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

PLoS Pathogens

Laurent Chorro¹  Grégoire Lauvau²  Emily Spaulding²  Boris Reizis²  David Fooksman²  Alex Saidi²  Jamie M. Moore³  Johanna Daily⁴  Catherine M. Feintuch⁵ 

[1] Albert Einstein College of Medicine, Department of Medicine, Division of Infectious Diseases, Bronx, NY, United States Of America;Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, NY, United States Of America;Albert Einstein College of Medicine, Department of Pathology, Bronx, NY, United States Of America;New York University Medical Center, Department of Pathology and Department of Medicine, New York, NY, United States Of America;University of Malawi College of Medicine, Blantyre Malaria Project, Blantyre, Malawi

关键词: Blood;    Malaria;    Mouse models;    Macrophages;    Bone marrow cells;    Inflammation;    Parasitic diseases;    Monocytes;   

DOI  :  10.1371/journal.ppat.1005975

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY