A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis.
Detection of cyclic-di-adenosine monophosphate (c-di-AMP), a bacterial second messenger, by the host cytoplasmic surveillance pathway (CSP) is known to elicit type I interferon (IFN) responses, which are crucial to antimicrobial defense. However, the mechanisms and role of c-di-AMP signaling in Mycobacterium tuberculosis virulence remain unclear. Here we show that resistance to tuberculosis requires CSP-mediated detection of c-di-AMP produced by M. tuberculosis and that levels of c-di-AMP modulate the fate of infection. We found that a di-adenylate cyclase (disA or dacA)-overexpressing M. tuberculosis strain that secretes excess c-di-AMP activates the interferon regulatory factor (IRF) pathway with enhanced levels of IFN-β, elicits increased macrophage autophagy, and exhibits substantial virulence attenuation in mice. We show that c-di-AMP-mediated IFN-β induction during M. tuberculosis infection requires stimulator of interferon genes (STING)-signaling. We observed that c-di-AMP induction of IFN-β is independent of the cytosolic nucleic acid receptor cyclic GMP-AMP (cGAMP) synthase (cGAS), but cGAS nevertheless contributes substantially to the overall IFN-β response to M. tuberculosis infection. In sum, our results reveal c-di-AMP to be a key mycobacterial pathogen-associated molecular pattern (PAMP) driving host type I IFN responses and autophagy. These findings suggest that modulating the levels of this small molecule may lead to novel immunotherapeutic strategies against tuberculosis.
1] Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
Bappaditya
B
Dey
Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.
Ruchi Jain
RJ
Dey
Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.
Laurene S
LS
Cheung
1] Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA. [2] Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland, USA.
Supriya
S
Pokkali
Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.
Haidan
H
Guo
Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.
Jong-Hee
JH
Lee
1] Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
William R
WR
Bishai
D000818:Animals; D001343:Autophagy; D001426:Bacterial Proteins / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D015226:Dinucleoside Phosphates / Q000378:metabolism*; D005260:Female; D005816:Genetic Complementation Test; D016899:Interferon-beta / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis; D009713:Nucleotidyltransferases / Q000378:metabolism; D019761:Phosphorus-Oxygen Lyases / Q000378:metabolism*; D015398:Signal Transduction; D014376:Tuberculosis / Q000378:metabolism* / Q000517:prevention & control; D014774:Virulence; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
D001426:Bacterial Proteins; D016207:Cytokines; D015226:Dinucleoside Phosphates; D016899:Interferon-beta; D007371:Interferon-gamma; D009713:Nucleotidyltransferases; D019761:Phosphorus-Oxygen Lyases; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase