Functions of IFNλs in Anti-Bacterial Immunity at Mucosal Barriers.

Type III interferons (IFNs), or IFNλs, are cytokines produced in response to microbial ligands. They signal through the IFNλ receptor complex (IFNLR), which is located on epithelial cells and select immune cells at barrier sites. As well as being induced during bacterial or viral infection, type III IFNs are produced in response to the microbiota in the lung and intestinal epithelium where they cultivate a resting antiviral state. While the multiple anti-viral activities of IFNλs have been extensively studied, their roles in immunity against bacteria are only recently emerging. Type III IFNs increase epithelial barrier integrity and protect from infection in the intestine but were shown to increase susceptibility to bacterial superinfections in the respiratory tract. Therefore, the effects of IFNλ can be beneficial or detrimental to the host during bacterial infections, depending on timing and biological contexts. This duality will affect the potential benefits of IFNλs as therapeutic agents. In this review, we summarize the current knowledge on IFNλ induction and signaling, as well as their roles at different barrier sites in the context of anti-bacterial immunity.

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

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.