title: Affecting Pseudomonas aeruginosa phenotypic plasticity by quorum sensing dysregulation hampers pathogenicity in murine chronic lung infection.
abstract: In Pseudomonas aeruginosa quorum sensing (QS) activates the production of virulence factors, playing a critical role in pathogenesis. Multiple negative regulators modulate the timing and the extent of the QS response either in the pre-quorum or post-quorum phases of growth. This regulation likely increases P. aeruginosa phenotypic plasticity and population fitness, facilitating colonization of challenging environments such as higher organisms. Accordingly, in addition to the factors required for QS signals synthesis and response, also QS regulators have been proposed as targets for anti-virulence therapies. However, while it is known that P. aeruginosa mutants impaired in QS are attenuated in their pathogenic potential, the effect of mutations causing a dysregulated timing and/or magnitude of the QS response has been poorly investigated so far in animal models of infection. In order to investigate the impact of QS dysregulation on P. aeruginosa pathogenesis in a murine model of lung infection, the QteE and RsaL proteins have been selected as representatives of negative regulators controlling P. aeruginosa QS in the pre- and post-quorum periods, respectively. Results showed that the qteE mutation does not affect P. aeruginosa lethality and ability to establish chronic infection in mice, despite causing a premature QS response and enhanced virulence factors production in test tube cultures compared to the wild type. Conversely, the post-quorum dysregulation caused by the rsaL mutation hampers the establishment of P. aeruginosa chronic lung infection in mice without affecting the mortality rate. On the whole, this study contributes to a better understanding of the impact of QS regulation on P. aeruginosa phenotypic plasticity during the infection process. Possible fallouts of these findings in the anti-virulence therapy field are also discussed.
authors.affiliation: Dept. of Sciences, University Roma Tre, Rome, Italy.
authors.forename: Roslen
authors.initials: R
authors.lastname: Bondí
authors.affiliation: Dept. of Sciences, University Roma Tre, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Messina
authors.affiliation: Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS - San Raffaele Scientific Institute, Milan, Italy; Italian Cystic Fibrosis Research Foundation c/o Ospedale Maggiore, Verona, Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: De Fino
authors.affiliation: Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS - San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bragonzi
authors.affiliation: Dept. of Sciences, University Roma Tre, Rome, Italy.
authors.forename: Giordano
authors.initials: G
authors.lastname: Rampioni
authors.affiliation: Dept. of Sciences, University Roma Tre, Rome, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Leoni
mesh_terms: D000818:Animals; D058491:Bacterial Load; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002908:Chronic Disease; D054884:Host-Pathogen Interactions; D008171:Lung Diseases / Q000382:microbiology / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D009154:Mutation; D010641:Phenotype; D011552:Pseudomonas Infections / Q000382:microbiology / Q000473:pathology*; D011550:Pseudomonas aeruginosa / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D053038:Quorum Sensing / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D012097:Repressor Proteins; D037521:Virulence Factors; C118377:rsaL protein, Pseudomonas aeruginosa