Testing the hypothesis that malaria-induced immune remodeling of monocytes plays a role in immunity to malaria

Abstract

Abstract In malaria-naïve individuals, Plasmodium falciparum infection results in high levels of parasite-infected red blood cells (iRBCs) that trigger the systemic inflammation and fever characteristic of malaria. But, individuals in endemic areas who are repeatedly infected with P. falciparum are often asymptomatic and have low levels of iRBCs, even young children who have yet to acquire fully protective antibodies. The molecular mechanisms underlying these clinical observations remain unclear. We earlier showed that PBMCs collected from uninfected Malian children before the malaria season responded to iRBCs by producing pro-inflammatory mediators such as IL-1β, IL-6. However, following febrile malaria there was a marked shift in the response to iRBCs with the same children’s PBMCs producing lower levels of those cytokines. Moreover, genome-wide expression analysis showed that genes involved in phagocytosis and intracellular killing were upregulated in PBMCs after malaria as compared to before. Together, these data suggest that malaria-induced remodeling of innate immune cells might play a role in immunity to malaria. In ongoing work we are dissecting the underlying molecular pathways involved in P. falciparum-induced changes in monocyte/macrophages. We are studying monocytes ex vivo from malaria-exposed children, as well as monocytes stimulated with iRBCs in vitro. Initial data support the hypothesis that malaria-induced immune-remodeling of monocytes dampens pathogenic inflammation while enhancing anti-parasite effector mechanisms, consistent with our observation that children in malaria endemic areas are often afebrile and tend to control parasite replication in the face of repeated P. falciparum exposures.