Phage-host interaction in <i>Pseudomonas aeruginosa</i> clinical isolates with functional and altered quorum sensing systems

Quorum sensing (QS) plays a crucial role in regulating key traits, including the upregulation of phage receptors, which leads to heightened phage susceptibility in <i>Pseudomonas aeruginosa</i>. As a result, higher cell densities typically increase the risk of phage invasions. This has led to speculation that bacteria may have evolved strategies to counterbalance this increased susceptibility. Additionally, non-synonymous mutations in LasR, the master regulator of QS, are common among cystic fibrosis patients, but the impact of these mutations on phage interactions remains poorly understood. Here, we systematically investigated the role of QS in shaping these interactions using bacterial strains with functional or altered QS systems. In the QS-functional strain ZS-PA-35, disruption of the Las system reduces cell susceptibility to the type IV pili-dependent phage phipa2, delaying bacterial lysis during the early logarithmic growth phase. At high cell densities, Las-induced dormancy further inhibits phage proliferation despite enhanced phage adsorption. Notably, nutrient supplementation fully restores phage proliferation in the strains with a functional Las system. In contrast, the QS-deficient strain ZS-PA-05, carrying a LasR mutation, fails to regulate phage-host interactions via QS. Moreover, our findings reveal that within mixed microbial populations, cells benefit from the presence of closely related kin, which collectively reduce prey density and limit phage-host interaction frequencies under nutrient-rich conditions. These results underscore the flexibility of QS-regulated defense strategies, highlighting their critical role in optimizing bacterial resilience against phage predation, particularly in heterogeneous communities most vulnerable to phages.IMPORTANCEBacteria have developed various strategies to combat phage infection, posing challenges to phage therapy. In this study, we demonstrate that <i>Pseudomonas aeruginosa</i> strains with functional or altered quorum sensing (QS) systems may adapt different survival tactics for prolonged coexistence with phages, contingent upon bacterial population dynamics. The dynamics of phage infection highlight the influence of intrinsic heterogeneity mediated by QS, which leads to the emergence of different phage-host outcomes. These variants may arise as a result of coevolutionary processes or coexistence mechanisms of mutational and non-mutational defense strategies. These insights enhance our comprehension of how bacteria shield themselves against phage attacks and further underscore the complexity of such approaches for successful therapeutic interventions.