A VgrG2b fragment cleaved by caspase-11/4 promotesPseudomonas aeruginosainfection through suppressing the NLRP3 inflammasome

The T6SS ofPseudomonas aeruginosaplays an essential role in the establishment of chronic infections. Inflammatory cytokines mediated by inflammasomes are crucial for the body to resist bacterial infections. Here we found that during the infection ofP. aeruginosa, non-canonical inflammasome was activated in macrophages, but the activation of downstream NLRP3 inflammasome was inhibited. The VgrG2b ofP. aeruginosais recognized and cleaved by caspase-11, generating a free C-terminal fragment. The VgrG2b C-terminus can bind to NLRP3, inhibiting the activation of the NLRP3 inflammasome by rejecting NEK7 binding to NLRP3. Administrating a specific peptide that inhibits the cleavage of VgrG2b by caspase-11 to mice can significantly improve their survival rate during infection. Our discovery elucidates a mechanism by whichP. aeruginosainhibits host immune response, providing a new approach for the future clinical treatment ofP. aeruginosainfections.