TY - JOUR
T1 - Mycobacterium tuberculosis activates the DNA-dependent cytosolic surveillance pathway within macrophages
AU - Manzanillo, Paolo S.
AU - Shiloh, Michael U.
AU - Portnoy, Daniel A.
AU - Cox, Jeffery S.
N1 - Funding Information:
We thank T. Taniguchi, R. Vance, G. Barber, G. Barton, D. Stetson, S. Akira, and members of their labs for reagents and macrophages. We are grateful to Charlie Kim for assistance with mice, J. MacGurn for EM images, L. Kohler for generating M. tuberculosis KO strains, A. Casadevall for sharing unpublished results, and L. Connolly for critical reading of the manuscript. This work was supported by NIH grant P01 AI063302 (D.A.P. and J.S.C.), NIH K08 AI076632 (M.U.S.), and NIH training grant T32 AI060537 (P.S.M.). D.A.P. has a consulting relationship with and a financial interest in Aduro BioTech.
PY - 2012/5/17
Y1 - 2012/5/17
N2 - 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.
AB - 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.
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U2 - 10.1016/j.chom.2012.03.007
DO - 10.1016/j.chom.2012.03.007
M3 - Article
C2 - 22607800
AN - SCOPUS:84861170022
SN - 1931-3128
VL - 11
SP - 469
EP - 480
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 5
ER -