Bacterial Type I CRISPR-Cas systems influence inflammasome activation in mammalian host by promoting autophagy.

The clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated systems (CRISPR-Cas) systems in prokaryotes function at defending against foreign DNAs, providing adaptive immunity to maintain homeostasis. CRISPR-Cas may also influence immune regulation ability in mammalian cells through alterations of pathogenic extent and nature. Recent research has implied that Type I CRISPR-Cas systems of Pseudomonas aeruginosa strain UCBPP-PA14 impede recognition by Toll-like receptor 4, and decrease pro-inflammatory responses both in vitro and in vivo. However, the molecular mechanism by which CRISPR-Cas systems affect host immunity is largely undemonstrated. Here, we explored whether CRISPR-Cas systems can influence autophagy to alter the activation of inflammasome. Using the wild-type PA14 and total CRISPR-Cas region deletion (∆TCR) mutant strain, we elucidated the role and underlying mechanism of Type I CRISPR-Cas systems in bacterial infection, and showed that CRISPR-Cas systems impacted the release of mitochondrial DNA and induction of autophagy. CRISPR-Cas deficiency led to an increase of mitochondrial DNA release, a decrease in autophagy, an increase of inflammasome activation and, ultimately, an elevation of pro-inflammatory response. Our findings illustrate a new important mechanism by which Type I CRISPR-Cas systems control their virulence potency to evade host defense.