Cerebral Malaria Is Regulated by Host-Mediated Changes in Plasmodium Gene Expression

Cerebral malaria (CM), the deadliest complication of Plasmodium infection, is a complex and unpredictable disease. However, our understanding of the host and parasite factors that cause CM is limited. Using a mouse model of CM, experimental CM (ECM), we performed a three-way comparison between ECM-susceptible C57BL/6 mice infected with ECM-causing Plasmodium ANKA parasites [ANKA((C57BL/6))], ECM-resistant BALB/c mice infected with Plasmodium ANKA [ANKA((BALB/c))], and C57BL/6 mice infected with Plasmodium NK65 that does not cause ECM [NK65((C57BL/6))]. All ANKA((C57BL/6)) mice developed CM. In contrast, in ANKA((BALB/c)) and NK65((C57BL/6)), infections do not result in CM and proceed similarly in terms of parasite growth, disease course, and host immune response. However, parasite gene expression in ANKA((BALB/c)) was remarkably different than that in ANKA((C57BL/6)) but similar to the gene expression in NK65((C57BL/6)). Thus, Plasmodium ANKA has an ECM-specific gene expression profile that is activated only in susceptible hosts, providing evidence that the host has a critical influence on the outcome of infection.