Cyclic GMP-AMP Synthase Is an Innate Immune DNA Sensor for Mycobacterium tuberculosis

Angela C. Collins, Haocheng Cai, Tuo Li, Luis H. Franco, Xiao Dong Li, Vidhya R. Nair, Caitlyn R. Scharn, Chelsea E. Stamm, Beth Levine, Zhijian J. Chen, Michael U. Shiloh

Research output: Contribution to journalArticlepeer-review

205 Scopus citations

Abstract

Activation of the DNA-dependent cytosolic surveillance pathway in response to Mycobacterium tuberculosis infection stimulates ubiquitin-dependent autophagy and inflammatory cytokine production, and plays an important role in host defense against M. tuberculosis. However, the identity of the host sensor for M. tuberculosis DNA is unknown. Here we show that M. tuberculosis activated cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) in macrophages to produce cGAMP, a second messenger that activates the adaptor protein stimulator of interferon genes (STING) to induce type I interferons and other cytokines. cGAS localized with M. tuberculosis in mouse and human cells and in human tuberculosis lesions. Knockdown or knockout of cGAS in human or mouse macrophages blocked cytokine production and induction of autophagy. Mice deficient in cGAS were more susceptible to lethality caused by infection with M. tuberculosis. These results demonstrate that cGAS is a vital innate immune sensor of M. tuberculosis infection.

Original languageEnglish (US)
Pages (from-to)820-828
Number of pages9
JournalCell Host and Microbe
Volume17
Issue number6
DOIs
StatePublished - Jun 1 2015

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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