A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signaling

Noémie Alphonse, Joseph J. Wanford, Andrew A. Voak, Jack Gay, Shayla Venkhaya, Owen Burroughs, Sanjana Mathew, Truelian Lee, Sasha l. Evans, Weiting Zhao, Kyle Frowde, Abrar Alrehaili, Ruth E. Dickenson, Mads Munk, Svetlana Panina, Ishraque F. Mahmood, Miriam Llorian, Megan l. Stanifer, Steeve Boulant, Martin w. BerchtoldJulien R.C. Bergeron, Andreas Wack, Cammie F. Lesser, Charlotte Odendall

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

Interferons (IFNs) induce an anti-microbial state, protecting tissues from infection. Many viruses antagonize IFN signaling, but whether bacterial pathogens also evade IFN responses remains unclear. Here, we demonstrate that the Shigella OspC family of type III-secreted effectors blocks signaling from all IFNs. The growth of Shigella lacking OspC1 and OspC3 was attenuated in epithelial cells in the presence of IFN, and in a murine model of infection. IFN inhibition was mediated by binding of OspC1 and OspC3 to the Ca2+ sensor calmodulin (CaM), blocking CaM kinase II and downstream JAK/STAT signaling. OspC effector proteins were conserved in other human pathogens. OspC homologs not only bound CaM but also inhibited IFN, suggesting that these bacteria share a common virulence strategy. These findings reveal a conserved but previously undescribed molecular mechanism of IFN inhibition, and demonstrate the critical role of Ca2+ and IFN targeting by pathogenic bacteria.
Original languageEnglish
Pages (from-to)2354-2369.e17
JournalCell
Volume185
Issue number13
Early online date23 Jun 2022
DOIs
Publication statusPublished - 23 Jun 2022

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