title: Inhibition of the Injectisome and Flagellar Type III Secretion Systems by INP1855 Impairs Pseudomonas aeruginosa Pathogenicity and Inflammasome Activation.
abstract: With the rise of multidrug resistance, Pseudomonas aeruginosa infections require alternative therapeutics. The injectisome (iT3SS) and flagellar (fT3SS) type III secretion systems are 2 virulence factors associated with poor clinical outcomes. iT3SS translocates toxins, rod, needle, or regulator proteins, and flagellin into the host cell cytoplasm and causes cytotoxicity and NLRC4-dependent inflammasome activation, which induces interleukin 1β (IL-1β) release and reduces interleukin 17 (IL-17) production and bacterial clearance. fT3SS ensures bacterial motility, attachment to the host cells, and triggers inflammation. INP1855 is an iT3SS inhibitor identified by in vitro screening, using Yersinia pseudotuberculosis Using a mouse model of P. aeruginosa pulmonary infection, we show that INP1855 improves survival after infection with an iT3SS-positive strain, reduces bacterial pathogenicity and dissemination and IL-1β secretion, and increases IL-17 secretion. INP1855 also modified the cytokine balance in mice infected with an iT3SS-negative, fT3SS-positive strain. In vitro, INP1855 impaired iT3SS and fT3SS functionality, as evidenced by a reduction in secretory activity and flagellar motility and an increase in adenosine triphosphate levels. As a result, INP1855 decreased cytotoxicity mediated by toxins and by inflammasome activation induced by both laboratory strains and clinical isolates. We conclude that INP1855 acts by dual inhibition of iT3SS and fT3SS and represents a promising therapeutic approach.
authors.affiliation: Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Ahalieyah
authors.initials: A
authors.lastname: Anantharajah
authors.affiliation: EA7366, Host-Pathogen Translational Research Group, Faculté de Médecine, Université Lille Nord de France, Lille, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Faure
authors.affiliation: Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Julien M
authors.initials: JM
authors.lastname: Buyck
authors.affiliation: Creative Antibiotics, Umeå, Sweden.
authors.forename: Charlotta
authors.initials: C
authors.lastname: Sundin
authors.affiliation: Creative Antibiotics, Umeå, Sweden.
authors.forename: Tuulikki
authors.initials: T
authors.lastname: Lindmark
authors.affiliation: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Joan
authors.initials: J
authors.lastname: Mecsas
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Yahr
authors.affiliation: Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Tulkens
authors.affiliation: Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Mingeot-Leclercq
authors.affiliation: EA7366, Host-Pathogen Translational Research Group, Faculté de Médecine, Université Lille Nord de France, Lille, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Guery
authors.affiliation: Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Françoise
authors.initials: F
authors.lastname: Van Bambeke
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D058847:Inflammasomes / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018410:Pneumonia, Bacterial / Q000382:microbiology / Q000473:pathology*; D011552:Pseudomonas Infections / Q000382:microbiology / Q000473:pathology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000472:pathogenicity*; D016019:Survival Analysis; D016896:Treatment Outcome; D000069296:Type III Secretion Systems / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D058847:Inflammasomes; D000069296:Type III Secretion Systems; D037521:Virulence Factors
keywords: Pseudomonas aeruginosa; anti-virulence strategy; cytotoxicity; flagellum; inflammasome activation; pulmonary infection; type III secretion system