ShiA Abrogates the Innate T-Cell Response toShigella flexneriInfection

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Abstract
Shigellaspp. are the causative agent of bacillary dysentery. Infection results in acute colonic injury due to the host inflammatory response. The mediators of the damage, infiltrating polymorphonuclear leukocytes (PMN), also resolve the infection.Shigella flexneri's virulence effectors are encoded on its large virulence plasmid and on pathogenicity islands in the chromosome. The SHI-2 pathogenicity island encodes the virulence factor ShiA, which down-regulatesShigella-induced inflammation. In the rabbit ileal loop model, infection with ashiAnull strain (ΔshiA) induces a more severe inflammation than wild-type infection. Conversely, aShigellastrain that overexpresses ShiA (ShiA+) is less inflammatory than the wild-type strain. To determine the host responses modulated by ShiA, we performed infection studies using the mouse lung model, which recapitulates the phenotypes observed in the rabbit ileal loop model. Significantly, ShiA+strain-infected mice cleared the bacteria and survived infection, while wild-type- and ΔshiAstrain-infected mice could not clear the bacteria and ultimately died. Surprisingly, microarray analysis of infected lungs revealed the regulation of genes involved in innate T-cell responses to infection. Immunohistochemistry showed that wild-type- and ΔshiAstrain-infected animals have greater numbers of PMN and T cells in their lungs over the course of infection than ShiA+strain-infected animals. These results suggest that the T-cell innate response is suppressed by ShiA inShigellainfections.