Plasmodium knowlesi

Like other Plasmodium parasites, P. knowlesi has a life cycle that requires it be passed back and forth between mammalian hosts and insect hosts. Primates are infected through the bite of an infected Anopheles mosquito which carries a parasite stage called the sporozoite in its salivary glands. Sporozoites follow the blood stream to the primate liver where they develop and replicate over five to six days before bursting, releasing thousands of daughter cells called merozoites into the blood (unlike the related P. vivax, P. knowlesi does not make latent hypnozoites in the liver). The zygote matures into an ookinete, which migrates through the wall of the mosquito gut and develops into an oocyst. The oocyst then releases thousands of sporozoites, which migrate through the mosquito to the salivary glands. This entire process in the mosquito takes 12 to 15 days. ==Cell biology==

P. knowlesi largely resembles other Plasmodium species in its cell biology. Its genome consists of 23.5 megabases of DNA separated into 14 chromosomes. Like other apicomplexans, P. knowlesi also has two organelles of endosymbiotic origin: a single large mitochondrion and the apicoplast, both of which are involved in the parasite's metabolism. ==Evolution and taxonomy==

Despite its morphological similarity to P. malariae, P. knowlesi is most closely related to P. vivax as well as other Plasmodium species that infect non-human primates. Among human parasites, P. knowlesi is most closely related to P. vivax, from which it diverged between 18 million and 34 million years ago. A phylogenetic tree comparing the Plasmodium species that infect humans is shown below: The relationship between these described subspecies and the populations described in the modern literature is not clear. ==Distribution==

Plasmodium knowlesi is found throughout Southeast Asia, where it primarily infects the long-tailed macaque, pig-tailed macaque, and Sumatran surili as well as the mosquito vectors Anopheles hackeri in peninsular Malaysia and Anopheles latens in Sarawak. without any apparent disease, even when they are simultaneously infected with various other Plasmodium species. P. knowlesi is rarely found outside of Southeast Asia, likely because the mosquitoes it infects are restricted to that region. ==Role in human disease==

P. knowlesi can cause both uncomplicated and severe malaria in humans. Those infected nearly always experience fever and chills. People with uncomplicated P. knowlesi malaria often also experience headaches, joint pain, malaise, and loss of appetite. Uncomplicated P. knowlesi malaria can be treated with antimalarial drugs such as artemisinin combination therapy (ACT) or chloroquine ACT is the preferred treatment as the drug is associated with a faster parasite clearance time. At least 10% of people infected with P. knowlesi develop severe malaria. Severe P. knowlesi malaria resembles severe malaria caused by P. falciparum. Those with severe disease may experience shortness of breath, abdominal pain, and vomiting. Older trophozoites appear more dispersed, forming a rectangular-shape spread across the host cell called a "band-form" that resembles the similar stage in P. malariae. While some rapid diagnostic tests can detect P. knowlesi, they tend to have poor sensitivity and specificity and are therefore not always reliable. Detection of nucleic acid by PCR or real-time PCR is the most reliable method for detecting P. knowlesi, and differentiating it from other Plasmodium species infection. However, due to the relatively slow and expensive nature of PCR, this is not available in many endemic areas. For those with severe malaria, the World Health Organization recommends administration of intravenous artesunate for at least 24 hours, followed by ACT treatment. and cases of P. knowlesi malaria have been reported in most countries of Southeast Asia as well as travelers from the region. Infection with P. knowlesi is associated with socioeconomic and lifestyle factors that bring people into the dense forests where the mosquito hosts are commonly found. In particular, those who work in the forest or at its margin such as farmers, hunters, and loggers are at increased risk for infection. Likely for this reason, males are infected more frequently than females, and adults are infected more frequently than children. ==Research==

P. knowlesi has long been used as a research model for studying the interaction between parasite and host, and developing antimalarial vaccines and drugs. Blood-infecting stages and sporozoites can be stored long-term by freezing with glycerolyte, allowing the preservation of strains of interest. ==History==

The Italian physician Giuseppe Franchini first described what may have been P. knowlesi in 1927 when he noted a parasite distinct from P. cynomolgi and P. inui in the blood of a long-tailed macaque. In 1931, the parasite was again seen in a long-tailed macaque by H. G. M. Campbell during his work on kala azar (visceral leishmaniasis) in Calcutta; Campbell's colleague Lionel Everard Napier drew blood from the affected monkey and inoculated three laboratory monkeys, one of which was a rhesus macaque that developed a severe infection. Campbell and Napier gave the infected monkey to Biraj Mohan Das Gupta who was able to maintain the parasite by serial passage through monkeys. In 1932, Das Gupta and his supervisor Robert Knowles described the morphology of the parasite in macaque blood, and demonstrated that it could infect three human patients (in each case it was used to induce fever with the hope of treating another infection). Also in 1932, John Sinton and H. W. Mulligan further described the morphology of the parasite in blood cells, determined it to be a distinct species from others described, and named it Plasmodium knowlesi in honor of Robert Knowles. the first documented case of a human naturally infected with P. knowlesi was in 1965 in a U.S. Army surveyor who developed chills and fever after a five-day deployment in Malaysia. Based on this finding, a team at the Institute for Medical Research in Peninsular Malaysia undertook a survey of people living in proximity to macaques, but failed to find evidence that simian malaria was being transmitted to humans. Over the following decade, several investigators used molecular detection methods capable of distinguishing P. knowlesi from morphologically similar parasites to attribute an increasing proportion of malaria cases to P. knowlesi throughout Southeast Asia. Work with archival samples has shown that infection with this parasite has occurred in Malaysia at least since the 1990s. == References ==