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 Berchtold; Julien R C Bergeron; Andreas Wack; Cammie F Lesser; Charlotte Odendall

doi:10.1016/j.cell.2022.04.028

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

Cell. 2022 Jun 23;185(13):2354-2369.e17. doi: 10.1016/j.cell.2022.04.028. Epub 2022 May 13.

Authors

Noémie Alphonse¹, Joseph J Wanford², Andrew A Voak², Jack Gay², Shayla Venkhaya², Owen Burroughs², Sanjana Mathew², Truelian Lee³, Sasha L Evans⁴, Weiting Zhao², Kyle Frowde², Abrar Alrehaili², Ruth E Dickenson², Mads Munk⁵, Svetlana Panina⁵, Ishraque F Mahmood², Miriam Llorian⁶, Megan L Stanifer⁷, Steeve Boulant⁷, Martin W Berchtold⁵, Julien R C Bergeron⁴, Andreas Wack⁸, Cammie F Lesser⁹, Charlotte Odendall¹⁰

Affiliations

¹ Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK; Immunoregulation Laboratory, Francis Crick Institute, London, UK.
² Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK.
³ Center for Bacterial Pathogenesis, Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴ Randall Centre for Cell and Molecular Biophysics, King's College London, London, UK.
⁵ Department of Biology, University of Copenhagen, Copenhagen, Denmark.
⁶ Bioinformatics and Biostatistics, The Francis Crick Institute, London, UK.
⁷ Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, USA.
⁸ Immunoregulation Laboratory, Francis Crick Institute, London, UK.
⁹ Center for Bacterial Pathogenesis, Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁰ Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK. Electronic address: charlotte.odendall@kcl.ac.uk.

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.

Keywords: Ca(2+); CaMKII; ISG; JAK/STAT; OspC1; OspC3; Shigella; T3SS; calcium; calmodulin; host-pathogen interactions; interferons.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Agents
Calcium Signaling
Epithelial Cells / metabolism
Interferons* / metabolism
Mice
Virulence Factors* / metabolism

Substances

Antiviral Agents
Virulence Factors
Interferons

Abstract

Publication types

MeSH terms

Substances

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