Document Type


Degree Name



Dept. of Molecular Microbiology & Immunology


Oregon Health & Science University


Respiratory virus infections are associated with the majority of asthma attacks in children and adults. Virus infection alters the neural control of the airways. Parasympathetic nerves release the neurotransmitter acetylcholine onto airway smooth muscle, inducing contraction. M2 muscarinic receptors on parasympathetic neurons normally function to limit the release of the acetylcholine. However, virus infection induces M2 receptor dysfunction, which causes more acetylcholine to be released, leading to bronchoconstriction. While virus-­‐induced M2 receptor dysfunction and airway hyperreactivity is well documented, little is known about the cellular mediators and mechanisms mediating these effects. While certain respiratory virus can infect airway neurons, I used mice to demonstrate that influenza and parainfluenza virus infect the airway epithelium, but do not infect airway neurons. I also demonstrated that airway neurons are not infected with parainfluenza virus in guinea pigs (Chapter III). This suggested other cellular mediators released during infection induce changes in neuronal control. Previous work has demonstrated a role for inflammatory mediators in airway hyperreactivity. In animal models, blocking TNF-­‐α prevents M2 receptor dysfunction and airway hyperreactivity after antigen or virus challenge. Blocking IL-­‐1β can prevent airway hyperreactivity in ozone or antigen-­‐challenged animals. In addition, xxi direct virus or TNF-­‐α treatment decreases M2 receptor expression in cultured parasympathetic neurons. Given that virus infection affects M2 receptor function on parasympathetic nerves, I developed a novel dissection technique in guinea pigs to show that parainfluenza virus infection decreased M2 receptor expression in parasympathetic neurons in vivo. This effect was prevented by blocking either TNF-­‐ α or IL-­‐1β (Chapter IV). Using a guinea pig model, I also demonstrated blocking IL-­‐ 1β during parainfluenza virus infection prevented M2 receptor dysfunction (Chapter V). In vitro, I determined IL-­‐1β directly decreases M2 receptor expression in human and guinea pig parasympathetic neurons, and TNF-­‐α is the major contributing factor of IL-­‐1β production (Chapter VI). In summary, I have demonstrated that influenza and parainfluenza virus do not infect sensory neurons or parasympathetic ganglia. I also developed a new dissection technique and showed parainfluenza virus infection indirectly decreased M2 receptor expression in parasympathetic neurons, which is mediated by TNF-­‐α and IL-­‐1β. Moreover, the IL-­‐1β-­‐mediated the loss of M2 receptor expression happens in vivo and in vitro. Furthermore, I demonstrated that blocking IL-­‐1β in vivo prevented the loss of inhibitory M2 receptors during parainfluenza virus infection. The data presented in this thesis provide novel findings in the field of virus-­‐induced M2 receptor function and airway hyperreactivity. These studies provide a new drug target for future therapies and suggest that blocking IL-­‐1β can be a potentially effective treatment for virus-­‐induced asthma exacerbations.




School of Medicine



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