The #FRAX597 solubility dmso randurls[1|1|,|CHEM1|]# inability of RB50ΔsigE to cause lethal infections in Rag1−/− mice (Figure 4) could be due to failure to enter or survive in the bloodstream and/or systemic organs of these mice. Since the mutation does not affect survival during incubation with serum in vitro, it is unlikely that the sigE-deficient strain is more susceptible to complement or other antimicrobial components in serum. The defect in infection

of Rag1−/− mice may then be related to altered interactions of the mutant strain with phagocytic cells in the bloodstream. RB50ΔsigE is more susceptible to peripheral blood PMNs than RB50 (Figure 6), and is also less cytotoxic to macrophages than RB50 (Figure 5). Either or both of these defects could explain the failure to recover RB50ΔsigE from systemic organs of mice lacking adaptive

immune responses and the decreased virulence in these mice. Why does the RB50ΔsigE mutant spread systemically and cause lethal infection in TLR4def and TNF-α−/− mice, but not Rag1−/− mice? The lower cytotoxicity of the sigE mutant and its AZD1480 increased sensitivity to phagocytic killing does not affect its virulence in mice lacking innate immune functions. This could be because bacterial numbers within the respiratory tract of TLR4def or TNF-α−/− mice are nearly an order of magnitude higher than in the lungs of Rag1−/− mice. As such, the large number of bacteria in TLR4def or TNF-α−/− mice may overwhelm limiting host antimicrobial defense mechanisms that can contain the lower bacterial numbers in the Florfenicol lungs of Rag1−/− mice. Alternatively, although the cytotoxicity of the sigE mutant is reduced, it may still be sufficient to establish lethal infections in the absence of TLR4 or TNF-α. Thus TLR4- and TNF-α-dependent functions, such as efficient phagocytosis and killing, appear to be sufficient to prevent lethal infection by RB50ΔsigE in Rag1−/− mice. Although the exact role remains to be elucidated, our results

clearly indicate that SigE is required for lethal infection of mice lacking B and T cells. Although the B. bronchiseptica strain RB50 causes asymptomatic infections in immunocompetent mice, other strains of B. bronchiseptica can cause a wide range of disease severity in other hosts [11–13]. In particular subsets of immunocompromised humans, such as those infected with HIV, severe systemic B. bronchiseptica infections have been observed [14]. These facts, along with the high degree of sequence conservation for the sigE locus in B. pertussis and B. parapertussis, highlights the importance of understanding the stressors that activate SigE and how the SigE system responds to them during infection. Conclusions In this work, we have demonstrated that the B.

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