Monocyte-derived dendritic cells in malaria

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Project Summary Cerebral malaria (CM) is a severe neurological manifestation of infection with Plasmodium species. Mortality is high and neurocognitive deficits may persist in recovered patients. Evidences obtained from humans and in a rodent malaria model indicate that sequestration of infected erythrocytes within cerebral blood vessels and neuroinflammation are essential components of CM. Hence, to fulfill the promise of immune-based therapeutic interventions, a better understanding of relevant mechanisms of CM pathogenesis is needed. While a variety of immune cells, primarily CD8+ T cells, are involved, the mechanisms that govern immune cell cooperation leading to this lethal pathology are poorly understood. Using selective depletions recent studies have demonstrated the importance of CD11c+MHC-IIhi dendritic cells (DCs) as well as CD11b+F4/80+Ly6c+CCR2+ inflammatory monocytes (iMOs), both in host resistance to Plasmodium and pathogenesis of CM. Although these cell subsets have overlapping functions, DCs are more specialized in antigen presentation and shaping T cell mediated immunity. However, the main DC subset(s) that mediate CM development has not been defined. We found that infection with P. berghei ANKA (Pba) promotes a massive differentiation of iMOs into splenic monocyte derived dendritic cells (MO- DCs) at 5 days post-infection, and two days later they emerge in the CNS culminating in the development of lethal CM. Thus, our main hypothesis is that MO-DCs are central players in promoting neuroinflammation in PbA infected mice. Our goal is to interrogate what are the endogenous elements that promote differentiation of iMOs into MO-DCs and the mechanism by which MO-DCs promote neuroinflammation in rodent malaria. Our first aim is to fully characterize the malaria-induced splenic MO-DCs based on cell surface markers, morphological properties, and unbiased analysis of gene expression. Our preliminary results indicate that the highly purified MO-DCs (CD11c+MHC-IIhi CD11b+F4/80+DC-SIGN+Ly6c+) express high levels of IFNγ-inducible chemokines, CXCL9 and CXCL10, as well as the chemokine receptor CCR5, thus we named these cells CCR5+CXCL9/10+ MO-DCs. Furthermore, activation of nucleic acid sensing TLRs have been shown to initiate cytokine response by both human and mouse macrophages and DCs exposed to Plasmodium components. Hence, in the second aim we will investigate the importance of TLR activation as well as IFNγ in promoting MO-DCs differentiation and function. Finally, in Aim 3 we will investigate the emergence of MO-DCs in the CNS of PbA infected mice. Our preliminary data also suggest that CCR5 is a key chemokine receptor that mediates MO-DC migration into inflamed brain. We hypothesize that once in the CNS, MO-DCs are important source of CXCL9 and CXCL10, amplifying recruitment and activation of pathogenic CD8+ T lymphocytes. Taken together, these studies will provide novel and significant insights into the mechanisms that DCs mediate the development of neuroinflammation and pathogenesis of malaria.