Our goals in this application are to understand the signaling events in the cell that control the endocytosis and genome delivery of influenza virus. Our rationale is that an understanding of the fundamental molecular events involved in the entry of influenza viruses into cells will be critical for the development of future antiviral drugs, designed to combat both the annual epidemics of influenza virus infection in the human population, as well as pandemic influenza. We have three specific aims: 1 - To investigate cellular signaling responses during influenza virus endocytosis. One of the major goals of this application is to understand the regulatory mechanisms underlying the route of influenza virus entry into cells. The initial focus of this project is to understand how influenza virus communicates with the signaling network of the cell. Activation of cellular signaling pathways by influenza virus has previously been studied at late times of infection;however critical signaling events occurring during influenza virus entry remain unexplored. 2 - To investigate the clathrin and non-clathrin routes of influenza virus entry and the role of the actin cytoskeleton. We have previously shown that influenza virus can efficiently enter cells in the absence of clathrin-mediated endocytosis. In contrast to the situation with clathrin- and caveolae-mediated endocytosis, there is a relative paucity of information on alternative routes of entry. The major goals of this section are to characterize the non-clathrin, non-caveolae route of influenza entry, and to integrate our knowledge of both clathrin- and non-clathrin endocytosis in polarized epithelial cells. 3 - To investigate the upstream signaling events during influenza entry that are required for influenza virus internalization. Our goal in this aim is to understand the specific interactions that occur at the cell surface to coordinate endocytic trafficking and signaling during influenza virus entry. Influenza is a major public health problem worldwide. In the United States, the virus is responsible for over 36,000 deaths annually, with the possibility of emergence of new and potentially deadly strains of the virus. As such, it is classed as an NIAID category C priority pathogen for biodefense and emerging infectious disease research. We believe our work will provide a framework for the basic understanding of influenza virus entry and lead to the development of new anti-viral drugs, which are still necessary to combat this potentially devastating viral disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology - B Study Section (VIRB)
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Hauguel, Teresa M
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Cornell University
Schools of Veterinary Medicine
United States
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Costello, Deirdre A; Whittaker, Gary R; Daniel, Susan (2015) Variations in pH sensitivity, acid stability, and fusogenicity of three influenza virus H3 subtypes. J Virol 89:350-60
Hamilton, Brian S; Chung, Changik; Cyphers, Soreen Y et al. (2014) Inhibition of influenza virus infection and hemagglutinin cleavage by the protease inhibitor HAI-2. Biochem Biophys Res Commun 450:1070-5
Zhang, Yueting; Whittaker, Gary R (2014) Influenza entry pathways in polarized MDCK cells. Biochem Biophys Res Commun 450:234-9
Tse, Longping V; Hamilton, Alice M; Friling, Tamar et al. (2014) A novel activation mechanism of avian influenza virus H9N2 by furin. J Virol 88:1673-83
Hamilton, Brian S; Whittaker, Gary R (2013) Cleavage activation of human-adapted influenza virus subtypes by kallikrein-related peptidases 5 and 12. J Biol Chem 288:17399-407
Tse, Longping V; Marcano, Valerie C; Huang, Weishan et al. (2013) Plasmin-mediated activation of pandemic H1N1 influenza virus hemagglutinin is independent of the viral neuraminidase. J Virol 87:5161-9
Hamilton, Brian S; Whittaker, Gary R; Daniel, Susan (2012) Influenza virus-mediated membrane fusion: determinants of hemagglutinin fusogenic activity and experimental approaches for assessing virus fusion. Viruses 4:1144-68
Hamilton, Brian S; Gludish, David W J; Whittaker, Gary R (2012) Cleavage activation of the human-adapted influenza virus subtypes by matriptase reveals both subtype and strain specificities. J Virol 86:10579-86
Costello, Deirdre A; Lee, Donald W; Drewes, Jennifer et al. (2012) Influenza virus-membrane fusion triggered by proton uncaging for single particle studies of fusion kinetics. Anal Chem 84:8480-9
Sun, Xiangjie; Tse, Longping V; Ferguson, A Damon et al. (2010) Modifications to the hemagglutinin cleavage site control the virulence of a neurotropic H1N1 influenza virus. J Virol 84:8683-90

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