Abstract
Malaria remains a global health burden causing significant morbidity, yet the mechanisms underlying disease outcomes and protection are poorly understood. Herein, we analyzed the peripheral blood of a unique cohort of Malawian children with severe malaria, and performed a comprehensive overview of blood leukocytes and inflammatory mediators present in these patients. We reveal robust immune cell activation, notably of CD14+ inflammatory monocytes, NK cells and plasmacytoid dendritic cells (pDCs) that is associated with very high inflammation. Using the Plasmodium yoelii 17X YM surrogate mouse model of lethal malaria, we report a comparable pattern of immune cell activation and inflammation and found that type I IFN represents a key checkpoint for disease outcomes. Compared to wild type mice, mice lacking the type I interferon (IFN) receptor exhibited a significant decrease in immune cell activation and inflammatory response, ultimately surviving the infection. We demonstrate that pDCs were the major producers of systemic type I IFN in the bone marrow and the blood of infected mice, via TLR7/MyD88-mediated recognition of Plasmodium parasites. This robust type I IFN production required priming of pDCs by CD169+ macrophages undergoing activation upon STING-mediated sensing of parasites in the bone marrow. pDCs and macrophages displayed prolonged interactions in this compartment in infected mice as visualized by intravital microscopy. Altogether our findings describe a novel mechanism of pDC activation in vivo and precise stepwise cell/cell interactions taking place during severe malaria that contribute to immune cell activation and inflammation, and subsequent disease outcomes.
Highlights
Malaria still remains a significant global health problem worldwide with 214 million people infected, and half a million deaths each year [1, 2]
We provide a comprehensive analysis of peripheral blood immune cells obtained from a cohort of children with severe malaria
We have utilized a mouse model of lethal malaria that recapitulates many features identified in this cohort of severe malaria patients to examine drivers of immune cell activation and inflammation
Summary
Malaria still remains a significant global health problem worldwide with 214 million people infected (range 149–303 million, WHO 2015), and half a million deaths each year [1, 2]. Death occurs as a result of severe malaria, a multi-systemic disorder resulting from blood stage Plasmodium infection that is associated with significant morbidity and high case fatality rates despite antimalarial treatment [1, 3]. It primarily affects young children in endemic areas and travelers, both lacking exposure-induced immunity. Lack of a highly effective vaccines and emergence of artemisinin resistance limits malaria control measures. Additional efforts to understand severe disease with the goal of improving clinical outcomes remains a very high priority [5, 6]
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