The Type I IFN Response to Infection with
                    <i>Mycobacterium tuberculosis</i>
                    Requires ESX-1-Mediated Secretion and Contributes to Pathogenesis

Sarah A Stanley, James E Johndrow, Paolo Manzanillo, Jeffery S Cox

doi:10.4049/jimmunol.178.5.3143

<jats:title>Abstract</jats:title> <jats:p>The ESX-1 secretion system is a major determinant of Mycobacterium tuberculosis virulence, although the pathogenic mechanisms resulting from ESX-1-mediated transport remain unclear. By global transcriptional profiling of tissues from mice infected with either wild-type or ESX-1 mutant bacilli, we found that host genes controlled by ESX-1 in vivo are predominantly IFN regulated. ESX-1-mediated secretion is required for the production of host type I IFNs during infection in vivo and in macrophages in vitro. The macrophage signaling pathway leading to the production of type I IFN required the host kinase TANK-binding kinase 1 and occurs independently of TLR signaling. Importantly, the induction of type I IFNs during M. tuberculosis infection is a pathogenic mechanism as mice lacking the type I IFNR were more restrictive for bacterial growth in the spleen than wild-type mice, although growth in the lung was unaffected. We propose that the ESX-1 secretion system secretes effectors into the cytosol of infected macrophages, thereby triggering the type I IFN response for the manipulation of host immunity.</jats:p>

The Type I IFN Response to Infection with <i>Mycobacterium tuberculosis</i> Requires ESX-1-Mediated Secretion and Contributes to Pathogenesis

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