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This dissertation, Immune Responses of Human Respiratory Epithelial Cells to Respiratory Syncytial Virus and Human Metapneumovirus by Ming-shum, Yip, 葉名琛, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Immune responses of Human Respiratory Epithelial Cells to Respiratory Syncytial Virus and Human Metapneumovirus submitted by Yip Ming Shum for the Degree of Master of Philosophy at The University of Hong Kong in August 2007 Human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) are recognized as substantial causes of acute respiratory tract infections worldwide. Infection particularly in infants, immunocompromised and elderly individuals could result in severe bronchiolitis and pneumonia. In Hong Kong, both viruses co-circulate in spring and summer and share similar epidemiological features and clinical manifestations in humans. However, little is known whether the viruses trigger distinct or overlapping immune responses. In BALB/c mice and nasal secretions of HMPV-infected children, HMPV and RSV induce different cytokine and chemokine production. Therefore, we hypothesize that HMPV and RSV may trigger differential host immune responses. Airway epithelial cells are the primary target for HMPV and RSV. In this study, we aim to characterize the responses induced by HMPV- and RSV- infection in the airway epithelial cell line, A549. We first examined the infection patterns of the viruses in A549. Using the immunofluorescence assay, we have demonstrated that HMPV and RSV required different multiplicity of infection (MOI) to achieve similar infectivity in A549, suggesting differential permissiveness of the cell line to the viruses. At similar infectivities, the gene expression pattern of viral polymerase gene (L) of HMPV and RSV was different, showing the variation of replication kinetics at transcription level between the viruses in the host. Nevertheless, by cytopathic assays, the virus titer in HMPV- and RSV-infected A549 cells and cell-culture supernatant increased and was comparable at equivalent infectivities during the period of culture. We next investigated the cytokine and chemokine responses of A549 cells to HMPV and RSV by quantitative RT-PCR. At similar infectivities, both HMPV- and RSV-infected epithelial cells showed low expression of antiviral cytokines (interferon α [IFN-α] and IFN-β). HMPV-infected epithelial cells failed to induce proinflammatory cytokines (tumor necrosis factor α [TNF-α] and interleukin [IL-] 6), and only low level upregulation of these cytokines was shown in RSV-infected cells. Gene expression of TNF-related apoptosis inducing ligand (TRAIL), but not FasL, was significantly upregulated in A549 cells infected with HMPV or RSV, with RSV being the stronger inducer of this death receptor ligand. RSV induced high level of inflammatory chemokines (IL-8, monocyte chemoattractant protein 1 [MCP-1], regulated on activation normal T cell expressed and secreted [RANTES]) in the first 3 hours of infection. However, HMPV did not induce IL-8 and RANTES mRNA and appeared to be a less potent inducer of MCP-1 than RSV. Also, it was found that RSV but not HMPV moderately upregulated the gene expression of interferon-gamma-inducible protein-10 (IP-10) and macrophage inflammatory protein 1α (MIP-1α) in epithelial cells during the late phase of infection. Our results suggest that RSV and HMPV may trigger differential innate immune responses in human respiratory epithelial cells. Further work should include the impact of these infected respirat

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