Listeria exploits IFITM3 to suppress antibacterial activity in phagocytes

Author:

Tan Joel M. J.ORCID,Garner Monica E.,Regeimbal James M.,Greene Catherine J.,Márquez Jorge D. Rojas,Ammendolia Dustin A.ORCID,McCluggage Adam R. R.,Li Taoyingnan,Wu Katherine J.,Cemma Marija,Ostrowski Philip P.,Raught Brian,Diamond Michael S.ORCID,Grinstein SergioORCID,Yates Robin M.ORCID,Higgins Darren E.ORCID,Brumell John H.ORCID

Abstract

AbstractThe type I interferon (IFN) signaling pathway has important functions in resistance to viral infection, with the downstream induction of interferon stimulated genes (ISG) protecting the host from virus entry, replication and spread. Listeria monocytogenes (Lm), a facultative intracellular foodborne pathogen, can exploit the type I IFN response as part of their pathogenic strategy, but the molecular mechanisms involved remain unclear. Here we show that type I IFN suppresses the antibacterial activity of phagocytes to promote systemic Lm infection. Mechanistically, type I IFN suppresses phagosome maturation and proteolysis of Lm virulence factors ActA and LLO, thereby promoting phagosome escape and cell-to-cell spread; the antiviral protein, IFN-induced transmembrane protein 3 (IFITM3), is required for this type I IFN-mediated alteration. Ifitm3−/− mice are resistant to systemic infection by Lm, displaying decreased bacterial spread in tissues, and increased immune cell recruitment and pro-inflammatory cytokine signaling. Together, our findings show how an antiviral mechanism in phagocytes can be exploited by bacterial pathogens, and implicate IFITM3 as a potential antimicrobial therapeutic target.

Funder

U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health

Gouvernement du Canada | Canadian Institutes of Health Research

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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