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

Emily Spaulding, David R. Fooksman, Jamie M. Moore, Alex Saidi, Catherine M. Feintuch, Boris Reizis, Laurent Chorro, Johanna P. Daily, Gregoire Lauvau

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1005975
JournalPLoS Pathogens
Volume12
Issue number10
DOIs
StatePublished - Oct 1 2016

Fingerprint

Plasmodium malariae
Plasmodium yoelii
Interferon Type I
Dendritic Cells
Bone Marrow
Macrophages
Malaria
Inflammation
Parasites
Interferon alpha-beta Receptor
Plasmodium
Macrophage Activation
Cell Communication
Natural Killer Cells
Monocytes
Leukocytes
Morbidity
Infection

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

STING-Licensed Macrophages Prime Type I IFN Production by Plasmacytoid Dendritic Cells in the Bone Marrow during Severe Plasmodium yoelii Malaria. / Spaulding, Emily; Fooksman, David R.; Moore, Jamie M.; Saidi, Alex; Feintuch, Catherine M.; Reizis, Boris; Chorro, Laurent; Daily, Johanna P.; Lauvau, Gregoire.

In: PLoS Pathogens, Vol. 12, No. 10, e1005975, 01.10.2016.

Research output: Contribution to journalArticle

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