Bacteriophages inhibit and evade cGAS-like immune function in bacteria

Area of Science:

• Microbiology
• Immunology
• Molecular Biology

Background:

• Eukaryotic antiviral immunity relies on the cGAS-STING pathway, synthesizing 2',3'-cGAMP.
• Bacterial cyclic GMP-AMP synthase (cGAS)-like enzymes, known as CBASS, produce cyclic oligonucleotides for anti-phage activity, but endogenous function remains unproven.

Purpose of the Study:

• To investigate the endogenous anti-phage activity of CBASS in Pseudomonas aeruginosa.
• To understand the mechanisms of bacterial anti-phage defense and phage counter-defense strategies.

Main Methods:

• Identification of an endogenous cGAS-like enzyme in Pseudomonas aeruginosa.
• Analysis of cyclic nucleotide synthesis (3',3'-cGAMP) during phage infection.
• Characterization of the anti-CBASS protein (Acb2) and its interactions with cyclic nucleotides and effectors.
• Assessment of phage evasion strategies through genetic mutations.

Main Results:

• An endogenous cGAS-like enzyme in P. aeruginosa generates 3',3'-cGAMP upon phage infection, activating a phospholipase effector to limit phage replication.
• Phages evolved Acb2, an anti-CBASS protein that inhibits phospholipase activity by binding 3',3'-cGAMP and other cyclic nucleotides, including mammalian cGAS products.
• CBASS effectively blocks phage replication and lysogenic induction, but phages can evade this defense via mutations in major capsid genes.

Conclusions:

• This study demonstrates the endogenous anti-phage function of CBASS in bacteria.
• CBASS employs sophisticated inhibition and evasion strategies, highlighting a dynamic co-evolutionary relationship between bacteria and phages.
• The findings reveal broad inhibitory potential of Acb2 against cGAS-based immunity across species.