Identification of cGAS as an innate immune sensor of extracellular bacterium Pseudomonas aeruginosa

Summary Cyclic GMP-AMP synthase (cGAS) is reported essential for detecting intracellular bacteria. However, it remains to be determined whether and how cGAS is involved in extracellular bacterial infection. Here, we report that cGAS is essential for mediating Type I IFNs production in infection by multiple extracellular pathogens, including Pseudomonas aeruginosa, Klebsiella pneumoniae, and Staphylococcus aureus. In addition, the canonical cGAS-STING-IFN axis is required for protecting mice from P. aeruginosa-induced mouse acute pulmonary infection, confirmed in cGAS pathway-specific gene deficiency mouse models. cGAS-/- and STING-/- mice exhibited reduced Type I IFNs, excessive inflammatory response accompanied with decreased resistance to P. aeruginosa challenge. Unfolded protein response (UPR) was also modulated by cGAS through IRF3 and Type I IFNs under P. aeruginosa infection. Collectively, these findings uncover the importance of cGAS in initiating immune responses against extracellular bacterial infection.