A Murine Model of Genetic Determinants of RSV Disease Public Deposited

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  • March 19, 2019
Creator
  • High, Monica Denise
    • Affiliation: School of Medicine, Curriculum in Toxicology
Abstract
  • Respiratory Syncytial Virus (RSV) is the leading cause of lower respiratory tract infection (LRTI) in infants. Approximately 70% of infants are infected with RSV within the first year of life. Epidemiological studies show that individuals have varying severity of RSV disease, ranging from "cold-like" symptoms to death. Previous in vivo studies have suggested that RSV susceptibility is a polygenic trait; however, the specific genes regulating RSV disease have yet to be identified. The objective of this dissertation was to identify candidate genes that regulate differences in RSV disease severity between inbred mouse strains. Thirty-six inbred mouse strains were infected with a single dose of 1x106 plaque forming units of RSV or control and sacrificed 1 and 5 days post-infection (pi). Inflammatory response, lung permeability, pathology, mucus cell metaplasia, and viral load were analyzed and compared among and within all inbred strains. Using in silico haplotype association mapping, the degree of correlation between the observed phenotypic differences and the genotype of the inbred strains was used to determine candidate QTLs. RSV disease phenotypes were distributed continuously across inbred strains. Furthermore, the strain distribution patterns varied for each phenotype and time point, suggesting that multiple mechanisms influence RSV susceptibility. Correlation analysis of phenotype relatedness also suggests that the response to RSV at 1 and 5 days pi are independent. Gene expression was minimally altered by RSV infection in "non-responsive" strains (e.g. C3H/HeJ); however, gene expression did vary significantly as a result of RSV infection in responsive inbred strains (e.g. BALB/cByJ). In responsive strains the most significant change in gene expression was noted 1 day following infection when a significant number of genes were either up-regulated or down-regulated. It was determined that genes involved in antigen presentation, infection mechanisms, and inflammatory response pathways were differentially activated between responsive and non-responsive strains. Based on the expression profile and biological plausibility a few of these genes (e.g. Marco, Tlr4, Stat4, Mx1, Ccl12, Cx3cr1) were identified as candidate genes for response to RSV infection. In vivo proof-of-principle investigations confirmed the role of Cx3cr1 and Marco as candidate genes for RSV susceptibility and disease.
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  • "... in partial fulfillment of the requirements for the degree of Philosophy Doctorate in the Curriculum in Toxicology."
Advisor
  • Kleeberger, Steven R.
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  • Chapel Hill, NC
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  • Open access
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