Cigarette smoke (CS) suppresses the immune system, and smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). Exposure to cigarette smoke is associated with a significant increase in the risk for respiratory viral infections. Our work is to understand how CS compromises the human innate immune system's response to influenza virus infection, and to find novel methods to control the infection. Epidemiological studies show that influenza infection is seven times more common and is much more severe in smokers than nonsmokers. Retinoic acid-inducible protein I (RIG-I) plays an important role in the recognition of, and cytokine induction by, influenza virus and other RNA viruses. Our previous studies, using an ex vivo human organ culture model, have found that cigarette smoke extract (CSE) suppresses antiviral and innate immune responses in influenza virus infected human lung through oxidative inhibition of viral-mediated induction of the pattern recognition receptor, RIG-I. This immunosuppressive effect of CS may play a role in the enhanced susceptibility of smokers to serious influenza infection in the lung. We propose to use an in vivo mouse model to study the mechanism by which CS suppresses the expression and function of the RIG-I initiated innate response to influenza virus. The hypothesis of this proposal is that long-term CS impairs the protective RIG-I initiated antiviral response to influenza virus in vivo while RIG-I overexpression and antioxidants provide therapeutic inhibition of immunosuppression from smoking. To test the central hypothesis, we propose to pursue the following integrated specific aims:
AIM 1 : Is RIG-I knockdown by CS responsible for the suppression of the RIG-I initiated antiviral response in CS-exposed mice? AIM 2: Can RIG-I overexpression in mouse lung reverse the CS-mediated suppression of the antiviral response in CS-exposed mice? AIM 3: Can antioxidants restore the RIG-I initiated antiviral response in CS-exposed mice? These studies will significantly enhance our understanding of the mechanism whereby CS suppresses the human immune system and predisposes humans to worse outcomes of influenza virus infection. Determination of the molecular mechanisms of immunosuppression will be important in designing strategies for the development of new and novel treatments for cigarette smoke enhanced lung infections, particularly those due to influenza.

Public Health Relevance

Cigarette smoke (CS) suppresses the immune system, and smoking is a well-known major risk factor for chronic obstructive pulmonary disease and respiratory tract infections. We have shown that cigarette smoke extract (CSE) suppresses antiviral and innate immune responses in influenza virus-infected human lung through oxidative inhibition of viral-mediated induction of the pattern recognition receptor, RIG-I. The present studies will broaden our knowledge of the mechanism whereby CS suppresses the human immune system and also the process that controls influenza virus infection and inflammation due to this pathogen. This will be important in designing strategies for reducing the damage caused by cigarette smoke and for influenza prevention and therapy in veterans.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX001937-01A2
Application #
8821143
Study Section
Respiration (PULM)
Project Start
2014-10-01
Project End
2018-09-30
Budget Start
2014-10-01
Budget End
2015-09-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Oklahoma City VA Medical Center
Department
Type
DUNS #
020719316
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
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