Malaria affects about a quarter of a billion people and leads to almost 900,000 deaths annually (World Health Organization, 2009). This disease is caused by infection with single-celled protozoan parasites of the genus Plasmodium. Five Plasmodium spp. are known to infect humans: P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. P. falciparum and P. vivax cause most of the malarial infections worldwide. Of these, P. falciparum accounts for the majority of the burden of malaria in sub-Saharan Africa and is associated with the most severe disease. P. vivax accounts for half of the malaria burden in South and East Asia and >80% of the malarial infections in the America. Malaria due to P. ovale and P. malariae is relatively uncommon but requires identification both for treatment (P. ovale, like P. vivax, forms hypnozoites with the potential for relapse) and for epidemiological purposes (malarial infection, due mostly to P. malariae, can arise from blood transfusion). P. knowlesi, previously thought to infect only nonhuman primates, has emerged as a zoonotic malarial parasite and now is an important, sometimes lethal, cause of human malaria in parts of Southeast Asia (including Malaysia, Indonesia, Thailand, Singapore, and the Philippines; Cox-Singh et al., 2008). P. knowlesi should therefore be considered as a potential cause of malaria among travelers returning from this region. The vast majority of malaria cases occur via infection from Anopheles mosquitoes in endemic regions. Infections acquired congenitally or via transfusions or contaminated needles are known to occur but are rare. Screening of blood donors has reduced the risk of transfusion-transmitted malaria to 1:4,000,000 in the U.S.
Research on malaria has entered the genomic era; the complete genome sequence has been determined for multiple Plasmodium species, including P. falciparum, P. vivax, P. knowlesi, and other species infecting rodents and non-human primates. The availability of a robust culture system for P. falciparum erythrocytic stages, combined with methods to experimentally infect mosquitoes and generate sporozoite and liver stage parasites, has generated key platforms for drug discovery. These platforms include genetic modifications by gene knockout, heterologous expression and complementation, allelic replacement, high throughput screening of the pathogenic asexual blood stage parasites, and lower throughput assays against other stages of the parasite life cycle (Hayton and Su, 2008; Winzeler, 2008). Similar laboratory approaches have not yet been successful for P. vivax. Methods for sustained in vitro culture of blood stage forms of P. vivax are not yet available but are being developed for P. knowlesi and P. cynomolgi, which share important biological similarities with P. vivax.
BIOLOGY OF MALARIAL INFECTION
Plasmodium sporozoites, which initiate infection in humans, are inoculated into the dermis and enter the bloodstream following the bite of a Plasmodium-infected female anopheline mosquito. Within minutes, sporozoites travel to the liver, where they infect hepatocytes via cell surface receptor-mediated events. This process initiates the asymptomatic ...