disrupts TLR2-MYD88-p38 signaling early during infection to delay apoptosis of macrophages and promote virulence in the host.

is a zoonotic pathogen and the causative agent of tularemia. replicates to high levels within the cytosol of macrophages and other host cells while subverting the host response to infection. Critical to the success of is its ability to delay macrophage apoptosis to maintain its intracellular replicative niche. However, the host-signaling pathway(s) modulated by to delay apoptosis are poorly characterized. The outer membrane channel protein TolC is required for virulence and its ability to suppress apoptosis and cytokine expression during infection of macrophages. We took advantage of the ∆ mutant phenotype to identify host pathways that are important for activating macrophage apoptosis and that are disrupted by the bacteria. Comparison of macrophages infected with wild-type or ∆ revealed that the bacteria interfere with TLR2-MYD88-p38 signaling at early times post infection to delay apoptosis, dampen innate host responses, and preserve the intracellular replicative niche. Experiments using the mouse pneumonic tularemia model confirmed the relevance of these findings, revealing contributions of TLR2 and MYD88 signaling to the protective host response to , which is modulated by the bacteria to promote virulence IMPORTANCE is a Gram-negative intracellular bacterial pathogen and the causative agent of the zoonotic disease tularemia. , like other intracellular pathogens, modulates host-programmed cell death pathways to ensure its replication and survival. We previously identified the outer membrane channel protein TolC as required for the ability of to delay host cell death. However, the mechanism by which delays cell death pathways during intracellular replication is unclear despite being critical to pathogenesis. In the present study, we address this gap in knowledge by taking advantage of ∆ mutants of to uncover signaling pathways governing host apoptotic responses to and which are modulated by the bacteria during infection to promote virulence. These findings reveal mechanisms by which intracellular pathogens subvert host responses and enhance our understanding of the pathogenesis of tularemia.