| Shigella spp. are the etiologic agents of dysentery, a severe diarrheal syndrome characterized by acute inflammation in the colon. The inflammatory response, which includes recruitment of polymorphonuclear leukocytes (PMN), damages the colonic mucosa and exacerbates the infection. Shigella encodes a pathogenicity island (PAI), SHI-2, localized in a chromosomal region linked to inflammation and containing the gene shiA. Infection with a shiA deletion (DeltashiA) strain induces dramatically elevated levels of inflammation when compared to the wild-type strain (M90T). In contrast, infection with a wild-type strain containing multiple copies of shiA (ShiA+) results in fewer infiltrating PMN and apoptgtic cells, as well as preservation of normal villus architecture at the site of infection, thus superceding the pro-inflammatory mechanisms of Shigella. The molecular mechanism of action of ShiA is independent of any in vitro phenotype associated with Shigella virulence suggesting that ShiA allows Shigella to attenuate the host inflammatory response in a novel manner.;The inflammatory phenotypes of ShiA+, M90T and DeltashiA can be recapitulated in the mouse lung model of infection. Significantly, ShiA+-infected mice reduce their bacterial load and survive infection, while M90T- and DeltashiA-infected mice cannot clear the bacteria and ultimately die. Microarray analysis of infected lungs suggests that ShiA affects the IL-17 pathway of inflammation and PMN migration. IL-17 is an important initiator of inflammation, produced solely by T cells. In an M90T infection, IL-17, and the downstream inflammatory mediators IL-6, IL-1alpha, IL-1beta, MIP-2, MCP-1 and KC are all elevated, as compared to a ShiA+ infection. Immunohistology reveals that M90T- and DeltashiA-infected animals have greater numbers of PMN and T cells in their lungs over the course of infection than ShiA+-infected animals. We propose that ShiA down-regulates inflammation by negatively influencing the number of T cells at the infection site, and thereby decreasing the levels of pro-inflammatory IL-17 signal to the immune system. This ultimately allows Shigella to fine tune the host's immune response and establish productive infection and replication without premature host death or clearance. This is the first example establishing T cells as an important mediator of innate immunity in Shigella infection. |
