TY - JOUR
T1 - Listeria exploits IFITM3 to suppress antibacterial activity in phagocytes
AU - Tan, Joel M.J.
AU - Garner, Monica E.
AU - Regeimbal, James M.
AU - Greene, Catherine J.
AU - Márquez, Jorge D.Rojas
AU - Ammendolia, Dustin A.
AU - McCluggage, Adam R.R.
AU - Li, Taoyingnan
AU - Wu, Katherine J.
AU - Cemma, Marija
AU - Ostrowski, Philip P.
AU - Raught, Brian
AU - Diamond, Michael S.
AU - Grinstein, Sergio
AU - Yates, Robin M.
AU - Higgins, Darren E.
AU - Brumell, John H.
N1 - Funding Information:
We are grateful to P. Cossart, N. Freitag, P. Lauer, M. Loessner, and D. Portnoy for providing reagents, to P. Paroutis for help with confocal microscopy, and to the SickKids SPARC BioCentre for help with mass spectrometry. J.H.B. holds the Pitblado Chair in Cell Biology. Infrastructure for the Brumell Laboratory was provided by a John Evans Leadership Fund grant from the Canadian Foundation for Innovation and the Ontario Innovation Trust. D.A.A. was supported by a studentship from the Research Training Committee at the Hospital for Sick Children and an NSERC CGS-D scholarship. M.C. was supported by NSERC PGS-D scholarship and CIHR Training Fellowship (TGF-53877). This work was supported by operating grants from the Canadian Institutes of Health Research (FDN#154329 to J.H.B, FDN#143202 to S.G. and MOP#119289 to B.R) and the National Institutes of Health (#R01AI146102 to D.E.H. and #R01AI145296 to M. S.D.). B.R. holds a Canada Research Chair in Proteomics and Molecular Medicine.
Funding Information:
M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, and Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immu-nome. The Diamond laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. The remaining authors declare no competing interests.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85113155401&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-24982-0
DO - 10.1038/s41467-021-24982-0
M3 - Article
C2 - 34404769
AN - SCOPUS:85113155401
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4999
ER -