Study of the communication between receptors, and their signaling pathways, in fungus-induced cytokine secretion in epithelial cells

Abstract

During an infection, epithelial cells interact with pathogens or their products, and can secrete cytokines and chemokines, these molecules, in turn, modulate the immune system. Paracoccidioides brasiliensis and Histoplasma capsulatum are two dimorphic fungi that cause systemic mycoses in humans. Recently, we found that both species induce the secretion of IL-6 and IL-8 cytokines in human lung epithelial cells A549. And besides, this secretion is dependent on integrins, protease-activated receptors (PARs), and activation of the kinases p38 MAPK, ERK 1/2 and PKC delta. This project aims to study the interaction between receptors that can lead to modulation of secretion of IL-6 and IL-8 cytokines during infection of epithelial cells with P. brasiliensis or H. capsulatum yeasts. Using different methodologies, integrin alpha 3 and alpha 5, Toll-like receptor 2 (TLR), TLR4, dectin-1 and PARs will be analyzed to identify whether these receptors: i) interact with each other, ii) are recruited to membrane rafts, iii ) are important in the modulation of protein expression of other receptors (e.g., the interaction of the fungus with TLR2 stimulates the expression of dectin-1), and iv) are involved in cytokine secretion by epithelial cells. Moreover, it is also analyzed how communication is established between the signaling pathways of these receptors, and which microRNAs modulate these pathways. Together, these results will elucidate some mechanisms by which pathogenic fungi promote cytokine secretion in epithelial cells, and we also understand some processes that are used by these cells for host defense. (AU)