Pandemic influenza remains an important public liealth concern and a research priority for the Biodefense and Emerging Diseases program of NIAID. This is exemplified by the recent creation of six Centers of Excellence for Influenza Research and Surveillance (CEIRS) funded by NIAID. Although these centers cover important areas in influenza research, studies with the 1918 strain of influenza virus were excluded from these centers. This strain caused a severe pandemia in humans, with more than 40 million persons dying in the world. In 2004, we teamed up under a Program Project Grant an outstanding group of investigators with different expertises, ranging from structural biology to genetics, molecular biology, virology, molecular pathogenesis, animal models of disease, systems biology and biocontainment to better understand the biology of this virus strain. During the past 4 years of support we have sequenced and reconstructed from historical human tissues the 1918 virus. Our research has resulted in significant contributions that increased our knowledge on the structure, biology, host adaptation and pathogenesis of this virus. At the same time, we established novel animal models for studying influenza viruses, such as a non-human primate model of pathogenesis and vaccine efficacy, and a guinea pig model of transmission. Based on our previous studies, we now propose to continue to explore questions of relevance for pandemic influenza using the 1918 virus as a prototype human pandemic influenza virus: How influenza virus induces severe disease? What are the determinants of virulence of the 1918 virus? And of host tropism? How we can use humoral immunity to better prevent influenza virus disease? How host responses shape viral pathogenesis? We have kept the same team of investigators and added new co-PIs and core directors that expanded our previous expertise. We propose that by integrating multiple disciplines we will be able to address the scientific questions of this proposal, and therefore our team includes structural biologists, molecular biologists, virologists, immunologists, pathologists, systems biology experts and bioinformaticians. This integrated view of pandemic influenza virus biology fills a research gap not covered by the CEIRS.

Public Health Relevance

The identification of determinants of virulence and host adaptation of influenza viruses is important for the discovery of possible targets for therapeutic and prophylactic intervention. A limiting factor in this research is the use of safe procedures, trained personnel and adequate facilities. Our multidisciplinary team will nvestigate these determinants using state-of-the-art biocontainment facilities and trained personnel.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI058113-07
Application #
7933901
Study Section
Special Emphasis Panel (ZAI1-CCH-M (M1))
Program Officer
Hauguel, Teresa M
Project Start
2004-07-01
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
7
Fiscal Year
2010
Total Cost
$3,963,191
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Orgel, Kelly A; Duan, Shiteng; Wright, Benjamin L et al. (2017) Exploiting CD22 on antigen-specific B cells to prevent allergy to the major peanut allergen Ara h 2. J Allergy Clin Immunol 139:366-369.e2
Rivera, Andrea; Barr, Tasha; Rais, Maham et al. (2016) microRNAs Regulate Host Immune Response and Pathogenesis During Influenza Infection in Rhesus Macaques. Viral Immunol 29:212-27
McBride, Ryan; Paulson, James C; de Vries, Robert P (2016) A Miniaturized Glycan Microarray Assay for Assessing Avidity and Specificity of Influenza A Virus Hemagglutinins. J Vis Exp :
Cheng, Chu-Wen; Chou, Chi-Chi; Hsieh, Hsiao-Wu et al. (2015) Efficient Mapping of Sulfated Glycotopes by Negative Ion Mode nanoLC-MS/MS-Based Sulfoglycomic Analysis of Permethylated Glycans. Anal Chem 87:6380-8
Yoon, Sun-Woo; Chen, Noam; Ducatez, Mariette F et al. (2015) Changes to the dynamic nature of hemagglutinin and the emergence of the 2009 pandemic H1N1 influenza virus. Sci Rep 5:12828
Riegger, David; Hai, Rong; Dornfeld, Dominik et al. (2015) The nucleoprotein of newly emerged H7N9 influenza A virus harbors a unique motif conferring resistance to antiviral human MxA. J Virol 89:2241-52
de Vries, Robert P; Zhu, Xueyong; McBride, Ryan et al. (2014) Hemagglutinin receptor specificity and structural analyses of respiratory droplet-transmissible H5N1 viruses. J Virol 88:768-73
Wang, Zhen; Chinoy, Zoeisha S; Ambre, Shailesh G et al. (2013) A general strategy for the chemoenzymatic synthesis of asymmetrically branched N-glycans. Science 341:379-83
Laursen, Nick S; Wilson, Ian A (2013) Broadly neutralizing antibodies against influenza viruses. Antiviral Res 98:476-83
Perez, Jasmine T; García-Sastre, Adolfo; Manicassamy, Balaji (2013) Insertion of a GFP reporter gene in influenza virus. Curr Protoc Microbiol Chapter 15:Unit 15G.4

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