Antibody targeting of TSG101 on influenza-infected cells
Aurelio Bonavia1*, Leyla S Diaz1*, David Santos1, Josephine Cassella1, Zena Fesseha1, Douty Bamba1, Baoquan Sui1, Wu-Bo Li1, Roxanne Duan1, Li-Mei Chen2, Ruben O Donis2, Michael Goldblatt1, Michael S Kinch1
1Functional Genetics, Inc, Gaithersburg, MD, USA; 2Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA, USA; *These authors contributed equally to this work.
Abstract: Influenza remains a significant cause of morbidity and mortality worldwide. Although vaccination programs and conventional antiviral therapies can reduce disease burden, increasing resistance to conventional therapies renders much of the population susceptible to infection. The present study focuses on an important host protein target, tumor susceptibility gene 101 (TSG101), which is functionally exploited (hijacked) by certain enveloped viruses to facilitate viral budding and release. We find that influenza viruses depend on TSG101 for progeny virion morphogenesis in infected host cells. Antibody-binding studies revealed that TSG101 is exposed at the surface of influenza-infected cells but remains intracellular in uninfected cells. Using recombinant TSG101 and influenza M1 protein, we demonstrated a direct interaction between these proteins involving the ubiquitin E2 variant domain of TSG101. These findings identify an interaction between TSG101 and M1 protein in infected cells. Furthermore, a monoclonal antibody directed against TSG101 reduced virus yields in cell-based assessment of influenza virus infection, underscoring the potential of the TSG101-M1 interaction as a possible antiviral therapeutic target. The display of TSG101 at the surface of infected cells, combined with evidence that TSG101 antibodies reduce virus yields, suggest that TSG101 plays an essential role in the budding process of influenza virus. Our findings may also suggest potential opportunities for influenza treatment and prevention by using monoclonal antibody therapeutics to interfere with virus replication.
Keywords: influenza, TSG101, infected cells, vaccine
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