Influenza epidemics exact a formidable toll on world health. Last year, the emergence of a novel influenza A H1N1 viral strain created a pandemic, producing illness around the globe. Additionally, the related avian influenza A viral strain, H5N1, represents a potentially catastrophic global health risk. Like all viruses, influenza A virus exploits host factors to replicate. To defend against this exploitation, the host mobilizes factors to confront the virus. A distinct class of protein signaling molecules, the interferons (IFNs), orchestrates a large component of this anti-viral response at both a cellular and organismal level. IFN stimulation results in over 2000 gene products being differentially regulated after IFN stimulation. To find host-cell modifiers of influenza A H1N1 viral infection, we completed a large scale genetic screen and detected several proteins which are important in decreasing influenza A virus infection, including a role for interferon-inducible trans-membrane protein 3 (IFITM3). The loss of IFITM3 resulted in elevated viral replication in multiple cell lines tested, and proved to be critical for IFN-induced viral resistance, accounting for 50% to 80% of IFN's protective ability. IFITM3 belongs to a family of four closely related proteins in humans, and five proteins in mice. This application aims to elucidate the role of the IFITM proteins in the host response to influenza A virus infection. Successful achievement of the aims of this proposal will provide in depth knowledge of the actions of the IFITM proteins and will inform us more fully on the innate interferon response to viruses. Relevance to Public Health: Influenza A virus is a threat to world health. Our previous studies have shown that the IFITM proteins play an important role in blocking influenza A virus infection. We are studying how IFITM3 decreases influenza A virus infection, and trying to find ways to use this knowledge to inhibit viral infections.

Public Health Relevance

Influenza A virus is a single stranded RNA virus that creates epidemics of respiratory illness. The studies proposed here will determine the molecular mechanism underlying IFITM3's ability to block influenza A virus infection, and identify proteins that partner with IFITM3 to stop viral infection. This work will improve our understanding of how the IFITM proteins inhibit the replication of influenza A virus and will likely provide insight into how to stop and possibly treat influenza A virus infection.

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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University of Massachusetts Medical School Worcester
Schools of Medicine
United States
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Tao, Liang; Zhang, Jie; Meraner, Paul et al. (2016) Frizzled proteins are colonic epithelial receptors for C. difficile toxin B. Nature 538:350-355
Savidis, George; Perreira, Jill M; Portmann, Jocelyn M et al. (2016) The IFITMs Inhibit Zika Virus Replication. Cell Rep 15:2323-30
Perreira, Jill M; Meraner, Paul; Brass, Abraham L (2016) Functional Genomic Strategies for Elucidating Human-Virus Interactions: Will CRISPR Knockout RNAi and Haploid Cells? Adv Virus Res 94:1-51
Chin, Christopher R; Perreira, Jill M; Savidis, George et al. (2015) Direct Visualization of HIV-1 Replication Intermediates Shows that Capsid and CPSF6 Modulate HIV-1 Intra-nuclear Invasion and Integration. Cell Rep 13:1717-31
Tripathi, Shashank; Pohl, Marie O; Zhou, Yingyao et al. (2015) Meta- and Orthogonal Integration of Influenza ""OMICs"" Data Defines a Role for UBR4 in Virus Budding. Cell Host Microbe 18:723-35
Perreira, Jill M; Aker, Aaron M; Savidis, George et al. (2015) RNASEK Is a V-ATPase-Associated Factor Required for Endocytosis and the Replication of Rhinovirus, Influenza A Virus, and Dengue Virus. Cell Rep 12:850-63
Desai, Tanay M; Marin, Mariana; Chin, Christopher R et al. (2014) IFITM3 restricts influenza A virus entry by blocking the formation of fusion pores following virus-endosome hemifusion. PLoS Pathog 10:e1004048
Zhu, Jian; Davoli, Teresa; Perriera, Jill M et al. (2014) Comprehensive identification of host modulators of HIV-1 replication using multiple orthologous RNAi reagents. Cell Rep 9:752-66
Lin, Tsai-Yu; Chin, Christopher R; Everitt, Aaron R et al. (2013) Amphotericin B increases influenza A virus infection by preventing IFITM3-mediated restriction. Cell Rep 5:895-908
John, Sinu P; Chin, Christopher R; Perreira, Jill M et al. (2013) The CD225 domain of IFITM3 is required for both IFITM protein association and inhibition of influenza A virus and dengue virus replication. J Virol 87:7837-52

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