Legionella persister physiological adaptation to host-derived nitric oxyde – NITRIC

Intracellular persisters represent a subpopulation of bacteria that transiently evade the bactericidal activities of antibiotics, causing non-resolving infection and relapse. The signals and associated signalling pathways that control intracellular persister emergence remain poorly understood. Among the stressors produced by the host cell, nitric oxide (NO), which is part of the oxidative response to infection, was proposed to be not only a bactericidal agent but also to promote the formation of intra-host persisters. Legionella pneumophila is the etiological agent of a life-threatening pneumonia called legionellosis, and a model organism to study the formation of intracellular persister. Combining methods in microbiology, biochemistry and molecular biology to cutting-edge single-cell acquisition systems, proteomics analysis, the NITRIC project aims to decipher the signalling pathway that links host-derived NO, emergence of persisters and the active persister physiological adaptation to the host cell. It will fill an important gap in the emerging field of intracellular persisters by establishing how bacterial persisters emerge, survive, and might underlie the severity/persistence of bacterial infection. Since NO sensing depends on c-di-GMP, as demonstrated by our previous research, this ambitious project will propose a novel role of this bacterial secondary messenger. Importantly, c-di-GMP is highly conserved among bacteria, making our work transferable beyond Legionella. Moreover, c-di-GMP signalling pathways that control persisters could become alternatives or complements to classical antibiotic targets for the development of new effective treatment strategies reducing evolutionary pressure associated with anti-infective resistance. Thus, NITRIC would provide the molecular blueprints for the development of future strategies in combating bacterial diseases in addition to making a seminal contribution to the understanding of persisters emergence biology.