IAI Accepts, published online ahead of print on 2 November 2009

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Infect. Immun. doi:10.1128/IAI.00533-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Virulence, Inflammatory Potential and Adaptive Immunity Induced by Shigella msbB Mutants

Ryan T. Ranallo^*, Robert W. Kaminski, Tonia George, Alexis A. Kordis, Qing Chen, Kathleen Szabo, and Malabi M. Venkatesan

Division of Bacterial and Rickettsial Diseases, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States

The ability of genetically detoxified LPS to stimulate adaptive immune responses is an ongoing area of investigation with significant consequences for the development of safe and effective bacterial vaccines and adjuvants. One approach to genetic detoxification is deletion of genes whose product modifies LPS. The msbB1 and msbB2 genes which encode late acyltransferases were deleted in the S. flexneri 2a human challenge strain 2457T to evaluate the virulence, inflammatory potential and acquired immunity induced by strains producing underacylated lipid A. Consistent with a reduced endotoxic potential, S. flexneri 2a msbB mutants were attenuated in an acute mouse pulmonary challenge model. Attenuation correlated with a decrease in the production of proinflammatory cytokine and chemokine release without significant changes in lung histopathology. Specific proinflammatory cytokines (IL-1, MIP-1, and TNF-) were also significantly reduced after infection of mouse macrophages with either single or double msbB mutants. Surprisingly, the msbB double mutant displayed defects in the ability to invade, replicate and spread within epithelial cells. Complementation restored these phenotypes, but the exact nature of the defects was not determined. Acquired immunity and protective efficacy were also assayed in the mouse lung model using a vaccination-challenge study. Both humoral and cellular responses were generally robust in msbB-immunized mice and afforded significant protection from lethal challenge. These data suggest that loss of either msbB gene reduces the endotoxicity of Shigella LPS, but does not coincide with a reduction in protective immune responses.