Modulation of the pulmonary epithelial cell mechanisms by Paracoccidioides

Abstract

Over the past 10 years, our group has been studying the mechanisms involved in cytokine secretion that result from the interaction between human pulmonary epithelial cells and pathogenic fungi of the genus Paracoccidioides. During one of these studies, we found out that P. brasiliensis modulates alfa3 integrin expression in epithelial cells, increasing the expression of this protein in the first five hours of infection. However, after 24 hours of infection, we observed that this fungus promotes a 99% reduction in the levels of this integrin in a Toll-like Receptor 2 (TLR2)-dependent manner. Thus, in order to elucidate the mechanisms involved in this process, after interaction with P. brasiliensis yeasts, we will analyze in human pulmonary epithelial cells the steps of alfa3 integrin degradation, such as ubiquitination and localization of this protein in early or late endosomes. In addition to degradation, we hypothesized that P. brasiliensis can also regulate alfa3 integrin expression levels, which can be modulated by microRNAs. Thus, in this project, miR-124-3p and miR-199 family levels will be analyzed in epithelial cells during infection with P. brasiliensis, since these microRNAs have been described in the literature as modulators of alfa3 integrin levels. In addition to these studies, an in vitro model of pulmonary epithelial barrier will be implemented in our laboratory to study the effect of P. brasiliensis on the integrity of this barrier and the cellular signaling pathways involved in this process. The results of this project will aid in having a better understanding of the cellular mechanisms that promote fungal infection, enabling, in the future, the development of new therapies for systemic mycoses. (AU)