Thesis
Emergence and evolution of avian-origin genes in pandemic influenza A virus ribonucleoprotein complexes
- Abstract:
- Zoonotic influenza A viruses (IAVs) remain a persistent and significant threat to global health. Despite the availability of vaccines and antiviral drugs, the emergence of pandemic IAVs continues to impose a considerable economic and public health burden. A key concern is the ability of novel zoonotic IAVs to bypass pre-existing immunity acquired through prior infections or vaccination. For successful human infection and sustained transmission, these viruses must overcome numerous functional, physiological, and biological barriers. This thesis investigates the molecular determinants that facilitate the adaptation of avian-derived IAVs to human hosts, with a particular focus on the viral ribonucleoprotein (vRNP) complex. Through a combination of molecular virology, reverse genetics, and pathology-based approaches, I characterize the contribution of avian-origin PB1 genes to host adaptation and pathogenesis. The first two chapters focus on the PB1 segments from the 1918 H1N1, 1957 H2N2, and 1968 H3N2 pandemic viruses, assessing their function in avian and human IAV backgrounds. Despite high sequence similarity to low-pathogenic avian influenza viruses (LPAIV), subtle amino acid changes in these pandemic PB1 genes can significantly alter polymerase function and viral fitness. Notably, I demonstrate that a model LPAIV PB1 gene supports efficient viral replication at febrile-range temperatures in a human IAV background—highlighting a potential role in facilitating avian-to-human transmission. In response to the recent publication of first-wave 1918 H1N1 genome sequences, the final chapter explores viral evolution during the 1918 pandemic. Using reverse genetics, I show that first- and second-wave strains differ in sensitivity to Mx1 antiviral activity, suggesting that 1918 H1N1 evolved innate immune escape mechanisms after the initial wave. Together, these findings advance our understanding of the molecular barriers to zoonotic IAV emergence and the evolutionary trajectories of pandemic vRNP genes. Insights from this work may enhance surveillance efforts and guide the development of targeted countermeasures against future pandemic threats.
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Authors
Contributors
+ Taubenberger, J
- Institution:
- National Institutes of Health
- Research group:
- NIH/NIAID
- Role:
- Supervisor
+ Fodor, E
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- Pathology Dunn School
- Role:
- Supervisor
- ORCID:
- 0000-0003-3249-196X
+ Hutchinson, E
- Institution:
- University of Glasgow
- Research group:
- CVR
- Role:
- Examiner
+ Carroll, M
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- NDM
- Role:
- Examiner
- DOI:
- Type of award:
- DPhil
- Level of award:
- Doctoral
- Awarding institution:
- University of Oxford
- Language:
-
English
- Keywords:
- Subjects:
- Deposit date:
-
2026-04-22
- ARK identifier:
Terms of use
- Copyright holder:
- Stephanie Leeann Williams
- Copyright date:
- 2025
- Rights statement:
- This research was supported [in part] by the Intramural Research Program of the National Institutes of Health (NIH). The contributions of the NIH author(s) were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.
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