Degree Type

Dissertation

Date of Award

2012

Degree Name

Doctor of Philosophy

Department

Theses & dissertations (Interdisciplinary)

Major

Immunobiology

First Advisor

Marian L. Kohut

Abstract

The role exercise plays in the modulation of the immune response has been a topic of interest to exercise immunologists for the last two to three decades. Some important issues that remain to be addressed include exercise-training induced adaptations of immune response, along with the effect of exercise dose on immune function. Results from multiple studies have determined that a high dose of exercise to exhaustion causes immune impairments and a poor infectious disease outcome in animal models. A moderate dose of exercise appears to improve disease outcome to infection. However, the mechanisms by which different doses of exercise affect infectious disease outcome remain to be clearly elucidated. In this dissertation, we used regular moderate exercise as our dose in comparison to no exercise (sedentary controls) to assess alterations in the immune response to influenza virus infection. Studies focused on the impact of moderate exercise training on 1) long-term primary antibody response and secondary antibody response to influenza challenge, 2) resident and recruited memory cell response in the lungs, 3) antigen-presenting cell (APC) function in young and old mice, and 4) immune response to influenza in obese mice. The primary topic of this dissertation was the effect of exercise on immunity. However, there was also an emphasis on the topic of aging and immunity. The results from many studies have shown that aging results in an immune-dysregulated state in the context of the immune response to influenza virus. In this dissertation, the effect of age on interferon-alpha related responses to influenza infection was evaluated.

The first exercise-immunity study (Chapter II) examined the long term effect of exercise on the memory response to influenza A virus. This study showed that levels of serum anti-influenza antibody were reduced in young treadmill-exercised mice. One mechanism that may have been responsible for the exercise-associated reduction in antibody was a decrease in lung viral load, rather than impaired immune function. Support for this possibility include the finding that lung viral load is decreased with exercise at early time points post-infection, and the finding that exercise did not reduce antibody response when virus was administered through an intraperitoneal route. These exercise-associated reductions in antibody, while not detrimental to the host, and were also noted following a secondary lethal challenge with the same strain of influenza A virus. However, as mice were re-challenged with a lethal dose of influenza virus, they showed no clinical signs of illness indicating that the primary antibody response was sufficient to protect the mice from disease. Furthermore, the study showed that characteristics of the memory response were also altered with exercise. The non-dominant subtype of anti-influenza antibody (IgG1) was increased in the exercised mice after re-challenge. However, exercise training prior to the primary infection resulted in reduced numbers specific lung cell populations after rechallenge. The cell populations that were decreased included the influenza specific CD8+ granzyme B+ recruited cells as well as the influenza-specific CD8+ granzyme B+ resident cells. Taken together, our findings suggest that the reduction in CD8+ cells following secondary challenge was due to decreased viral load during the primary infection.

A subsequent study (Chapter III) evaluated the differential effect(s) of exercise on dendritic cell function in aged as compared to young mice infected with influenza virus. In this study, we determined the extent to which exercise may alter the innate or adaptive function of the pulmonary dendritic cells. The dendritic cell is important for recognition of foreign antigen in the respiratory tract and transportation of that antigen to secondary lymph nodes for the development of specific-immunity. The overall results showed that exercise altered dendritic cell function in both young and aged mice, however, the dendritic cell-associated immune response were differentially affected by exercise in the young compared to aged. The conclusions from the dendritic cell study suggest that exercise can have a beneficial effect on various dendritic cells functions even though the effects might be different in a young compared to aged host.

Finally, the effect of exercise on the immune response to influenza A virus (IAV) infection in diet-induced obese mice was evaluated in Chapter V of this dissertation. A higher incidence of viral and bacterial infections has been associated with obesity. Not surprisingly, during the 2009 Influenza pH1N1 outbreak a greater number of individuals with a higher BMI (>30) were hospitalized due to increased morbidity caused by the IAV infection. Studies using the diet-induce obese mouse model have demonstrated an impairment of immune response to IAV infection as compared to lean mice. The purpose of the last study in this dissertation was to determine whether exercise might improve immune responsiveness to IAV in obese mice (similar to our other findings in lean mice). The results showed that exercise improved specific immune responses in obese mice (enhanced immune cell infiltration, Type-I interferon production, influenza-specific CD8+ IFN gamma+ cells numbers). The same immune measures have been shown to be dysregulated in diet-induce obese mice. Overall the findings suggest that exercise can rescue the obesity-related impairments of immune function, although the mechanisms appear to differ in lean as compared to obese mice.

In Chapter IV, the impact of age on immune response was examined. The immunomodulatory effect of interferon alpha in response to influenza A virus (IAV) infection was compared in the young and old. The role of IFN alpha had not been studied to a great extent in the elderly, and the results from our study demonstrate that IFN alpha appears to have different effects in young and aged mice during IAV infection. The effect of anti-IFN alpha treatment had consistent effects in young and old mice with respect to a reduction in IFN alpha-associated gene expression and bronchoalveolar lavage fluid cytokine/chemokine concentration at day 4 p.i., decreased CD8+ cells in the lungs at day 8 p.i., but increased levels of serum anti-influenza IgG and IgG1 antibody at day 8 and 28 p.i.. One of the most interesting findings was that illness severity was reduced in the aged mice that had been treated with neutralizing anti-IFN alpha antibody whereas the young mice had increased illness severity to influenza virus infection when they were treated with neutralizing anti-IFN alpha antibody. Similarly, by day 10 p.i., aged mice treated with antibody had reduced viral loads in the lung whereas antibody-treated young mice had elevated viral loads. The concentration of specific cytokines and chemokines in the bronchoalveolar lavage fluid was altered by anti-IFN alpha treatment, but at day 8 and 10 p.i., the effects were different in young and old mice. Taken together, the findings from this study demonstrate for the first time that the immunomodulatory effects of IFN alpha differ in young and aged mice.

DOI

https://doi.org/10.31274/etd-180810-575

Copyright Owner

Kristi J. Warren

Language

en

File Format

application/pdf

File Size

244 pages

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