OPINION Mosquitoes Reset Malaria Parasites

Serial blood passage of Plasmodium universally increases parasite virulence, which can be reversed by mosquito transmission. How mosquitoes reset Plasmodium virulence has been unknown. We have shown that mosquito transmission modifies expression of Plasmodium subtelomeric multigene families, including those that code for variant surface antigens (VSA), and transforms the systemic immune response to blood-stage infection. In this way, the mos-quito regulates malaria disease severity. Here, we present a model in which expression of multi-gene families is reset by epigenetic reprogramming of Plasmodium within the mosquito. This prepares the malaria parasite for entry into a new unknown host and transforms the early para-site–host interactions that shape disease severity. Studying the molecular mechanisms that operate outside the human host to regulate Plasmodium virulence is therefore a priority. Historical Perspective It has been recognised for decades that serial blood passage of Plasmodium through rodents, primates, or humans universally increases parasite virulence. In 1917, induced malaria was first used as pyretic therapy for neurosyphilis, with Plasmodium vivax routinely inoculated to elicit a mild form of disease. Yet passage through the human host elevated parasitaemia and exacer