Browsing by Subject "Influenza A Virus"
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Item Host Modulagtors of the Death Response to Influenza a Infection(2012-07-17) Ward, Samuel Enoch; White, Michael A.Influenza A virus infects 5-20% of the population annually, resulting in ~35,000 deaths and significant morbidity. Current treatments include vaccines and drugs that target viral proteins. However, both of these approaches have limitations, as vaccines require yearly development and the rapid evolution of viral proteins gives rise to drug resistance. In consequence additional intervention strategies, that target host factors required for the viral life cycle, are under investigation. Here I employed arrayed whole-genome siRNA screening strategies to identify cell-autonomous molecular components that are subverted to support H1N1 influenza A virus infection of human mucosal epithelial cells. Integration across relevant public data sets exposed druggable gene products required for epithelial cell infection or required for viral proteins to deflect host cell suicide checkpoint activation. Pharmacological inhibition of representative targets, RGGT and CHEK1, resulted in significant protection against infection of human epithelial cells by the A/WS/33 virus. In addition, chemical inhibition of RGGT partially protected against H5N1 and the 2009 H1N1 pandemic strain. The observations reported here thus contribute to decoding vulnerabilities in the command and control networks specified by influenza virulence factors. [Keywords: Influenza A, genomewide screen, RNAi, innate immunity, CHEK1, IFITM3, virus]Item The Role of NS1-BP in Influenza Virus Replication(2012-08-13) Tsai, Pei-Ling; Fontoura, Beatriz, M.A.Influenza A viruses are negative-sense, segmented RNA viruses which cause about 500,000 deaths worldwide per year. Genomic studies have shown that the non-structural protein (NS1) of influenza A virus is a major virulence factor that is essential for pathogenesis. NS1 is a multifunctional protein localized in the nucleus and in the cytoplasm. In the cytoplasm, NS1 inhibits host signaling pathways that result in down-regulation of interferon expression and innate immune response. In the nucleus, NS1 represses host gene expression. I have shown that NS1 binds an mRNA complex containing NXF1/TAP, NXT/p15, Rae1, and E1B-AP5, which are key components of the mRNA export machinery. By targeting this complex, NS1 blocks host mRNA export, and cells become highly permissive to viral replication. Another intranuclear pool of NS1 was found to interact with a host protein termed NS1-BP, which has been suggested to play a role in pre-mRNA splicing. However, the functions and mechanisms of NS1-BP involved in influenza life cycle remain to be elucidated. To investigate the function of NS1-BP, I first identified its binding partners by immunoprecipitation followed by mass spectrometry. I found interactions of NS1-BP with viral polymerase complex and host RNA polymerase II indicating that NS1-BP has a role in regulating viral RNA transcription and replication. I further showed that low levels of NS1-BP led to a decrease in viral polymerase activity resulting in inhibition of virus replication. Thus, I identified NS1-BP as a novel pro-viral factor required for proper replication of influenza virus. Since NS1 is a key contributor to the virulence of influenza viruses, discovering the function of NS1 interacting partners has major implications for antiviral therapy. [Keywords: NSI-BP, influenza, virus, polymerase, RNA]