Inflammatory Factors of Host-mediated Response During Acute Phase Colitis

Salmonella enterica serotype Typhimurium is a gram negative enteric pathogen that elicits a robust inflammatory response in the human host. Streptomycin pre-treated mice are used study the elements of inflammation caused by colonization of S. Typhimurium in the gut. Previous studies have elucidated the importance of local cells including T cells in the inflammatory host response. Additionally, cumulative studies have identified NK cells as prime contributors to IFNgamma production during the acute phase of the inflammatory response during Salmonella infection. However, many components of the host immune response are still under investigation. Our studies have demonstrated that NK cells in our in vivo model contribute to modest but significant amounts of IL-17A production. These data suggest that NK cells play a nominal role in the IL-17 axis of inflammation. In contrast to many ex vivo studies, the depletion of NK1.1+ cells did not contribute to a significant decrease of IFNg transcript levels. Additionally, the tissue from infected mice did not reflect any significant histopathological differences from mice that were mock depleted or depleted of NK1.1+ cells. Further investigations to identify important cellular orchestrators of inflammation during acute infection revealed that neutrophils were a major source of IFNgamma production in vivo. Flow cytometric analysis demonstrated that neutrophils were in fact producing significant levels of IFNgamma 48 hours after infection in the gut of streptomycin pre-treated mice. Additionally, the depletion of Ly6G+ cells resulted in a significant decrease in pathology, exacerbated systemic spread of bacterial numbers and a reduction of IFNgamma mRNA. Together these data identify neutrophils, not NK cells, as being major contributors to the IFNgamma axis of inflammation during acute Salmonella infection.;The gut is a complex place wherein an immune response is orchestrated by many factors. There is a growing body of literature that supports the immunological importance of various members of the gut environment including the microbiota, the epithelium and the local immune cells. The streptomycin pre-treated mouse model has been used since the 1950's to study colonization of the gut with various pathogenic bacteria. Bacteria, including various Escherichia coli strains that do not naturally colonize the mouse intestine, are able to establish a niche following streptomycin pre-treatment. Historically, the concept that the presence of commensal communities prevents pathogenic bacteria from establishing a growth niche has been termed "colonization resistance". The changes in the gut following antibiotic treatment that reduce colonization resistance are still being worked out. Our experiments have demonstrated that there is a mild but significant inflammatory change in the gut 48-72 hours after streptomycin treatment. This mild inflammation is characterized by an influx of inflammatory cells including neutrophils (defined as CD3- B220- NK1.1- Cd11b+ Ly6C+ Ly6G+) and inflammatory monocytes (defined as CD3- B220- NK1.1- Cd11b+ Ly6C+ Ly6G+). Additionally, there are marked pathological differences including minor epithelial damage and submucosal edema. Collectively, our studies point to many host immune factors that mediate acute inflammation in the gut. Local and recruited immune cells play key roles in this orchestration. Additionally, the importance of mild host-induced inflammation in the gut due to antibiotic treatment is a switch away from the paradigm of "colonization resistance" to the initiation of inflammation as a host-mediated response to antibiotic treatment.