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3. The role of influenza virus gene constellation and viral morphology on cytokine induction. pathogenesis and viral virulence   Funds : Research Fund for the Control of Infectious Diseases (investigator-initiated projects) Project Status : Closed Reference No. : 01030172 Project Title : The role of influenza virus gene constellation and viral morphology on cytokine induction. pathogenesis and viral virulence Applicant(s) : Peiris JSM(1) Poon LM(1) Nicholls J(2) Guan Y(1) Affiliation(s) : Department of Microbiology, The University of Hong Kong(1) Department of Pathology, The University of Hong Kong Approved Amount (HK$) : $824,164.00 Abstract : Purpose: Influenza A virus subtype H5N1 has caused human disease and death in 1997 and February 2003. H5N1 avian flu remains a significant pandemic threat and WHO has initiated a program for vaccine development. The basis for the unusual severity of human H5N1 disease is unknown. In addition, even the basis of influenza virus virulence in general is still poorly understood. We have previously shown that human H5N1 virus isolates hyper-induce pro-inflammatory cytokines and have suggested that this may be relevant to the unusual severity of H5N1 disease in humans. We find that there are at least two pathways by which influenza viruses hyper-induce cytokines - one requiring active virus replication and the other not. Others have recently reported that the viral M and NP genes are critical in determining viral replication competence and viral morphology (e.g. spherical vs filamentous virus particles). Objectives and hypothesis: We hypothesise that the virus morphology is relevant to virus mediated cytokine induction in vitro and that filamentous forms of the virus are able to activate cytokine induction though membrane interactions (e.g. via TOLL-like receptors) independent of viral replication. The objectives of our study is to correlate the cytokine induction phenotype with viral genotype and morphology.Design and study plan: We have a panel of naturally occurring and recombinant viruses (generated by reverse genetics) which hyper-induce cytokines from macrophages in either a viral replication dependent or independent manner. We propose to correlate these phenotypes with virus replication competence, virus morphology (filamentous vs. spherical virus particles) and virus genotype. In the second phase of the study, we will use reverse genetics to engineer recombinant viruses which contain human or avian influenza M or N genes which are known to alter virus morphology. We also will extend these experiments to the mouse macrophage model and use knock-out mice for individual toll-like receptors to detemine the mechanisms invovled. Main outcomes: Understanding the mechnisms underlying cytokine hyperinduction by influenza viruses will elucidate the the pathogenesis of disease caused by avian viruses such as H5N1 viruses in particular and of influenza viruses in general. Such understanding is essential for better influenza pandemic preparedness. It will help in a) identifying animal influenza viruses likely to be more virulent for humans and b) may lead to novel theraputic options for treating human influenza in general and those caused by H5N1-like influenza viruses in particular. Keywords : influenza, pathogenesis, virulence, cytokine, morphology Instruments : Remarks : Dissemination Report : [PDF file] 01030172dr.pdf Final Report : [PDF file] 01030172fr.pdf [add to bookmark]

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