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: Ahalieyah Anantharajah, Emmanuel Faure, Julien M Buyck, Charlotta Sundin, Tuulikki Lindmark, Joan Mecsas, Timothy L Yahr, Paul M Tulkens, Marie-Paule Mingeot-Leclercq, Benoît Guery, Françoise Van Bambeke
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 214 Issue 7 Pg. 1105-16 (10 01 2016) ISSN: 1537-6613 [Electronic] United States
• PMID: 27412581 (Publication Type: Journal Article)
• Copyright: © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail [email protected].

Chemical References

• Enzyme Inhibitors
• Inflammasomes
• Type III Secretion Systems
• Virulence Factors

Topics

• Animals
• Disease Models, Animal
• Enzyme Inhibitors (therapeutic use)
• Inflammasomes (metabolism)
• Mice, Inbred C57BL
• Pneumonia, Bacterial (microbiology, pathology)
• Pseudomonas Infections (microbiology, pathology)
• Pseudomonas aeruginosa (drug effects, pathogenicity)
• Survival Analysis
• Treatment Outcome
• Type III Secretion Systems (metabolism)
• Virulence Factors (metabolism)