1. A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signaling
- Author
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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. Berchtold, Julien R.C. Bergeron, Andreas Wack, Cammie F. Lesser, and Charlotte Odendall
- Subjects
Model organisms ,Chemical Biology & High Throughput ,Human Biology & Physiology ,Virulence Factors ,FOS: Clinical medicine ,Genome Integrity & Repair ,Immunology ,Virulence Factors/metabolism ,Epithelial Cells ,Infectious Disease ,Tumour Biology ,Antiviral Agents ,General Biochemistry, Genetics and Molecular Biology ,Epithelial Cells/metabolism ,Mice ,Animals ,Interferons ,Calcium Signaling ,Genetics & Genomics ,Computational & Systems Biology ,Interferons/metabolism - Abstract
Interferons (IFNs) induce an antimicrobial state, protecting tissues from infection. Many viruses inhibit IFN signaling, but whether bacterial pathogens evade IFN responses remains unclear. Here, we demonstrate that the Shigella OspC family of type-III-secreted effectors blocks IFN signaling independently of its cell death inhibitory activity. Rather, IFN inhibition was mediated by the binding of OspC1 and OspC3 to the Ca2+ sensor calmodulin (CaM), blocking CaM kinase II and downstream JAK/STAT signaling. The growth of Shigella lacking OspC1 and OspC3 was attenuated in epithelial cells and in a murine model of infection. This phenotype was rescued in both models by the depletion of IFN receptors. OspC homologs conserved in additional pathogens not only bound CaM but also inhibited IFN, suggesting a widespread 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 in bacterial pathogenesis.
- Published
- 2022
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