Bandi, Jyothsna and Munir, Muhammad and Copeland, Nikki (2025) Unveiling the Antiviral Potential of chicken Poly (ADP-ribose) polymerases Against Influenza A Virus. PhD thesis, Lancaster University.
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Abstract
The Influenza A Virus (IAV) continues to pose a significant global health risk due to its capacity to trigger seasonal epidemics and occasional pandemics. Although vaccines and antiviral medications are available, the emergence of drug-resistant strains necessitates the development of novel therapeutic approaches. Poly (ADP-ribose) polymerases (PARPs) are a family of enzymes that participate in diverse cellular processes, such as DNA repair and immune response. Recent research has emphasized the potential of targeting PARPs as a novel antiviral strategy. This study aims to investigate the antiviral properties of the chicken PARP (chPARP) against IAV infection. To identify potential antiviral PARP candidates, we employed a bioinformatic approach to analyse the PARP family in chickens, which is a susceptible host for IAV infection. We focused on chPARP due to its unique structural features and potential role in antiviral immunity. To further investigate the antiviral mechanism of chPARP, we performed transcriptomic analysis to identify differentially expressed genes in IAV-infected cells treated with chPARPs. Our findings provides a comprehensive understanding of the role of PARP proteins in IAV infection. Bioinformatic analysis of chicken PARP genes revealed diverse domain organizations, evolutionary divergence, and potential antiviral roles. RNA-seq analysis of IAV-infected cells identified over 3,700 differentially expressed genes, including significant upregulation of several PARP family members, particularly PARP14. Functional studies on chPARP14 demonstrated its antiviral activity, with some truncated forms exhibiting reduced viral replication. Notably, full-length chPARP14 and chPARP14ΔCWC exhibited the most significant antiviral effects. While human PARP14 homologues showed varying antiviral activity, with some even exhibiting proviral effects, certain constructs, such as huPARP14ΔMACD, displayed potent antiviral activity. These findings highlight the potential of targeting PARPs, particularly chPARP14, for developing novel antiviral strategies. However, further research with increased sample sizes and employing alternative approaches, such as chemical inhibition, RNA interference, and gene editing, is crucial to fully elucidate the role of PARPs in antiviral defence. This work has significant implications for our understanding of viral pathogenesis and the development of novel antiviral strategies. The identification of chPARP14 as a key player in antiviral defence, coupled with the observation that specific domains within the protein contribute to its antiviral activity, suggests novel therapeutic targets for combating IAV and potentially other viral infections. Furthermore, the study highlights the importance of considering species-specific variations in antiviral responses, as observed in the differing antiviral activities of chicken and human PARP14 homologues. These findings lay the groundwork for future investigations into the specific mechanisms of PARP14-mediated antiviral activity and the development of strategies to modulate its activity for therapeutic purposes.