Função e regulação de transportadores de ácidos carboxílicos em Candida albicans e C. glabrata e o seu papel na formação de biofilmes, resistência a antifúngicos e fagocitose
Year: 2020
Type: dissertation
Abstract: Candida species are the most frequent opportunistic fungal pathogens in humans and a common source of life-threatening infections in intensive care patients. The urgent need to find adequate therapeutic approaches to treat these infections has boosted the efforts to elucidate the genetic circuits governing immune evasion and host adaptation, but also antifungal resistance in Candida species. This thesis displays a set of studies addressing the physiological impact of two non-fermentable carbon sources commonly found in the human host, namely lactate and acetate, in both C. albicans and C. glabrata. Under certain circumstances, these carboxylic acids represent the main carbon and energy sources that sustain the survival of these pathogens. The efficient uptake of these substrates by regulated plasma membrane transporters play a critical role in such conditions. Therefore, Candida carboxylate transporters were studied regarding their physiology and regulation, as well as their potential role in biofilm formation, antifungal drug resistance and immune recognition. Growth of C. albicans in the presence of lactate was found to affect biofilm formation and morphology, as well as susceptibility to fluconazole. These phenotypes are dependent on Jen1 and Jen2 carboxylate transporters. Adaptation to lactate induces cell wall remodeling, a process that was found to be partially mediated by the Rlm1 transcription factor and to affect the interaction of C. albicans with immune cells. In a second part of the work, global transcriptomic analyses in C. glabrata revealed that fluconazole treatment induces gene expression reprogramming in a carbon source and pH-dependent manner. The mitochondrial cochaperone Mge1 has emerged as a key regulator of fluconazole susceptibility during these conditions, by reducing the metabolic flux towards toxic sterol formation. Additionally, three putative carboxylate transporters of C. glabrata, that belong to the AceTr family, were also studied. These transporters were shown to play a critical role in acetate assimilation and contribute to the persistence of C. glabrata within the human host. The systematic analysis of how host microenvironments influence the physiology of Candida species highlighted important mediators of host-pathogen interactions, such as carboxylate transporters. These proteins allow a rapid adaptation of Candida to the human host, contributing to their pathogenic potential.
Author: Alves, Rosana Maria Abreu
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7084231927