Influenza virus is a globally significant infectious agent with the potential to cause catastrophic pandemic outbreaks. Present treatment of influenza infections is restricted to only four anti-viral drugs, but there are increasing global reports of anti-viral resistance in several seasonal strains and also the 2009 pandemic swine-origin influenza virus H1N1. Possible future pandemic outbreaks, emerging new strains and drug resistance underscore the need to understand this complex virus and its pathogenicity with the goal that novel targets can be uncovered for future therapeutic development.
Extensive lung tissue damage during influenza virus infection is proposed to contribute to the development of aberrant host immune responses. Strong evidence now demonstrates the significance of the cellular death pathway in promoting efficient influenza virus replication and disease progression. Viruses rely heavily on the machinery of their host for productive replication, which is also an Achilles’ heel that could be targeted for treatment. In pursuit of unraveling the complex nature of influenza virus replication, I carried out a global shRNA screen to identify specific host factors and signaling pathways that are involved in influenza-induced cell death and replication. In this study I identified 138 genes required for influenza viruses to induce infected host cell death. These genes were found to be involved in Protein Kinase A, NF-kB and PI3K signaling cascades. These signaling pathways are well known regulators of cell death and survival, which suggests influenza viruses may carefully regulate these pathways to reach a balance that suit their requirements for efficient proliferation, eventually at the cost of the host cell. I chose five candidate genes—BAD, MxB, TNFSF12-13,TNFSF13, and USP47—that were associated with apoptosis and the major signaling pathways determined in my network analysis to further verify the genome-wide screen as well as elucidate the role of these potentially novel host factors in influenza virus replication.
I show in my study that influenza virus-induced cytopathology and cell death are considerably inhibited in BAD knockdown cells and both virus replication and viral protein production also are dramatically reduced. I also report here that MxB depletion protected cells from virus-mediated cytopathology and resulted in significant inhibition of influenza virus replication for H1N1 and H3N2 subtypes. Additionally, I report that TNFSF12-13, TFNSF13, and USP47, similarly, are required for efficient influenza virus replication and induction of cell death. Depletion of these proteins resulted in significant inhibition of viral propagation and conferred protection of host cells to virus killing.
Overall, my study has provided a list of novel host factors that play significant roles during influenza virus infection. Further studies on these potential genes and their encoded protein products may uncover possible new targets for drug development for future therapeutic treatment. In addition to providing greater understanding of influenza virus infection, these studies will also highlight important fundamentals of cellular processes that may be broadly applicable to other fields of research.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:MWU.1993/18323 |
| Date | 03 1900 |
| Creators | Tran, Anh Thuy |
| Contributors | Coombs, Kevin (Medical Microbiology and Infectious Diseases), Yao, Xiao-Jian (Medical Microbiology and Infectious Diseases) Yang, Xi (Medical Microbiology and Infectious Diseases) Kirshenbaum, Lorrie (Physiology) Pattnaik, Asit Kumar (University of Nebraska-Lincoln) |
| Publisher | Journal of Virology |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Detected Language | English |
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