title: Mycobacterium tuberculosis activates the DNA-dependent cytosolic surveillance pathway within macrophages.
abstract: Cytosolic bacterial pathogens activate the cytosolic surveillance pathway (CSP) and induce innate immune responses, but how the host detects vacuolar pathogens like Mycobacterium tuberculosis is poorly understood. We show that M. tuberculosis also initiates the CSP upon macrophage infection via limited perforation of the phagosome membrane mediated by the ESX-1 secretion system. Although the bacterium remains within the phagosome, this permeabilization results in phagosomal and cytoplasmic mixing and allows extracellular mycobacterial DNA to access host cytosolic receptors, thus blurring the distinction between "vacuolar" and "cytosolic" pathogens. Activation of cytosolic receptors induces signaling through the Sting/Tbk1/Irf3 axis, resulting in IFN-β production. Surprisingly, Irf3(-/-) mice, which cannot respond to cytosolic DNA, are resistant to long-term M. tuberculosis infection, suggesting that the CSP promotes M. tuberculosis infection. Thus, cytosolic sensing of mycobacterial DNA plays a key role in M. tuberculosis pathogenesis and likely contributes to the high type I IFN signature in tuberculosis.
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, CA 94158, USA.
authors.forename: Paolo S
authors.initials: PS
authors.lastname: Manzanillo
authors.forename: Michael U
authors.initials: MU
authors.lastname: Shiloh
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Portnoy
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Cox
mesh_terms: D000818:Animals; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004269:DNA, Bacterial / Q000276:immunology* / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000172:deficiency; D007370:Interferon Type I / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity*; D010588:Phagosomes / Q000378:metabolism / Q000382:microbiology; D015398:Signal Transduction
chemical_list: D004269:DNA, Bacterial; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C494233:Irf3 protein, mouse