Project Summary/Abstract Malaria caused by the Plasmodium parasite remains a global health threat, affecting ~200 million people and leading to more than 400,000 deaths per year. Understanding the mechanisms contributing to pathological inflammation during malaria can provide insight for the development of adjunctive therapies that can reduce disease severity and mortality. In transmission settings where children suffer multiple malaria episodes per year, blunting inflammation during early parasitemia can mitigate disease severity while adaptive immunity ramps up to control parasite replication. Likewise, defining host processes that can reduce parasites during the liver stage, when parasite burden is at its lowest, may lead to strategies to prevent infection. We have previously shown that expression of p53 and p53 targets were increased in the blood of uninfected children who would later present with asymptomatic P. falciparum parasitemia relative to children who later presented with febrile malaria. Increasing p53 dampened the production of inflammatory cytokines in human monocytes stimulated with P. falciparum, suggesting that p53 plays a role in modulating malaria-induced inflammation. It was also previously shown that boosting p53 levels can reduce liver-stage parasite burden in a mouse malaria model. Thus, systemic increases in host p53 may also benefit the host, and coincidently the established parasite, by inhibiting liver- stage superinfection by other Plasmodium parasites. The goal of this proposal is to identify host pathways amenable to therapeutic intervention that would either reduce malaria disease severity and/or prevent liver-stage infection by Plasmodium parasites. Using both in vitro studies with human blood samples from malaria-exposed individuals and mouse models, we propose to determine the mechanisms that drive the activation of p53 and associated pathways in innate immune cells of malaria-exposed children. We will also investigate the systemic effects of p53 activation in not only immune cells but also host tissue, namely the liver and vascular endothelium, as it relates to Plasmodium infection and malaria pathogenesis. We hypothesize that chronic inflammation induced by repeated malaria episodes, which frequently occurs in sub-Saharan African children, or chronic parasitemia activates p53 and its downstream pathways systemically to modulate the host response to both the current and subsequent Plasmodium infections. To test this hypothesis, we propose to: 1) investigate the effect of Plasmodium infection on p53 and its downstream pathways in innate immune cells and their subsequent response to repeat malaria exposure; 2) investigate the effect of Plasmodium blood-stage infection on p53 and p53 downstream pathways within the host liver and determine the potential role for p53 in modulating liver-stage superinfection; and 3) evaluate the role of p53 and p53 targets in regulating host vascular endothelium during Plasmodium blood-stage infection. Completion of these proposed aims will provide mechanistic insight into the role of p53 in modulating malaria-induced pathogenesis and liver-stage infection, which may identify druggable targets for interventions aimed at mitigating malaria disease severity and/or liver-stage prophylaxis.

Project Narrative Understanding the mechanisms contributing to pathological inflammation during malaria and the processes that govern the control of malaria parasites within the host can provide insight for the development of adjunctive therapies against this deadly infection. Using human samples and relevant model systems, we will investigate the interactions between multiple stages of the Plasmodium parasite and p53 pathways within relevant host tissues and how such interactions impact malaria pathogenesis and infection biology. Results from this study will provide mechanistic insight into the role of p53 in modulating malaria-induced pathogenesis and liver-stage infection, which may identify druggable targets for interventions aimed at mitigating malaria disease severity and/or liver-stage prophylaxis.