A biologia de Cryptococcus spp.: do remodelamento celular e transcricional ao tratamento

Abstract

Cryptococcus gattii and C. neoformans are the main etiologic agents of cryptococcosis, an invasive mycosis that affects the lungs and can progress to meningoencephalitis. The treatment of the disease involves a limited arsenal of antifungals, associated with high toxicity, cost and induction of resistance, which directly impacts the clinical prognosis. During the interaction with the host, Cryptococcus spp can present different morphologies, ranging from microcells, normal-sized cells to titanic cells. Despite this knowledge, the understanding of morphological reorganization in the initial and late periods of infection remains little explored. In this scenario, this thesis explores the cellular remodeling of Cryptococcus spp. during infection and drug repositioning in the context of Cryptococcosis, through four studies. Study (i) addressed the dynamics of morphological reorganization of Cryptococcus neoformans and C. gattii at different stages of infection. Initially, we observed that the induction of small cells is important for increasing reproductive/energetic fitness, invasion of the pulmonary epithelium and dissemination to the central nervous system. Subsequently, the increase in polysaccharide capsule in vivo was able to predict virulence for C. neoformans, but not for C. gattii. In (ii) we comment on the importance of understanding the role of capsular polysaccharide (PC) from C. gattii in the recognition of Cryptococcus by CD11b and how this knowledge can influence strategies for the development of new vaccines against cryptococcosis. In addition, we present an overview of Cryptococcosis, ranging from the understanding of fungal biology and its interaction in the environment to the currently existing therapeutic and vaccine limitations. Based on the premise of new therapeutic strategies, study (iii) addressed the repositioning of antimalarials (ATMs) in the treatment of Cryptococcosis. We demonstrated that the combination of antimalarials and amphotericin B resulted in a synergistic interaction and increased survival in a murine model. In (iv) we address the effect of sex hormones on the action of clinical antifungals against Cryptococcus spp. Interestingly, we saw that estradiol and testosterone, as well as ATMs, also present synergism with amphotericin B, which may reduce the minimum concentration required for the fungicidal action of this antifungal. In general, the set of data presented in this thesis shows the biological complexity of Cryptococcus during the interaction with the host and the perspective of new treatments that can be used in the scenario of Cryptococcosis.