics for this infection have been used.

There are no treatment modalities for acute and chronic chikungunya that currently exist. Majority of treatment plans use supportive and symptomatic care like analgesics for pain and anti-inflammatories for inflammation caused by arthritis. In acute stages of this virus, rest, antipyretics and analgesics are used to subside symptoms. Most use non-steroidal anti-inflammatory drugs (NSAIDs). In some cases, joint pain may resolve from treatment but stiffness remains.

The sterile insect technique (SIT) uses irradiation to sterilize insect pests before releasing them in large numbers to mate with wild females. Since they do not produce any offspring, the population, and consequently the disease incidence, is reduced over time. Used successfully for decades to combat fruit flies and livestock pests such as screwworm and tsetse flies, the technique can be adapted also for some disease-transmitting mosquito species. Pilot projects are being initiated or are under way in different parts of the world.