The importance of understanding the mechanisms of immune protection from the human opportunistic pathogen Aspergillus fumigatus has rapidly increased along with the number of susceptible individuals. Results of published studies suggest that Th1 responses provide the most protection from A. fumigatus infection, while Th2 responses result in increased morbidity and mortality. Recently, we developed a novel infection model utilizing an A. fumigatus isolate that induced Th2-skewed immunity mediated by immune recognition of increased chitin exposure. Using this model, we observed that the presence of eosinophils resulted in increased fungal burden and morbidity in neutropenic mice. These results identified eosinophils as a potential therapeutic target in individuals that respond to A. fumigatus infection with detrimental Th2 immunity. The overall goal of this project is to further define the role of eosinophils in fungal infection and identify the related mechanisms that inhibit the development of protective immunity to A. fumigatus. Our long-term goal is to identify pathways that could be targeted in individuals that respond inappropriately to fungal infection. Our hypothesis is that eosinophil activation promotes immune pathology in A. fumigatus infection. We will compare serum fungal burden and eosinophil activation in aspergillosis patients and experimental animals to determine if a positive correlation exists between serum levels of major basic protein, eosinophil peroxidase, indoleamine 2,3-dioxygenase and Aspergillus galactomannan. Using our mouse model, we will also determine the efficacy of anti-IL-5 therapy by assaying changes in these factors, thus providing a preclinical assessment of the validity of this treatment in aspergillosis patients with detrimental responses to infection. These studies will define critical components in the balance between protective and detrimental immunity following fungal infection, and could also aid in the development of new immune therapies for individuals afflicted with allergy or infection.
Understanding how the immune system senses and responds appropriately to the presence of disease causing fungi is critical for development of new therapies for the treatment/prevention of allergy and infection in susceptible individuals. The study outlined in this proposal will evaluate potential therapies that could enhance protection from infection in vulnerable patients. Thus, we hope our results will ultimately reduce the burden of lung disease in these populations.