Characterization of the role of Alt a 1, a fungal effector, in the induction and exacerbation of respiratory inflammatory diseases

Resumen

Asthma is a major chronic inflammatory disease of the airways affecting over 350 million people worldwide. Its prevalence is rapidly increasing since the second half of the 20th century and despite be being the most common chronic disease in children, issues of underdiagnosis and undertreatment persist, especially when it is triggered by allergens. The main objective of this thesis was to study the role of Alternaria alternata in the induction of allergic inflammation. Alternaria is one of the four fungal aeroallergen sources directly associated with the exacerbation of asthma. Thus, the first section of the thesis is focused on the study of the contribution of A. alternata to asthma attacks suffered from grass pollen-allergic patients in a time (early-fall) when grass pollen levels were undetectable. After reproducing the symptomatology in mice and identifying homologous proteins of pollen allergens in the senescent grass material, the results of the study have allowed proposing a new role of the fungal spores as foreign allergen carriers, and, in turn, explaining the origin of co-sensitizations with Alternaria. The second objective of the thesis has focused on the characterization of the immunological role of Alt a 1, a small protein mainly located in the spores, and the only one described as a major allergen of A. alternata. Studies about the interactions of Alt a 1 and bronchial epithelium have led to the identification of an epithelial receptor, SLC22A17, as a mediator of Alt a 1-triggered pro-inflammatory responses when the allergen carries its native ligand, a flavonoid similar to plant quercetin. Later, a mice model of allergic inflammation demonstrated that the ligand presence does not determine the potential of Alt a 1 as a sensitizer, suggesting the implication of other factors in the Alt a 1 recognition. Once the epithelial response seems to be not sufficient for allergen transport and subsequent presentation by antigen-presenting cells (necessary step to trigger Th2 response), the last section of the thesis project sought to study the interactions of Alt a 1 with the other main players of the lung defence barrier, the alveolar macrophages. Summarizing, the results presented in the thesis demonstrate that Alt a 1, by itself, may induce allergic asthma in mice, introducing the contribution of macrophages as potentially key players in the overcoming of the defence barriers by the allergen.