Grant: Discovery Grants Program - Individual

The innate immune system is armed with an array of cellular receptors, which rapidly detect invading microorganisms and initiate host defense. Ten years ago, the intracellular NOD-like receptors (NLR) were recognized as an essential part of innate immunity. Their role in antimicrobial host defence is the subject of intensive research, but current knowledge on their specific functions is limited. During the last 6 years, my NSERC-funded research has focused on molecular mechanisms involved in innate immune responses to pathogenic bacteria Pseudomonas aeruginosa. My research aims to understand how this microorganism escapes immune responses resulting in severe infections. I hypothesize that NLRs are able to activate immune responses to P. aeruginosa, but as bacteria undergo mutations and lose some virulence factors in the process of host-pathogen interactions, they escape recognition by NLRs and subsequently overcome host defenses. The major objective of my proposed research program: to investigate the involvement of NLRs in innate immune and inflammatory responses to P. aeruginosa. I will address the following specific questions: 1. Which microbial virulence factors are essential in the activation of NLR-mediated innate immune responses? 2. Which critical NLR-mediated innate immune mechanisms are activated following recognition of P. aeruginosa? 3. Which intracellular signaling pathways are involved in NLR-mediated cellular responses to P. aeruginosa? This research program will engage advanced cellular and molecular methodology, including the examination of a collection of P. aeruginosa mutant strains with differential expression of major virulence factors. The anticipated results will provide novel understanding of mechanisms of innate immunity that are fundamental in host defense against pathogenic microorganisms.