Monday, October 2, 2023
10/2/2023
Project Summary Influenza, as a global threat to human health, continues to cause significant morbidity and high rates of mortality. To effectively control influenza, it is important to understand the interplay between the host and influenza by identifying host factors that regulate viral replication and defining the mechanisms by which influenza virus manipulates the cellular defense or signaling pathway. Sphingolipids are bioactive lipid mediators and include sphingosine 1-phosphate (S1P). Although S1P and its metabolizing enzymes, such as S1P lyase (SPL) and sphingosine kinase 2 (SK2), have been reported to regulate versatile cellular or disease processes, their roles in influenza virus infection are poorly understood. Preliminary data indicate that SPL promoted IKKe-mediated type I interferon (IFN) responses to display anti-influenza viral activity. However, influenza viruses effectively downregulated SPL, suggesting that influenza virus strives to evade the host defense mechanism. Furthermore, influenza virus increased the level of another S1P-metabolizing enzyme, SK2, which accelerated influenza virus replication. Inhibition of SK2 impaired influenza virus propagation in vitro and increased the viability of virus-infected mice, demonstrating the pro-influenza function of SK2. These findings heighten the need to further investigate the interplay between the S1P-metabolizing enzymes, host defense and signaling, and influenza virus. The research aims of this proposal include 1) determining the mechanisms by which influenza virus manipulates SPL and SK2 to enhance virus replication, 2) investigating the mechanisms of how these S1P-metabolizing enzymes display antiviral or pro-influenza viral activities, and 3) establishing the functions of the S1P-metabolizing enzymes during influenza virus infection in vivo. Collectively, these research results can define the regulatory functions of S1P-metabolizing enzymes that impact host defenses and influenza pathogenicity. Furthermore, the project could provide a foundation for designing new therapeutic interventions to cure influenza.
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