Phagosomal Acidification Prevents Macrophage Inflammatory Cytokine Production to Malaria, and Dendritic Cells Are the Major Source at the Early Stages of Infection IMPLICATION FOR MALARIA PROTECTIVE IMMUNITY DEVELOPMENT

Abstract Inflammatory cytokines produced at the early stages of malaria infection contribute to shaping protective immunity and pathophysiology. To gain mechanistic insight into these processes, it is important to understand the cellular origin of cytokines since both cytokine input and cytokine-producing cells play key roles. Here, we determined cytokine responses by monocytes, macrophages, and dendritic cells (DCs) to purified P. falciparum and P. berghei ANKA, and by spleen macrophages and DCs from P. yoelii 17NXL- and P. berghei ANKA-infected mice. The results demonstrate that monocytes and macrophages do not produce inflammatory cytokines to malaria parasites, and that DCs are the primary source early during infection and DC subsets differentially produce cytokines. Importantly, blocking of phagosomal acidification by inhibiting vacuolar-type H+-ATPase enabled macrophages to elicit cytokine responses. Since cytokine responses to malaria parasites are mediated primarily through endosomal TLRs, our data indicate that the inability of macrophages to produce cytokines is due to the phagosomal acidification that disrupts endosomal ligand-receptor engagement. Macrophages efficiently produced cytokines to LPS upon simultaneously internalizing parasites, and to heat-killed E. coli, demonstrating that phagosomal acidification affects endosomal receptors-mediated, but not cell surface receptors-mediated, recognition of TLR agonists. Enabling monocytes/macrophages to elicit immune responses to parasites by blocking endosomal acidification can be a novel strategy for the effective development of protective immunity to malaria. The results have important implications for enhancing the efficacy of a whole parasite-based malaria vaccine, and designing strategies for protective immunity development to pathogens that induce immune responses primarily through endosomal receptors.