Lung pathology is a significant cause of the morbidity and mortality associated with acute respiratory virus infection. Respiratory viruses, such as influenza virus not only cause damage to the epithelium, but activate immune defense mechanisms. Although these immune mechanisms are employed to destroy and remove infected cells in an attempt to clear the virus, they can also promote lung pathology. However, the key cellular and molecular mechanisms that regulate the balance between protection and tissue damage during acute viral infection remain poorly understood. This lack of knowledge severely limits the development of novel therapies to treat the disease. Therefore, understanding the fundamental mechanisms whereby respiratory viral infection induces lung damage is critical for the development of improved therapies for treatment of disease. Our exciting and intriguing preliminary results suggest that the lymphotoxin beta receptor, LTR, a member of the TNFR superfamily, promotes influenza-associated lung damage. The overall objective of this proposal is to define how LT?R controls lung damage associated with influenza infection. Our working hypothesis is that LT?R signaling in respiratory epithelial cells inhibits mucus production during influenza infection allowing for elevated viral replication and increased lung damage. To test this hypothesis, we propose two specific aims.
In Aim 1, we will use biochemical and genetic approaches to determine the impact of LT?R signaling on mucus production and viral replication.
In Aim 2, we will test that LT?R signaling in respiratory epitheial cells is essential to promote lung immunopathology during influenza infection. We propose that LT?R signaling in respiratory epithelial cells promotes viral replication and induction of potent inflammatory responses which cause severe lung damage. Completion of these aims will define the LT?R-dependent mechanisms that contribute to lung damage. The research proposed is significant, because it will provide a deeper understanding of the mechanisms regulating virus-induced immunopathology and will help in developing new immunotherapeutic strategies to control respiratory disease.

Public Health Relevance

Lung pathology induced by acute respiratory viral infection is a significant cause of morbidity and mortality worldwide. The specific aims of this proposal are designed to define the role of lymphotoxin signaling in the pathogenesis of viral-induced lung damage. The proposed research is relevant to public health because it will provide a deeper understanding of the fundamental mechanisms controlling lung damage, and will help in developing new strategies for treating respiratory disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI111000-02
Application #
8994268
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Dong, Gang
Project Start
2015-02-01
Project End
2017-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Trudeau Institute, Inc.
Department
Type
DUNS #
020658969
City
Saranac Lake
State
NY
Country
United States
Zip Code
12983
Koroleva, Ekaterina P; Fu, Yang-Xin; Tumanov, Alexei V (2018) Lymphotoxin in physiology of lymphoid tissues - Implication for antiviral defense. Cytokine 101:39-47