| Abstrakt: |
ABSTRACTThe highly infectious bacterium Francisella tularensisis a facultative intracellular pathogen and the causative agent of tularemia. TolC, which is an outer membrane protein involved in drug efflux and type I protein secretion, is required for the virulence of the F. tularensislive vaccine strain (LVS) in mice. Here, we show that an LVS ΔtolCmutant colonizes livers, spleens, and lungs of mice infected intradermally or intranasally, but it is present at lower numbers in these organs than in those infected with the parental LVS. For both routes of infection, colonization by the ΔtolCmutant is most severely affected in the lungs, suggesting that TolC function is particularly important in this organ. The ΔtolCmutant is hypercytotoxic to murine and human macrophages compared to the wild-type LVS, and it elicits the increased secretion of proinflammatory chemokines from human macrophages and endothelial cells. Taken together, these data suggest that TolC function is required for F. tularensisto inhibit host cell death and dampen host immune responses. We propose that, in the absence of TolC, F. tularensisinduces excessive host cell death, causing the bacterium to lose its intracellular replicative niche. This results in lower bacterial numbers, which then are cleared by the increased innate immune response of the host. |
