Paramyxovirus regulation of STAT signaling

The ability of viruses to modulate the immune response is a well-documented phenomenon that is crucial for viable infection. The paramyxoviruses have evolved to possess a myriad of immunomodulatory properties. However, the immunomodulatory properties of two paramyxoviruses, human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) have not been fully characterized. The overarching purpose of this dissertation was to elucidate STAT regulation by hMPV and RSV. This study investigated the ability of hMPV to modulate host immune responses in human epithelial cells, the primary cells of hMPV infection, by examining the impact of hMPV infection on STAT-mediated IFN signaling. Indeed, hMPV does possess immunomodulatory properties. Herein, we show that hMPV can infect and replicate in lung epithelial cells with a competent IFN system and that hMPV is not susceptible to exogenous IFN-alpha treatment. IFN-alpha-mediated signal transduction and the subsequent induction of interferon stimulated genes (ISGs) after treatment with IFN-alpha was antagonized by hMPV. Infection with hMPV prevented IFN-alpha-mediated phosphorylation and subsequent nuclear translocation of STAT1. However, upstream signaling components in the IFN-a signaling cascade were unchanged by hMPV infection. Furthermore, this study also investigated the hypothesis that RSV can infect dendritic cells (DCs) and impede type I IFN signaling in these innate immune cells. We demonstrate that BMDCs are permissive for infection by RSV, by showing that RSV is readily able to infect, express encoded viral genes, and replicate in cultured BMDCs. We also show that DCs infected with RSV are unable to activate STAT1, STAT2, and STAT3 in response to IFN-beta. Regulation of STAT signaling in BMDCs by RSV was limited to type I IFN signaling, as STAT phosphorylation in response to the type II IFN, IFN-gamma, and the regulatory cytokine IL-10 were not altered by RSV. Additionally, RSV diminished MHC class I upregulation by type I IFN in BMDCs, and inhibited T cell activation, as measured by IFN-y secretion, in an antigen-specific T cell differentiation assay. Together, these studies of hMPV and RSV infection provide essential insight into paramyxovirus-host interactions and increase our understanding of the pathogenesis of hMPV and RSV.