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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

29 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2354-2369.e17
Journal	Cell
Volume	185
Issue number	13
DOIs	https://doi.org/10.1016/j.cell.2022.04.028
Publication status	Published - 23 Jun 2022

Keywords

Ca
calcium
calmodulin
CaMKII
host-pathogen interactions
interferons
ISG
JAK/STAT
OspC1
OspC3
Shigella
T3SS

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10.1016/j.cell.2022.04.028

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Alphonse, N., Wanford, J. J., Voak, A. A., Gay, J., Venkhaya, S., Burroughs, O., Mathew, S., Lee, T., Evans, S. L., Zhao, W., Frowde, K., Alrehaili, A., Dickenson, R. E., Munk, M., Panina, S., Mahmood, I. F., Llorian, M., Stanifer, M. L., Boulant, S., ... Odendall, C. (2022). A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signaling. Cell, 185(13), 2354-2369.e17. https://doi.org/10.1016/j.cell.2022.04.028

@article{4946be657dab4808bbf0a8e6ad057dcf,

title = "A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signaling",

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, calcium, calmodulin, CaMKII, host-pathogen interactions, interferons, ISG, JAK/STAT, OspC1, OspC3, Shigella, T3SS",

author = "No{\'e}mie Alphonse and Wanford, {Joseph J.} and Voak, {Andrew A.} and Jack Gay and Shayla Venkhaya and Owen Burroughs and Sanjana Mathew and Truelian Lee and Evans, {Sasha L.} and Weiting Zhao and Kyle Frowde and Abrar Alrehaili and Dickenson, {Ruth E.} and Mads Munk and Svetlana Panina and Mahmood, {Ishraque F.} and Miriam Llorian and Stanifer, {Megan L.} and Steeve Boulant and Berchtold, {Martin W.} and Bergeron, {Julien R.C.} and Andreas Wack and Lesser, {Cammie F.} and Charlotte Odendall",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = jun,

day = "23",

doi = "10.1016/j.cell.2022.04.028",

language = "English",

volume = "185",

pages = "2354--2369.e17",

journal = "Cell",

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Alphonse, N , Wanford, JJ , Voak, AA, Gay, J, Venkhaya, S, Burroughs, O, Mathew, S, Lee, T, Evans, SL , Zhao, W, Frowde, K, Alrehaili, A , Dickenson, RE, Munk, M, Panina, S, Mahmood, IF, Llorian, M, Stanifer, ML, Boulant, S, Berchtold, MW, Bergeron, JRC, Wack, A, Lesser, CF & Odendall, C 2022, 'A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signaling', Cell, vol. 185, no. 13, pp. 2354-2369.e17. https://doi.org/10.1016/j.cell.2022.04.028

TY - JOUR

T1 - A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signaling

AU - Alphonse, Noémie

AU - Wanford, Joseph J.

AU - Voak, Andrew A.

AU - Gay, Jack

AU - Venkhaya, Shayla

AU - Burroughs, Owen

AU - Mathew, Sanjana

AU - Lee, Truelian

AU - Evans, Sasha L.

AU - Zhao, Weiting

AU - Frowde, Kyle

AU - Alrehaili, Abrar

AU - Dickenson, Ruth E.

AU - Munk, Mads

AU - Panina, Svetlana

AU - Mahmood, Ishraque F.

AU - Llorian, Miriam

AU - Stanifer, Megan L.

AU - Boulant, Steeve

AU - Berchtold, Martin W.

AU - Bergeron, Julien R.C.

AU - Wack, Andreas

AU - Lesser, Cammie F.

AU - Odendall, Charlotte

PY - 2022/6/23

Y1 - 2022/6/23

N2 - 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.

AB - 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.

KW - Ca

KW - calcium

KW - calmodulin

KW - CaMKII

KW - host-pathogen interactions

KW - interferons

KW - ISG

KW - JAK/STAT

KW - OspC1

KW - OspC3

KW - Shigella

KW - T3SS

UR - http://www.scopus.com/inward/record.url?scp=85132734310&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2022.04.028

DO - 10.1016/j.cell.2022.04.028

M3 - Article

C2 - 35568036

AN - SCOPUS:85132734310

SN - 0092-8674

VL - 185

SP - 2354-2369.e17

JO - Cell

JF - Cell

IS - 13

ER -

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

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Keywords

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