Whether IL-17A has pathogenic and/or protective roles in the gut mucosa is controversial and few studies have analyzed specific cell populations for protective functions within the inflamed colonic tissue. Here we provide evidence for IL-17A dependent regulation of the tight junction protein occludin during epithelial injury that limits excessive permeability and maintains barrier integrity. Analysis of epithelial cells showed that in the absence of Act-1 signaling, the protective effect of IL-17A was abrogated and inflammation was enhanced. We demonstrate that following acute intestinal injury, IL-23R+ RORγt+ γδ T cells in the colonic lamina propria are the primary producers of early, gut-protective IL-17A, over other cell populations such as memory Th17 cells and ILC3. This production of IL-17A was IL-23 independent, leaving protective IL-17 intact in the absence of IL-23. These results suggest that IL-17 producing resident γδ T cells are important for the maintenance, and protectionof epithelial barriers in the intestinal mucosa.

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The ESX-1, type VII, secretion system represents the major virulence determinant of Mycobacterium tuberculosis, one of the most successful intracellular pathogens. Here, by combining genetic and high-throughput approaches, we show that EspL, a protein of 115 amino acids, is essential for mediating ESX-1-dependent virulence and for stabilization of EspE, EspF and EspH protein levels. Indeed, an espL knock-out mutant was unable to replicate intracellularly, secrete ESX-1 substrates or stimulate innate cytokine production. Moreover, proteomic studies detected greatly reduced amounts of EspE, EspF and EspH in the espL mutant as compared to the wild type strain, suggesting a role for EspL as a chaperone. The latter conclusion was further supported by discovering that EspL interacts with EspD, which was previously demonstrated to stabilize the ESX-1 substrates and effector proteins, EspA and EspC. Loss of EspL also leads to downregulation in M. tuberculosis of WhiB6, a redox-sensitive transcriptional activator of ESX-1 genes. Overall, our data highlight the importance of a so-far overlooked, though conserved, component of the ESX-1 secretion system and begin to delineate the role played by EspE, EspF and EspH in virulence and host-pathogen interaction.

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Enteric bacterial pathogens such as Enterohemorrhagic E. coli (EHEC) and Salmonella typhimurium target the intestinal epithelial cells (IEC) lining the gastrointestinal (GI) tract. Despite expressing Toll like receptors (TLRs), IEC are generally hypo-responsive to invading bacteria and their products. One reason is Single Ig IL-1 Related Receptor (SIGIRR), a negative regulator of interleukin (IL)-1R/ TLR signaling expressed by IEC. To address whether SIGIRR expression impacts on enteric host defense, Sigirr deficient (-/-) mice were infected with the EHEC related pathogen Citrobacter rodentium. Sigirr -/- mice responded with accelerated IEC proliferation and strong pro-inflammatory and antimicrobial responses that were primarily IL-1R signaling dependent. Surprisingly the Sigirr -/- mice were highly susceptible to infection, carrying 100-1000x heavier pathogen burden at Day (D) 6 and D10 post infection (pi). Sigirr -/- mice were also found to be unusually susceptible to intestinal S. typhimurium colonization, developing enterocolitis without the requirement for antibiotic based removal of commensal microbes. Strikingly, the exaggerated antimicrobial responses in the Sigirr -/- mice led to the rapid loss of competing commensal microbes (~80%) from the infected intestine, reducing colonization resistance as early as D1 pi. Thus, despite limiting IEC responses to infection, SIGIRR aids host defense by promoting commensal based resistance to pathogen colonization of the GI tract.

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