rhl deficient-Pseudomonas aeruginosa induces enhanced host necroptosis through upregulation pqs within quorum sensing

As the leading cause of nosocomial infections, the relationship between Pseudomoans aeruginosa (P. aeruginosa) and host innate immune responses still arouses the interest in innate immunity research. Quorum sensing (QS), a communication system evolved by P. aeruginosa to mediates its density, is involved in various activities during bacterial infection. Recent study has revealed the link between QS and host innate inflammatory responses, extending the role of QS in interaction with host defense. Although previous evidence suggests PCD exists during anti-P. aeruginosa responses, it remains unclear that what role of quorum sensing plays in connection with PCD during infection. In this study, we exhibited that the deficiency of QS subsystems, rhl, dramatically increased the cell death induced by P. aeruginosa in mouse bone marrow-derived macrophages (BMMs). However, the cell death was completely blocked by using the Casp1/11^−/−Casp8^−/−Ripk3^−/− BMMs, indicating the association between QS and host PANoptosis. Intriguingly, we discovered the rhl deficiency upregulated downstream pqs signaling in P. aeruginosa, which significantly promoted the activation of necroptosis through elevated phosphorylation of MLKL. Deletion of pqsA gene in rhl deficiency strains of P. aeruginosa successfully rescued the necroptosis in BMMs. Taken together, our data highlight the crosstalk between QS and host PCD, ae well as a novel rhl – pqs – necroptosis axis in cell death signaling pathway.