Characterization of the type I IFN response to liver stage infection with genetically attenuated malaria parasite vaccines.

Malaria, a disease caused by Plasmodium parasites, kills nearly 600,000 people annually. Inoculated by an infectious mosquito bite, Plasmodium sporozoites travel to the liver and infect hepatocytes. Here, they develop into merozoites that are released into the blood to cause malaria associated mortality and morbidity. No fully protective malaria vaccine exists, but immunizations with genetically attenuated parasites (GAPs) that arrest in the liver confer sterile protection from challenge in mice. Moreover, using a novel super-infection assay, we observed that GAP immunization induces a potent type I IFN response to control liver stage infection. However, the factors required for the induction and propagation of the IFN response, and the influence of this response on adaptive immunity had not been elucidated. To identify the upstream inducers of IFN signaling, we immunized mice with either mosquito debris or GAPs and measured gene expression in hepatocytes by RNA-Seq. 800 genes were significantly upregulated upon GAP immunization, including transcripts for cytosolic RNA and DNA sensors. To examine the influence of the IFN response on adaptive immunity, WT, IRF3 −/− and IFNAR −/− mice were immunized with a suboptimal dose of GAP, and challenged 4 weeks later with WT parasite. The immunization regimen elicited sterile protection in 20% of the WT mice, while 100% protection was achieved in IRF3 −/− or IFNAR −/− mice. Taken together, the data suggest that hepatocytes utilize RNA and DNA sensors to induce a type I IFN response that is necessary for early control of liver stage infection, yet detrimental to adaptive immunity. Current studies are examining the mechanisms behind the IFN-mediated suppression of adaptive immunity.