Determinants of the Il-1beta response to Pseudomonas aeruginosa

IL-1beta is a potent proinflammatory cytokine produced in response to Pseudomonas aeruginosa infection. While it is appreciated that IL-1beta is a critical modulator of the host response to P. aeruginosa infection, the host and bacterial determinants of IL-1beta production during both acute and chronic infections are less well understood. This thesis is focused on the determinants of the IL-1beta response to P. aeruginosa. The effects of bacterial phenotypic changes during chronic infection, such as loss of flagellar motility, on the IL-1beta response are poorly understood. Bacterial flagellar motility is a fundamental mechanism, which enables bacterial association with leukocytes. Therefore, we hypothesized that loss of bacterial flagellar motility would facilitate evasion of contact-dependent inflammasome activation and IL-1beta production. In support of this hypothesis, we demonstrate that bacterial flagellar motility contributes to inflammasome activation and correspondingly, nonmotile P. aeruginosa evades inflammasome activation both in vitro and in vivo. Our work provides a better understanding of the role of loss of flagellar motility in evading inflammatory immune responses during chronic P. aeruginosa infections. Based on the known pathological contributions of excessive IL-1beta production and the observation that IL-1beta is potently produced in response to wild type, motile P. aeruginosa, we hypothesized that genetic loss of ASC (apoptosis associated speck-like protein containing a caspase recruitment domain), which is required for IL-1beta production by macrophages, would lead to reduced IL-1beta production and preferentially protect mice in a model of hyperinflammatory lethal challenge. This thesis identifies that loss of ASC does not lead to preferential protection in response to P. aeruginosa acute infection and ASC-deficient mice display no defect for IL-1beta production in vivo. We identify the contributions of different host immune cells dynamically recruited during infection and their role in IL-1beta production. Our work identifies neutrophils as a noncanonical source of IL-1beta during acute P. aeruginosa infection. The neutrophil IL-1beta response is predominantly dependent on caspase-1 but independent of ASC. This thesis elucidates both host and bacterial determinants that regulate IL-1beta production in response to P. aeruginosa. These insights are relevant to both acute and chronic P. aeruginosa infections and contribute to our better understanding of the potent IL-1beta response.