Aspergillus fumigatus is a ubiquitous fungus that can cause allergic bronchopulmonary aspergillosis (ABPA) in susceptible individuals. The populations at high risk for this disease include patients with cystic fibrosis (CF) and severe asthma. Together, alveolar macrophages, neutrophils and dendritic cells serve to promote both inflammatory and protective responses against Aspergillus. Our preliminary data on mechanisms that trigger Aspergillus-induced pathology suggest important roles for specific cell surface and secreted molecules that together modulate the immune response to Aspergillus. These include cell surface molecules such as dectint on macrophages and DCs, lung expressed surfactant proteins (collectins) and specific cytokines/chemokines (RANTES and IL-12p40) secreted by Aspergillus-stimulated DCs. Also, an early pathogen-expressed molecule, Aspfl, was a poor allergen in vivo even in the context of strong Th2-skewing adjuvants. Interestingly, peptides derived from Aspfl were reported to be tolerogenic in mice. Collectively, these observations lead us to hypothesize that a) interactions between different cell types involving beta glucan on Aspergillus and dectint on host cells and immune defense molecules such as surfactants play an important role in inducing imrhunomodulatory cytokines and chemokines that induce the characteristic eosinophilic inflammation in ABPA and b) tolerance induction to Aspergillus can be achieved using specific pathogen Ags that together with innate defense mechanisms is an important mechanism that prevents unwarranted immune responses against the pathogen. To test these hypotheses we will:
Aim I. Characterize the effect of A. fumigatus on the adaptive immune response and its dependence on specific cell surface components on cells of the immune system (dectin-1 and TLR2).
Aim II. Determine the effect of surfactant D on Aspergillus-induced immune responses.
Aim III. Determine whether repeated exposure to immunodominant peptides derived from Aspfl can induce tolerance to the whole pathogen. Thus, using a variety of molecular, biochemical and immunological approaches and genetically altered mice, our studies will focus on interactions between the pathogen, A. fumigatus, and the host in the induction and prevention of allergic responses to Aspergillus.
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