478,000 years ago. 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 population of P. knowlesi parasites is more genetically diverse than that of P. falciparum or P. vivax. Within P. knowlesi there are three genetically distinct subpopulations. Two are present in the same areas of Malaysian Borneo and may infect different mosquitoes. The third has been found only in laboratory isolates originating from other parts of Southeast Asia. Populations of P. knowlesi isolated from macaques are genetically indistinguishable from those isolated from human infections, suggesting the same parasite populations can infect humans and macaques interchangeably. Three subspecies of P. knowlesi have been described based on differences in their appearance in stained blood films: P. knowlesi edesoni, P. knowlesi sintoni, and P. knowlesi arimai, which were isolated from Malaysia, Java, and Taiwan respectively. 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. Long-tailed macaques in the wild can be infected with P. knowlesi 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. Less commonly, people report coughing, abdominal pain, diarrhea, nausea, and vomiting. Laboratory tests of infected people nearly always show a low platelet count, although this rarely leads to bleeding problems. Unlike other human malarias, P. knowlesi malaria tends to have fevers that spike every 24 hours, and is therefore often called daily or "quotidian" malaria. Uncomplicated P. knowlesi malaria can be treated with antimalarial drugs. 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,