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.

Animal models of shigellosis: a historical overview.

Shigella spp. are major causative agents of bacillary dysentery, a severe enteric disease characterized by destruction and inflammation of the colonic epithelium accompanied by acute diarrhea, fever, and abdominal pain. Although antibiotics have traditionally been effective, the prevalence of multidrug-resistant strains is increasing, stressing the urgent need for a vaccine. The human-specific nature of shigellosis and the absence of a dependable animal model have posed significant obstacles in understanding Shigella pathogenesis and the host immune response, both of which are crucial for the development of an effective vaccine. Efforts have been made over time to develop a physiological model that mimics the pathological features of the human disease with limited success until the recent development of genetically modified mouse models. In this review, we provide an overview of Shigella pathogenesis and chronicle the historical development of various shigellosis models, emphasizing their strengths and weaknesses.

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.

Interferons: Tug of War Between Bacteria and Their Host.

Type I and III interferons (IFNs) are archetypally antiviral cytokines that are induced in response to recognition of foreign material by pattern recognition receptors (PRRs). Though their roles in anti-viral immunity are well established, recent evidence suggests that they are also crucial mediators of inflammatory processes during bacterial infections. Type I and III IFNs restrict bacterial infection in vitro and in some in vivo contexts. IFNs mainly function through the induction of hundreds of IFN-stimulated genes (ISGs). These include PRRs and regulators of antimicrobial signaling pathways. Other ISGs directly restrict bacterial invasion or multiplication within host cells. As they regulate a diverse range of anti-bacterial host responses, IFNs are an attractive virulence target for bacterial pathogens. This review will discuss the current understanding of the bacterial effectors that manipulate the different stages of the host IFN response: IFN induction, downstream signaling pathways, and target ISGs.

COVID-19 and emerging viral infections: The case for interferon lambda.

With the first reports on coronavirus disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the scientific community working in the field of type III IFNs (IFN-λ) realized that this class of IFNs could play an important role in this and other emerging viral infections. In this Viewpoint, we present our opinion on the benefits and potential limitations of using IFN-λ to prevent, limit, and treat these dangerous viral infections.