Affiliation:
1. Division of Bacterial and Rickettsial Diseases, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910
2. Division of Diagnostic Pathology, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910
Abstract
ABSTRACT
The ability of genetically detoxified lipopolysaccharide (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 the deletion of genes whose products modify LPS. The
msbB1
and
msbB2
genes, which encode late acyltransferases, were deleted in the
Shigella 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 decreases in the production of proinflammatory cytokines and in chemokine release without significant changes in lung histopathology. The levels of specific proinflammatory cytokines (interleukin-1β [IL-1β], macrophage inflammatory protein 1α [MIP-1α], and tumor necrosis factor alpha [TNF-α]) 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 the loss of either
msbB
gene reduces the endotoxicity of
Shigella
LPS but does not coincide with a reduction in protective immune responses.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Immunology,Microbiology,Parasitology
Cited by
40 articles.
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