Listeria exploits IFITM3 to suppress antibacterial activity in phagocytes

Joel M. J. Tan, Monica E. Garner, James M. Regeimbal, Catherine J. Greene, Jorge D. Rojas Márquez, Dustin A. Ammendolia, Adam R. R. McCluggage, Taoyingnan Li, Katherine J. Wu, Marija Cemma, Philip P. Ostrowski, Brian Raught, Michael S. Diamond, Sergio Grinstein, Robin M. Yates, Darren E. Higgins () and John H. Brumell ()
Additional contact information
Joel M. J. Tan: Hospital for Sick Children
Monica E. Garner: Hospital for Sick Children
James M. Regeimbal: Blavatnik Institute, Harvard Medical School
Catherine J. Greene: University of Calgary
Jorge D. Rojas Márquez: Hospital for Sick Children
Dustin A. Ammendolia: Hospital for Sick Children
Adam R. R. McCluggage: Hospital for Sick Children
Taoyingnan Li: Hospital for Sick Children
Katherine J. Wu: Blavatnik Institute, Harvard Medical School
Marija Cemma: Hospital for Sick Children
Philip P. Ostrowski: Hospital for Sick Children
Brian Raught: University Health Network
Michael S. Diamond: Washington University School of Medicine
Sergio Grinstein: Hospital for Sick Children
Robin M. Yates: University of Calgary
Darren E. Higgins: Blavatnik Institute, Harvard Medical School
John H. Brumell: Hospital for Sick Children

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract The 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.

Date: 2021
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DOI: 10.1038/s41467-021-24982-0

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