The long term objective for this project is to understand the regulatory mechanisms and specific mediators of innate antiviral responses in human lung cells following influenza virus infections. Much is known in general about cellular virus detection by the innate immune system and the inducible gene expression events that accompany the acquisition of cellular and systemic responses. However, individual hosts can demonstrate variability in resistance to infection in a virus-specific or cell-specific fashion. These differential responses are the result of many factors including variable transcriptional responses or post- transcriptional regulation of gene expression at the primary site of infection. This application is designed to elucidate new paradigms for innate cellular responses to influenza virus infection with both basic research and clinical approaches.
One specific aim will examine the hypothesis that post-transcriptional gene regulation modulates canonical antiviral gene expression programs during influenza infections, and will decipher the roles of cytokine- and virus-induced microRNAs by examining their biogenesis and activity in infected lung cell lines.
A second aim will test the hypothesis that differential gene expression in the airway mucosa, the main site of influenza virus infection, relates to severity of clinical presentation of human influenza. Transcriptomes of airway mucosal samples will be analyzed during acute phase and convalescence of human influenza infections to identify novel gene expression patterns and pathways related to severe influenza infections. In addition, comparison of airway mucosal transcriptomes between those predisposed to severe influenza and those who experienced milder disease will identify novel gene expression patterns and pathways related to susceptibility to influenza infections. Together these aims will elucidate new fundamental innate immune mechanisms, provide a more sophisticated understanding of the antiviral response, and potential new targets for antiviral therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI082984-05
Application #
8261138
Study Section
Special Emphasis Panel (ZAI1-BDP-I (J4))
Program Officer
Miller, Lara R
Project Start
2009-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$706,543
Indirect Cost
$261,952
Name
Northwestern University at Chicago
Department
Type
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Mahdavinia, Mahboobeh; Hsu, Joy; Norton, James E et al. (2015) Association of common filaggrin null mutations with atopy but not chronic rhinosinusitis. Ann Allergy Asthma Immunol 114:420-1
Cho, Seong H; Hong, Seung J; Chen, Haimei et al. (2014) Plasminogen activator inhibitor-1 in sputum and nasal lavage fluids increases in asthmatic patients during common colds. J Allergy Clin Immunol 133:1465-7, 1467.e1-2
Buggele, William A; Krause, Katherine E; Horvath, Curt M (2013) Small RNA profiling of influenza A virus-infected cells identifies miR-449b as a regulator of histone deacetylase 1 and interferon beta. PLoS One 8:e76560
Hsu, Joy; Avila, Pedro C; Kern, Robert C et al. (2013) Genetics of chronic rhinosinusitis: state of the field and directions forward. J Allergy Clin Immunol 131:977-93, 993.e1-5
Bruns, Annie M; Pollpeter, Darja; Hadizadeh, Nastaran et al. (2013) ATP hydrolysis enhances RNA recognition and antiviral signal transduction by the innate immune sensor, laboratory of genetics and physiology 2 (LGP2). J Biol Chem 288:938-46
Freaney, Jonathan E; Kim, Rebecca; Mandhana, Roli et al. (2013) Extensive cooperation of immune master regulators IRF3 and NFκB in RNA Pol II recruitment and pause release in human innate antiviral transcription. Cell Rep 4:959-73
Buggele, William A; Horvath, Curt M (2013) MicroRNA profiling of Sendai virus-infected A549 cells identifies miR-203 as an interferon-inducible regulator of IFIT1/ISG56. J Virol 87:9260-70
Nagarkar, Deepti R; Poposki, Julie A; Comeau, Michael R et al. (2012) Airway epithelial cells activate TH2 cytokine production in mast cells through IL-1 and thymic stromal lymphopoietin. J Allergy Clin Immunol 130:225-32.e4
Kumar, Rajesh; Williams, L Keoki; Kato, Atsushi et al. (2012) Genetic variation in B cell-activating factor of the TNF family (BAFF) and asthma exacerbations among African American subjects. J Allergy Clin Immunol 130:996-9.e6
Buggele, William A; Johnson, Karen E; Horvath, Curt M (2012) Influenza A virus infection of human respiratory cells induces primary microRNA expression. J Biol Chem 287:31027-40

Showing the most recent 10 out of 13 publications