The Type I IFN response to infection with Mycobacterium tuberculosis requires ESX-1-mediated secretion and contributes to pathogenesis.
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.
Stanley
Sarah A
SA
Department of Microbiology and Immunology, University of California-San Francisco, San Francisco, CA 94158, USA.
Johndrow
James E
JE
Manzanillo
Paolo
P
Cox
Jeffery S
JS
D000818:Animals; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D007370:Interferon Type I / Q000172:deficiency / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology*
D007370:Interferon Type I; D037521:Virulence Factors; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases