Abstract
Infection with Citrobacter rodentium triggers robust tissue damage repair responses, manifested by secretion of IL-22, in the absence of which mice succumbed to the infection. Of the main hallmarks of C. rodentium infection are colonic crypt hyperplasia (CCH) and dysbiosis. In order to colonize the host and compete with the gut microbiota, C. rodentium employs a type III secretion system (T3SS) that injects effectors into colonic intestinal epithelial cells (IECs). Once injected, the effectors subvert processes involved in innate immune responses, cellular metabolism and oxygenation of the mucosa. Importantly, the identity of the effector/s triggering the tissue repair response is/are unknown. Here we report that the effector EspO ,an orthologue of OspE found in Shigella spp, affects proliferation of IECs 8 and 14 days post C. rodentium infection as well as secretion of IL-22 from colonic explants. While we observed no differences in the recruitment of group 3 innate lymphoid cells (ILC3s) and T cells, which are the main sources of IL-22 at the early and late stages of C. rodentium infection respectively, infection with ΔespO was characterized by diminished recruitment of sub-mucosal neutrophils, which coincided with lower abundance of Mmp9 and chemokines (e.g. S100a8/9) in IECs. Moreover, mice infected with ΔespO triggered significantly lesser nutritional immunity (e.g. calprotectin, Lcn2) and expression of antimicrobial peptides (Reg3β, Reg3γ) compared to mice infected with WT C. rodentium. This overlapped with a decrease in STAT3 phosphorylation in IECs. Importantly, while the reduced CCH and abundance of antimicrobial proteins during ΔespO infection did not affect C. rodentium colonization or the composition of commensal Proteobacteria, they had a subtle consequence on Firmicutes subpopulations. EspO is the first bacterial virulence factor that affects neutrophil recruitment and secretion of IL-22, as well as expression of antimicrobial and nutritional immunity proteins in IECs.
Highlights
Citrobacter rodentium is an extracellular, mouse specific, intestinal pathogen used to model mechanisms of virulence employed by the human pathogens enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC) and inflammatory bowel diseases [1]
Two of the hallmarks of C. rodentium infection are colonic damage repair responses and colitis; symptoms that are shared with inflammatory bowel diseases in humans
The processes leading to tissue damage repair responses and the implicated bacterial virulence factors are still elusive
Summary
Citrobacter rodentium is an extracellular, mouse specific, intestinal pathogen used to model mechanisms of virulence employed by the human pathogens enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC) and inflammatory bowel diseases [1]. Infection with C. rodentium elicits robust tissue repair responses, which are characterized by production of IL-22 and cell proliferation leading to colonic crypt hyperplasia (CCH) [3,4], as well as colitis. A number of host pathways involved in CCH have been identified [5,6], the C. rodentium virulence factor/s implicated in eliciting the tissue repair response remain elusive. Both innate and adaptive immune responses are vital for C. rodentium elimination [1]. Lee et al have recently reported that CD11b+ Ly6C+ Ly6G+ neutrophils are a main source of secreted colonic IL-22 in response to C. rodentium infection [16]
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