The Cytosolic Sensor cGAS Detects Mycobacterium tuberculosis DNA to Induce Type I
Interferons and Activate Autophagy
#MMPMID26048136
Watson RO
; Bell SL
; MacDuff DA
; Kimmey JM
; Diner EJ
; Olivas J
; Vance RE
; Stallings CL
; Virgin HW
; Cox JS
Cell Host Microbe
2015[Jun]; 17
(6
): 811-819
PMID26048136
show ga
Type I interferons (IFNs) are critical mediators of antiviral defense, but their
elicitation by bacterial pathogens can be detrimental to hosts. Many
intracellular bacterial pathogens, including Mycobacterium tuberculosis, induce
type I IFNs following phagosomal membrane perturbations. Cytosolic M.
tuberculosis DNA has been implicated as a trigger for IFN production, but the
mechanisms remain obscure. We report that the cytosolic DNA sensor, cyclic
GMP-AMP synthase (cGAS), is required for activating IFN production via the
STING/TBK1/IRF3 pathway during M. tuberculosis and L. pneumophila infection of
macrophages, whereas L. monocytogenes short-circuits this pathway by producing
the STING agonist, c-di-AMP. Upon sensing cytosolic DNA, cGAS also activates
cell-intrinsic antibacterial defenses, promoting autophagic targeting of M.
tuberculosis. Importantly, we show that cGAS binds M. tuberculosis DNA during
infection, providing direct evidence that this unique host-pathogen interaction
occurs in vivo. These data uncover a mechanism by which IFN is likely elicited
during active human infections.
free
free
free
