biostudies-literatureSha JNIAID NIH HHS815-28https://www.ebi.ac.uk/biostudies/studies/S-EPMC3584885biostudies-literatureUnknown81(3)Braun (murein) lipoprotein (Lpp) and lipopolysaccharide (LPS) are major components of the outer membranes of Enterobacteriaceae family members that are capable of triggering inflammatory immune responses by activating Toll-like receptors 2 and 4, respectively. Expanding on earlier studies that demonstrated a role played by Lpp in Yersinia pestis virulence in mouse models of bubonic and pneumonic plague, we characterized an msbB in-frame deletion mutant incapable of producing an acyltransferase that is responsible for the addition of lauric acid to the lipid A moiety of LPS, as well as a ?lpp ?msbB double mutant of the highly virulent Y. pestis CO92 strain. Although the ?msbB single mutant was minimally attenuated, the ?lpp single mutant and the ?lpp ?msbB double mutant were significantly more attenuated than the isogenic wild-type (WT) bacterium in bubonic and pneumonic animal models (mouse and rat) of plague. These data correlated with greatly reduced survivability of the aforementioned mutants in murine macrophages. Furthermore, the ?lpp ?msbB double mutant was grossly compromised in its ability to disseminate to distal organs in mice and in evoking cytokines/chemokines in infected animal tissues. Importantly, mice that survived challenge with the ?lpp ?msbB double mutant, but not the ?lpp or ?msbB single mutant, in a pneumonic plague model were significantly protected against a subsequent lethal WT CO92 rechallenge. These data were substantiated by the fact that the ?lpp ?msbB double mutant maintained an immunogenicity comparable to that of the WT strain and induced long-lasting T-cell responses against heat-killed WT CO92 antigens. Taken together, the data indicate that deletion of the msbB gene augmented the attenuation of the ?lpp mutant by crippling the spread of the double mutant to the peripheral organs of animals and by inducing cytokine/chemokine responses. Thus, the ?lpp ?msbB double mutant could provide a new live-attenuated background vaccine candidate strain, and this should be explored in the future.Infection and immunityDeletion of the Braun lipoprotein-encoding gene and altering the function of lipopolysaccharide attenuate the plague bacterium.PMC3584885N01-AI-30065N01AI30065AI064389AI060549AI070083UC7 AI070083R01 AI064389T32 AI060549Rosenzweig JASha JFitts ECvan Lier CJWang SErova TECong YKozlova EVChopra AKKirtley MLCao AfalseDeletion of the Braun lipoprotein-encoding gene and altering the function of lipopolysaccharide attenuate the plague bacterium.Braun (murein) lipoprotein (Lpp) and lipopolysaccharide (LPS) are major components of the outer membranes of Enterobacteriaceae family members that are capable of triggering inflammatory immune responses by activating Toll-like receptors 2 and 4, respectively. Expanding on earlier studies that demonstrated a role played by Lpp in Yersinia pestis virulence in mouse models of bubonic and pneumonic plague, we characterized an msbB in-frame deletion mutant incapable of producing an acyltransferase that is responsible for the addition of lauric acid to the lipid A moiety of LPS, as well as a ?lpp ?msbB double mutant of the highly virulent Y. pestis CO92 strain. Although the ?msbB single mutant was minimally attenuated, the ?lpp single mutant and the ?lpp ?msbB double mutant were significantly more attenuated than the isogenic wild-type (WT) bacterium in bubonic and pneumonic animal models (mouse and rat) of plague. These data correlated with greatly reduced survivability of the aforementioned mutants in murine macrophages. Furthermore, the ?lpp ?msbB double mutant was grossly compromised in its ability to disseminate to distal organs in mice and in evoking cytokines/chemokines in infected animal tissues. Importantly, mice that survived challenge with the ?lpp ?msbB double mutant, but not the ?lpp or ?msbB single mutant, in a pneumonic plague model were significantly protected against a subsequent lethal WT CO92 rechallenge. These data were substantiated by the fact that the ?lpp ?msbB double mutant maintained an immunogenicity comparable to that of the WT strain and induced long-lasting T-cell responses against heat-killed WT CO92 antigens. Taken together, the data indicate that deletion of the msbB gene augmented the attenuation of the ?lpp mutant by crippling the spread of the double mutant to the peripheral organs of animals and by inducing cytokine/chemokine responses. Thus, the ?lpp ?msbB double mutant could provide a new live-attenuated background vaccine candidate strain, and this should be explored in the future.2013-01-01T00:00:00Z2013 Mar2020-11-19T10:44:39Z2019-03-27T01:05:24ZS-EPMC35848852327509210.1128/iai.01067-1210.1128/IAI.01067-12