A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signalingMore about Open Access at the Crick
Authors listNoémie 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 RC Bergeron Andreas Wack Cammie F Lesser Charlotte Odendall
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 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.
Issue number 13