Apoptosis and Dysfunction of Blood Dendritic Cells in patients with falciparum and vivax malaria

Abstract

Malaria causes significant morbidity and a vaccine is urgently required. Plasmodium infection causes considerable immune dysregulation, and eliciting vaccine immunity remains challenging. Given the central role of dendritic cells (DC) in initiating immunity, understanding their biology during malaria will improve vaccination outcomes. Circulating DC are key to shaping immune responses in vivo and reflect the functional status of other subpopulations. We performed cross-sectional and longitudinal assessments of the frequency, phenotype and function of circulating DC in 67 Papuan adults during acute uncomplicated P. falciparum, P. vivax and convalescent P. falciparum infections. We demonstrate that malaria patients display a significant reduction in circulating DC numbers and the concurrent accumulation of immature cells. Such alteration is associated with marked levels of spontaneous apoptosis and impaired ability of DC to mature, capture and present antigens to T-cells. Interestingly, sustained levels of plasma IL-10 were observed in patients with acute infection and were implicated in the induction of DC apoptosis. DC apoptosis was reversed upon IL-10 blockade, and DC function recovered when IL-10 levels returned to baseline by convalescence. Our data provide key information on the mechanisms behind DC suppression during malaria and will assist in developing strategies to better harness DC's immunotherapeutic potential.