STING-Licensed Macrophages Prime Type I IFN Production by Plasmacytoid Dendritic Cells in the Bone Marrow during Severe Plasmodium yoelii Malaria

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. © 2016 spaulding et al.