Functional characterization of genes involved in the survival and intracellular replication of the fungal pathogen Histoplasma capsulatum

Abstract

Histoplasmosis is one of the most important systemic and endemic mycoses in the Americas and the world. The infection begins by inhaling the fungal particles that include the microconidia and small hyphae fragments of Histoplasma spp., which turn into yeast (the pathogenic form) in the lung or by reactivating an inactive focus. Histoplasma spp. it is an intracellular pathogen. Yeast cells produce factors that allow parasitic or invading phagocytic cells, which include macrophages, neutrophils and dendritic cells, and which, in turn, serve not only as host cells, but also as vectors of dissemination. The initial recognition of Histoplasma yeasts is mediated by receptors that are expressed in phagocytic cells, among which are described LFA-1 (CD11a / CD18), CR3 (CD11b / CD18; Mac-1) and CR4 (CD11c / CD18), and its union with adhesins or other molecules present in the fungus wall, this binding process is mainly due to the interaction with the CD18 chain of these receptors. Other receptors include Toll-like receptors (TLRs), type C lectins (Dectin-1) and the mannose receptor (MR), which recognize b-glucans and mannose present in the fungal cell wall, among others. Several mechanisms or strategies allow to neutralize the hostile environment provided by the host, mainly by the cells of the immune system. Histoplasma spp., has the ability to neutralize the stress induced by reactive oxygen species (ROS) and reactive nitrogen species (RNS) produced by the host cells, as well as neutralize the effect of oxidative radicals produced by its own metabolism. It is known that zinc and iron can play an important role in the survival and intracellular proliferation of Histoplasma capsulatum. In this context, the results of this proposal will allow us to obtain fundamental information on the acquisition of micronutrients (iron and zinc), in order to explore new therapeutic strategies and approaches to improve the existing antifungal therapy; as an example to develop specific inhibitors, such as the biosynthesis of siderophores and metal chelators, for therapeutic use alone or in conjunction with existing antifungal drugs (AU)