Abstract

Viral products that interact with host components and that suppress host defense mechanisms are considered important virulence factors. Recently it was shown that the nonstructural protein (NS1) of influenza A virus plays a role in overcoming the type I interferon-mediated antiviral response of the host. In this proposal, the molecular mechanisms by which the NS1 protein inhibits the interferon system will be studied by comparing the phenotypic characteristics of a wild-type influenza A virus with those of a recombinant virus lacking the NS1 gene.
The first aim will address the mechanism resulting in increased interferon synthesis in cells infected with the NS1 deletion virus.
The second aim will examine the inhibitory effects of the NS1 protein on several key components of the type I interferon system in the absence of viral infection. In the third aim the functional contributions of the different domains of the NS1 protein on inhibition of the interferon responses will be examined.
The fourth aim will assess virulence in mice using recombinant influenza viruses containing different mutations their NS1 genes. These recombinant viruses will also be characterized in mice as potential live attenuated vaccines against influenza.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046954-03
Application #
6511210
Study Section
Virology Study Section (VR)
Program Officer
Lambert, Linda C
Project Start
2000-07-01
Project End
2005-05-31
Budget Start
2002-07-01
Budget End
2003-05-31
Support Year
3
Fiscal Year
2002
Total Cost
$278,955
Indirect Cost

  Institution

Name
Mount Sinai School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029

  Publications

Ayllon, Juan; Domingues, Patricia; Rajsbaum, Ricardo et al. (2014) A single amino acid substitution in the novel H7N9 influenza A virus NS1 protein increases CPSF30 binding and virulence. J Virol 88:12146-51
Rajsbaum, Ricardo; García-Sastre, Adolfo; Versteeg, Gijs A (2014) TRIMmunity: the roles of the TRIM E3-ubiquitin ligase family in innate antiviral immunity. J Mol Biol 426:1265-84
Tsai, Pei-Ling; Chiou, Ni-Ting; Kuss, Sharon et al. (2013) Cellular RNA binding proteins NS1-BP and hnRNP K regulate influenza A virus RNA splicing. PLoS Pathog 9:e1003460
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
Weber, Michaela; Gawanbacht, Ali; Habjan, Matthias et al. (2013) Incoming RNA virus nucleocapsids containing a 5'-triphosphorylated genome activate RIG-I and antiviral signaling. Cell Host Microbe 13:336-46
Ramos, Irene; Carnero, Elena; Bernal-Rubio, Dabeiba et al. (2013) Contribution of double-stranded RNA and CPSF30 binding domains of influenza virus NS1 to the inhibition of type I interferon production and activation of human dendritic cells. J Virol 87:2430-40
Rajsbaum, Ricardo; García-Sastre, Adolfo (2013) Viral evasion mechanisms of early antiviral responses involving regulation of ubiquitin pathways. Trends Microbiol 21:421-9
Maamary, Jad; Pica, Natalie; Belicha-Villanueva, Alan et al. (2012) Attenuated influenza virus construct with enhanced hemagglutinin protein expression. J Virol 86:5782-90
Ayllon, Juan; Hale, Benjamin G; García-Sastre, Adolfo (2012) Strain-specific contribution of NS1-activated phosphoinositide 3-kinase signaling to influenza A virus replication and virulence. J Virol 86:5366-70
Zhang, Liang; Das, Priyabrata; Schmolke, Mirco et al. (2012) Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export. J Cell Biol 196:315-26

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