title: STING-Licensed Macrophages Prime Type I IFN Production by Plasmacytoid Dendritic Cells in the Bone Marrow during Severe Plasmodium yoelii Malaria.
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.
authors: Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, NY, United States Of America.
authors: Emily
authors: http://orcid.org/0000-0001-6152-1617
authors: E
authors: Spaulding
authors: 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.
authors: David
authors: D
authors: Fooksman
authors: Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, NY, United States Of America.
authors: Jamie M
authors: JM
authors: Moore
authors: University of Malawi College of Medicine, Blantyre Malaria Project, Blantyre, Malawi.
authors: Alex
authors: A
authors: Saidi
authors: Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, NY, United States Of America.|Albert Einstein College of Medicine, Department of Medicine, Division of Infectious Diseases, Bronx, NY, United States Of America.
authors: Catherine M
authors: CM
authors: Feintuch
authors: New York University Medical Center, Department of Pathology and Department of Medicine, New York, NY, United States Of America.
authors: Boris
authors: B
authors: Reizis
authors: Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, NY, United States Of America.
authors: Laurent
authors: L
authors: Chorro
authors: Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, NY, United States Of America.|Albert Einstein College of Medicine, Department of Medicine, Division of Infectious Diseases, Bronx, NY, United States Of America.
authors: Johanna
authors: J
authors: Daily
authors: Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, NY, United States Of America.
authors: Grégoire
authors: G
authors: Lauvau
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D007370:Interferon Type I / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008288:Malaria / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010967:Plasmodium yoelii; D000099197:STING Protein
chemical_list: D007370:Interferon Type I; D008565:Membrane Proteins; C532857:STING1 protein, human; D000099197:STING Protein