Date of Award
Doctor of Philosophy
Marian L. Kohut
Influenza virus is a negative sense, single stranded RNA virus that can cause severe respiratory tract infections in humans (along with other host animals such as horses, swine and poultry). Certain populations such as very young children, aged individuals, pregnant women and immunosuppressed individuals are more susceptible to influenza infections. One reason for the increased susceptibility to infection in the aged is a decreased efficacy of the seasonal influenza vaccine. As this particular section of our population continues to increase worldwide, research to improve vaccine efficacy is expanding along with efforts to identify lifestyle changes and interventions that can improve the immune response to vaccination. For these purposes, it is important to understand the mechanism by which age affects the immune response. Multiple age-related defects in T-cell or B-cell response to influenza infection have been well documented, but the impact of age on innate host defense to influenza is not well-characterized. Defects of the early innate host antiviral pathways have not been studied in depth and could impact early host defense as well as appropriate activation of adaptive immunity. The aim of the study conducted in chapter 2 was to identify age-associated alterations of innate recognition/response to influenza virus. The results identified an impairment of innate defense proteins and Toll Like Receptor signaling molecules in lungs of healthy old mice compared to young mice. The study also confirmed the presence of a chronic low level inflammation in the lungs usually systemically associated with aging. Mice infected with influenza virus elicited an impaired and possibly delayed anti-viral response to the virus.
It has been suggested that exercise can modulate the immune response to various respiratory pathogens. Physical activity may be beneficial for the immune response to pathogens and infections in aged immune systems by decreasing morbidity and mortality. In chapter 3, we studied the potential impact of exercise on innate immune pathogen recognition and anti-viral responses. We used a model of chronic, regular moderate exercise in comparison to no exercise to assess alterations in the immune response to influenza virus infection. An exercise-associated reduction of lung viral load was observed in aged exercised-treated mice that were infected with influenza virus as compared to aged non-exercised mice. The results from this chapter indicated that early host innate defenses were altered by exercise training and may lead to the decreased viral load early during the course of influenza infection.
In chapter 4, the acute effects of a single session of exercise were studied in lungs of young mice. This was done in order to identify an effect of exercise on the activation of stress or host defense pathways given that the response of lung tissue to exercise is not well known, as compared to the effect of exercise on other tissues such as cardiac or skeletal muscle. Activation of stress response or altered cellular defense pathways and immune cell populations could affect the lung response to a pathogen such as influenza virus. In our results we discovered that acute exercise resulted in heat shock protein response as well as activation of several genes associated with regulation of inflammation. The effects of chronic exercise on the same stress response was also studied, resulting in a down-regulation of heat shock proteins, and no change in expression of genes associated with apoptosis or inflammation. Exercise training may cause a shift of CD45 positive leukocytes from the BAL into the lungs as the CD45+ population decreased in the BAL, but increased in the lung. Taken together, these changes suggest that exercise training may promote an anti-inflammatory environment in the lung. We speculate that exercise training may cause the lung tissue to adapt to stress and downregulate the heat shock response and any inflammation caused due to exercise. A shift in immune cells from BALF to lungs may explain our previous findings of reduced viral titer and decreased inflammation with influenza infection in exercise trained mice.
Naik, Shibani, "Immunosenescence and exercise-mediated modulation of the innate immune response to Influenza infection in mice" (2013). Graduate Theses and Dissertations. 13342.