Respiratory viral infections, including seasonal epidemics of influenza A viral infections, remain a significant global public health challenge. Successful recovery from influenza virus infection requires clearance of the virus, resolution of infection-induced inflammation and effective repair of damaged lung epithelium. While multiple studies have demonstrated an essential role for adaptive immunity in controlling viral replication, the processes that promote repair and remodeling of lung epithelial cells following infection-induced damage remain poorly characterized. This proposal will interrogate the influence of innate lymphoid cells (ILCs) on promoting lung epithelial repair following influenza A virus infection. In preliminary studies, we identified a population of ILCs that is found constitutively n the healthy lung of mice and humans. Lung ILCs in mice constitutively express IL-25R, IL-33R and TSLPR and exhibited a significant population expansion following exposure to IL-25, IL-33 or TSLP or following influenza virus infection. Depletion of lung ILCs following influenza virus infection resulted in severely decreased lung function, impaired airway epithelial repair and increased host mortality, indicating a previously unrecognized role for ILCs as regulators of lung tissue homeostasis. Genome-wide transcriptional profiling of murine lung ILCs revealed a transcriptional signature strongly enriched for genes involved in wound healing and tissue repair including the epidermal growth factor (EGF) family member amphiregulin. Critically, delivery of amphiregulin to ILC-depleted mice restored epithelial repair in influenza virus-infected mice. These data provoke the hypothesis that targeting lung ILC responses could be used therapeutically to promote repair and reduce recovery time in multiple lung diseases including influenza virus infection. Employing bone marrow chimeras, selective in vivo cell depletions and manipulation of the IL-25-IL-25R, IL-33-IL-33R, TSLP-TSLPR or EGFR-dependent signaling pathways, two specific aims of this project will determine (i) how the epithelial cell-derived cytokines IL-25, IL-33 and TSLP regulate lung ILC responses;(ii) how ILC-derived amphiregulin and the EGFR pathway contributes to lung epithelial repair following influenza infection. Collectively, these studies will systematically interrogate the role and regulation of ILCs, amphiregulin and EGFR signaling in promoting lung epithelial repair. We anticipate that defining the contribution of lung ILC and the amphiregulin-EGFR pathway to lung epithelial repair will direct future clinical efforts to promote epithelial barrier function and tissue homeostasis in the context of multiple chronic infectious and inflammatory diseases of the respiratory tract.

Public Health Relevance

Respiratory viral infections continue to be a significant global public health and economic challenge. Seasonal epidemics of influenza viral infections alone account for over three million cases of severe illness and 250,000 deaths annually worldwide. While multiple studies have demonstrated an essential role for adaptive immunity in controlling viral replication, the processes that promote repair and remodeling of lung epithelial cells following infection-induced damage remain poorly characterized. This proposal will interrogate the role of innate lymphoid cells in regulating lung tissue repair following influenza virus infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI102942-03
Application #
8918198
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Hauguel, Teresa M
Project Start
2012-12-08
Project End
2017-11-30
Budget Start
2014-09-01
Budget End
2014-11-30
Support Year
3
Fiscal Year
2014
Total Cost
$322,542
Indirect Cost
$132,252
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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