ABSTRACT Cerebral malaria (CM), coma caused by Plasmodium falciparum-infected red blood cells (iRBCs), is the deadliest complication of malaria. The mechanisms that lead to CM development are incompletely understood. Here we report on the identification of activation and inhibition pathways leading to mouse CM with supporting evidence from the analysis of human specimens. We find that CM suppression can be induced by vascular injury when sporozoites exit the circulation to infect the liver and that CM suppression is mediated by the release of soluble factors into the circulation. Among these factors is insulin like growth factor 1 (IGF1), administration of which inhibits CM development in mice. IMPORTANCE Liver infection by Plasmodium sporozoites is a required step for infection of the organism. We found that alternate pathways of sporozoite liver infection differentially influence cerebral malaria (CM) development. CM is one of the primary causes of death following malaria infection. To date, CM research has focused on how CM phenotypes develop but no successful therapeutic treatment or prognostic biomarkers are available. Here we show for the first time that sporozoite liver invasion can trigger CM-inhibitory immune responses. Importantly, we identified a number of early-stage prognostic CM inhibitory biomarkers, many of which had never been associated with CM development. Serological markers identified using a mouse model are directly relevant to human CM.
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