;The underlying hypothesis of this application is that critical molecular features of host-pathogen interactions and responses dictate the pathogenic outcome of viral infection. Thus, a comprehensive understanding of viral-host interactions, innate responses to viral infection, and viral evasion strategies is pivotal for predictive modeling of viral pathogenesis. Here, we will provide a comprehensive overview ofthe genetic, chemical, and biochemical networks that play a role in controlling influenza virus infection by investigating host-virus interactions in an ex vivo setting using primary human cells. The impact of influenza virus replication on the host will be studied using next generation sequencing technologies to interrogate cellular RNA populations to define transcriptome-level changes (RNA-seq), conduct genome-wide survey of promoters engaged by RNA polymerase (GRO-seq), as well as evaluate epigenetic alterations in the chromosomal landscape (CHiP-seq). Furthermore, global alterations in intracellular and extracellular metabolite levels, protein abundance, as well as post-translational modifications induced upon viral infection will be measured. Combining these approaches with genome-wide functional genomic screening and high-throughput protein interactome analysis will enable the generation of high-resolution networks that accurately depict the hierarchies of interactions between influenza virus and the host. By conducting these analyses simultaneously with three viruses that drive varying pathogenic outcomes, computational modeling of these data will enable us to identify critical nodes ofthe viral-host network that are predictive of viral pathogenesis. The in vivo and clinical impact of these nodes will be evaluated in Projects 2 and 3, respectively.

Public Health Relevance

Developing novel therapies for influenza requires a systems-level understanding ofthe virus-host interactions. Predictive modeling of these networks will enable the identification of disease-relevant therapeutic targets that can be pharmacologically manipulated for clinical efficacy. Towards this end, in this project, we will conduct a series of global and targeted analyses of influenza host-pathogen interactions, and follow these with focused validation studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI106754-02
Application #
8689901
Study Section
Special Emphasis Panel (ZAI1-EC-M)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$798,687
Indirect Cost
$85,353
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Schotsaert, Michael; García-Sastre, Adolfo (2016) A High-Resolution Look at Influenza Virus Antigenic Drift. J Infect Dis 214:982
Hultquist, Judd F; Schumann, Kathrin; Woo, Jonathan M et al. (2016) A Cas9 Ribonucleoprotein Platform for Functional Genetic Studies of HIV-Host Interactions in Primary Human T Cells. Cell Rep 17:1438-1452
Heaton, Nicholas S; Moshkina, Natasha; Fenouil, Romain et al. (2016) Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection. Immunity 44:46-58
Tripathi, Shashank; Garcia-Sastre, Adolfo (2016) Antiviral innate immunity through the lens of systems biology. Virus Res 218:10-7
Muñoz-Moreno, Raquel; Cuesta-Geijo, Miguel Ángel; Martínez-Romero, Carles et al. (2016) Antiviral Role of IFITM Proteins in African Swine Fever Virus Infection. PLoS One 11:e0154366
Rialdi, Alex; Campisi, Laura; Zhao, Nan et al. (2016) Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. Science 352:aad7993
Shah, Priya S; Wojcechowskyj, Jason A; Eckhardt, Manon et al. (2015) Comparative mapping of host-pathogen protein-protein interactions. Curr Opin Microbiol 27:62-8
Ayllon, Juan; García-Sastre, Adolfo (2015) The NS1 protein: a multitasking virulence factor. Curr Top Microbiol Immunol 386:73-107
Cooper, Daphne A; Banerjee, Shuvojit; Chakrabarti, Arindam et al. (2015) RNase L targets distinct sites in influenza A virus RNAs. J Virol 89:2764-76
Miller, Matthew S; Rialdi, Alexander; Ho, Jessica Sook Yuin et al. (2015) Senataxin suppresses the antiviral transcriptional response and controls viral biogenesis. Nat Immunol 16:485-94

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