Thesis (Ph. D.)--University of Texas at Austin, 2002. / Vita. Includes bibliographical references. Available also from UMI Company.

Influenza A virus is one of the most common human pathogens which caused considerable disease burdens through annual epidemics and occasional pandemics. The consequences vary from mild to severe or even fatal. What are the host and viral elements which determine the consequence of infection? In the past 15 years, several avian influenza A viruses including H5N1, H9N2, H7N7 and H7N9 subtypes were found to cross host barrier and infect humans. Question about how avian influenza A viruses gained the ability to replicate in human cells remains unanswered. Studies on host factors associated with virus replication would provide important information for understanding host restriction, virus pathogenesis and for antiviral drug development. Nuclear factor 90 (NF90) is a host protein identified in our previous study to inhibit influenza A virus replication. Antiviral activity of NF90 was also found for other viruses. However, detailed mechanisms for the antiviral function of NF90 remains largely unknown. This study is focused on NF90’s antiviral functions through exploring its relationship with PKR activation and stress granules formation using influenza A virus as a model. I characterized the interaction between NF90 and PKR, and showed the C-terminal of NF90 interacts with PKR in an RNA-binding dependent manner. Using transient and stable NF90 knockdown cells, I found that NF90 is required for PKR activation upon stimulation by dsRNA or infection with a NS1 mutated virus. PKR activation leads to the formation of stress granules and stall of protein translation. I found that NF90 is a core component of stress granules, which may underlie the mechanism for the antiviral activity of NF90. However, NF90 may also complete with PKR for RNA binding and regulate PKR activation. To further delineate the interaction between NF90 and PKR by using influenza A virus, my study constructed a panel of NS1 mutant viruses which were attenuated in antagonizing specific host antiviral pathways. I characterized the NS1 123-127 mutant virus which is unable to inhibit PKR phosphorylation but retained other functions unaffected. It was demonstrated that NF90 mediates PKR-dependent antiviral pathway since NS1 123-127 mutant virus replicated to a comparable level as wild type virus in the NF90 knockdown but not scramble knockdown 293T cells or in the interferon deficient Vero cells. This study for the first time found NF90 serves as a regulator of PKR antiviral pathway. To understand the mechanism for NF90 inhibition of influenza A virus replication, I found that NP, but not the other polymerase subunits, of influenza A virus was targeted to the stress granules. Since NF90 interacts with NP, it is reasonable to postulate that NF90 mediates the localization of NP, and possibly viral mRNA, to the stress granules in order to inhibit influenza A virus replication through regulation of proteins synthesis. In summary, my study provided comprehensive evidence to support a novel NF90-PKR antiviral pathway and suggests that NF90 may play critical roles to balance PKR phosphorylation in response to virus infection in cells. / published_or_final_version / Microbiology / Doctoral / Doctor of Philosophy

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Thesis (Ph. D.)--University of Texas at Austin, 2005. / Vita. Includes bibliographical references.

Thesis (M.Sc.)--York University, 2008. Graduate Programme in Biology. / Typescript. Includes bibliographical references (leaves 94-99). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR38791

published_or_final_version / Microbiology / Master / Master of Medical Sciences

Thesis (Ph. D.)--State University of New York at Binghamton, Department of Chemistry, 2004. / Includes bibliographical references.

Thesis (M.S.)--The University of North Carolina at Greensboro, 2010. / Directed by Amy Adamson; submitted to the Dept. of Biology. Title from PDF t.p. (viewed Jul. 12, 2010). Includes bibliographical references (p. 42-48).

Thesis (Ph.D.)--Texas Christian University, 2006. / Title from dissertation title page (viewed Sept. 12, 2006). Includes abstract. Includes bibliographical references.