Browsing by Subject "Infection"
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Item Adaptation of Pseudomonas aeruginosa to the cystic fibrosis lung environment(2013-12) Huse, Holly Kristen; Whiteley, MarvinChronic microbial infections result from persistent host colonization that is not cleared via the immune response or therapeutics. Within the host, microbes can undergo adaptive evolution, whereby beneficial traits promoting persistence arise due to selection; these traits can therefore affect disease outcomes and treatment strategies. The Gram-negative opportunistic pathogen Pseudomonas aeruginosa is the primary cause of chronic, fatal respiratory infections in individuals with the heritable disease cystic fibrosis (CF). The goal of this dissertation is to identify adaptations that allow P. aeruginosa to persist in the host during chronic CF lung infection. To achieve this goal, P. aeruginosa was chronologically sampled from 3 CF patients, ranging from the first infecting bacterium (the ancestor) to ~40,000 generations post-infection. By comparing gene expression profiles of ancestral and evolved isolates sampled from multiple patients, I identified 24 parallel gene expression changes that occurred over time within each lineage, suggesting that these traits are beneficial to the bacterium. Because most of these traits had unknown physiological roles, I sought to characterize their biological significance. I used a gain-of-function genetic screen and discovered that a subset of these genes enhance biofilm formation, a sessile mode of growth proposed to be important during chronic CF lung infection. I showed that enhanced biofilm formation is due to increased production of the exopolysaccharide Psl, which is traditionally viewed as less critical for maintaining chronic infections than other virulence factors. Lastly, I demonstrated that a majority (~72%) of chronic P. aeruginosa isolates produce more Psl than their corresponding ancestor, suggesting that this exopolysaccharide is important during chronic infection and an adaptive trait.Item Characterization of DAI during MCMV infection(2015-08) Landsteiner, Vanessa J.; Upton, Jason W.; Sridharan, HaripriyaPathogen recognition initiates host cell defense mechanisms including activation of the innate immune system in an effort to clear an infection. As a survival mechanism, viruses have developed potent strategies to evade the host response. Viruses that persist for the life of their host, such as herpesviruses, are particularly adept at modulating host innate immunity to benefit the virus. Previous work has shown that receptor interacting protein kinase (RIP)3-dependent programmed necrosis is a critical host response toward murine cytomegalovirus (MCMV) infection, and this pathway is actively inhibited during infection by the MCMV M45 gene product, also known as vIRA. IRA inhibits the association of RIP3 with the DNA-dependent activator of interferon regulatory factors (DAI/ZBP-1), clearly implicating DAI in this pathway. In addition to programmed necrosis, DAI has also been implicated in the antiviral immune response toward herpesviruses. However, the mechanisms by which DAI mediates these functions during viral infection remain largely unexplored. Using the MCMV model, we have further characterized the role of DAI in the host innate immune response to MCMV infections.