CXCL9 Contributes to Antimicrobial Protection of the Gut during Citrobacter rodentium Infection Independent of Chemokine-Receptor Signaling

Abstract

Chemokines have been shown to be effective bactericidal molecules against a variety of bacteria and fungi in vitro. These direct antimicrobial effects are independent of their chemotactic activities involving immunological receptors. However, the direct biological role that these proteins may play in host defense, particularly against intestinal pathogens, is poorly understood. Here, we show that CXCL9, an ELR- chemokine, exhibits direct antimicrobial activity against Citrobacter rodentium, an attaching/effacing pathogen that infects the gut mucosa. Inhibition of this antimicrobial activity in vivo using anti-CXCL9 antibodies increases host susceptibility to C. rodentium infection with pronounced bacterial penetration into crypts, increased bacterial load, and worsened tissue pathology. Using Rag1-/- mice and CXCR3-/- mice, we demonstrate that the role for CXCL9 in protecting the gut mucosa is independent of an adaptive response or its immunological receptor, CXCR3. Finally, we provide evidence that phagocytes function in tandem with NK cells for robust CXCL9 responses to C. rodentium. These findings identify a novel role for the immune cell-derived CXCL9 chemokine in directing a protective antimicrobial response in the intestinal mucosa.

Conserved regulation of omptin proteases by the PhoPQ two-component regulatory system in Enterobacteriaceae

“…As seen in Figure 3, deletion of the phoP gene from three additional E. coli strains: AIEC strain LF82 (Boudeau et al, 1999;McPhee et al, 2014), AIEC strain NRG857c (Eaves-Pyles et al, 2008;McPhee et al, 2014), or EHEC strain 86-24 (Donnenberg et al, 1993;Kunwar and Foster, unpublished) also abrogated omptin activity in these strains. We also obtained a PhoPQ mutant in Citrobacter rodentium (Reid-Yu et al, 2015). Consistent with what we observed in all of the E. coli strains, we also observed complete abrogation of omptin protease activity in these strains when PhoP is absent.…”

Phage Therapy of Pneumonia Is Not Associated with an Overstimulation of the Inflammatory Response Compared to Antibiotic Treatment in Mice

“…MIG is a member of the CXC chemokine family known to be a T-cell chemoattractant. It is involved in various immunological pathways, including antiviral (eukaryotic viruses) (26-28) and antibacterial immunity, especially when the epithelial interface is involved (29)(30)(31)(32)(33). Its expression is mediated by IFN-␥, but not exclusively.…”

Transcriptional analysis defines TCR and cytokine-stimulated MAIT cells as rapid polyfunctional effector T cells that can coordinate the immune response

“…MAIT cells may also exercise direct killing of extracellular bacteria through the release of antibacterial peptides such as IL-26 (Meller et al, 2015) and antimicrobial chemokines such as CXCL9 and CXCL10 (Margulieux, Fox, Nakamoto, & Hughes, 2016; Reid-Yu, Tuinema, Small, Xing, & Coombes, 2015). This makes MAIT cells one of many cell populations contributing to the pool of antimicrobial peptides at the site of infection/inflammation.…”