Micrornas as biomarkers for determining respiratory syncytial virus disease pathogenesis and vaccine efficacy
Anderson, Lydia Jane
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Respiratory syncytial virus (RSV) is a respiratory tract virus that causes significant morbidity and mortality in children less than 5 years of age, and is a major global public health burden. RSV infection does not confer long-lasting protection, as reinfections occur throughout life, which poses a substantial disease risk on immunocompromised patients and the elderly population. Currently, there is no licensed vaccine to prevent RSV infection. RSV vaccine development has been hampered by the need for a strong and robust protective immune response as well as risk of inducing vaccine enhanced disease. Therefore, the establishment of precise measures of protection and disease severity to evaluate a wide range of RSV vaccine platforms early in development is necessary in order to avoid costly and time-intensive trials. Host microRNAs (miRNAs) implicated in chronic inflammatory diseases of the lung were screened in vaccinated and RSV-infected BALB/c mice, and their pattern and tempo of expression was evaluate during vaccination and RSV-challenge. Unique miRNA profiles may then be utilized as biomarkers for vaccine efficacy and disease severity upon RSV infection. Our studies indicate that the pattern and tempo of differentially expressed miRNA differ in a vaccine- and adjuvant-specific manner. In addition, these unique miRNA profiles correlate with known immune correlates and markers of disease severity for the RSV vaccines and vaccine adjuvants. Using an in vitro model of lung epithelial cells, we also identified key differences in cellular and exosomal miRNA-associated expression patterns; in addition, these studies demonstrate that exosomes preferentially incorporate specific miRNAs as their cargo during RSV infection. Lastly, RNA interference (RNAi) technology was used for in vivo delivery of exogenous miR-467f to both rescue and further exacerbate the formalin-inactivated RSV (FI-RSV) vaccine enhanced disease phenotype produced upon RSV infection. By inducing gain- and loss- of-function, these studies indicate a biologically relevant role for miR-467f in linking the innate and adaptive immune response to vaccine enhanced disease. Taken together, this work establishes that miRNAs are intimately involved in the immune response and intracellular mechanisms controlling RSV replication and disease pathogenesis, and can be measured as parameters of disease severity and manipulated for therapeutic purposes.