Publication: Identificación de los mecanismos moleculares involucrados en la morfogénesis de Cryptococcus neoformans y estudio de su función durante la infección
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2018-02-20
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Universidad Complutense de Madrid
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Abstract
Una de las principales características de la mayoría de los hongos es la capacidad de cambiar de morfología. En el caso de hongos patógenos, estos cambios ocurren durante la infección y juegan un papel importante en el desarrollo de la enfermedad. Las transiciones morfológicas pueden ocurrir por formación de hifas y pseudohifas, o por un crecimiento masivo de la blastoconidia. Cryptococcus neoformans es una levadura patógena cuya principal característica es una cápsula de polisacárido. Durante la infección, esta levadura cambia de tamaño sin modificar la forma de la célula. En concreto, este hongo puede incrementar su tamaño mediante dos mecanismos diferentes: aumentando el tamaño de la cápsula, o incrementando el diámetro tanto de la cápsula como del cuerpo celular, dando lugar a células gigantes (diámetro mayor de 30 micras). El principal objetivo de este trabajo es investigar los mecanismos que regulan la morfogénesis en C. neoformans, e intentar esclarecer los factores del huésped que inducen estos cambios. En la primera parte de este trabajo, se evaluó la síntesis de la cápsula utilizando una cepa que expresa el gen CAP59 (necesario para la síntesis capsular), fusionado al promotor regulable GAL7. La síntesis de la cápsula se produjo de manera dispersa y no polarizada. Además, se estudió si el incremento capsular era dependiente de la actividad mitocondrial utilizando para ello inhibidores de la fosforilación oxidativa. Observamos que este fenómeno no ocurría en presencia de inhibidores de los diferentes complejos de la cadena transportadora de electrones como antimicina A, ácido salicilhidroxámico o rotenona. Los resultados obtenidos han mostrado nuevos aspectos sobre la dinámica de aparición y crecimiento de la cápsula y abren nuevas vías de investigación necesarias para entender mejor la biología de la cápsula...
Pathogenic fungi represent a risk to public health because they are a common cause of superficial and invasive diseases. Topical infections, such as colonization of the skin and mucosae affect millons of people. However, in the last decades there has also been an increase in the incidence of invasive fungal infections associated with an increase in the proportion of immunocompromised patients, such as transplant recipients, cancer patients with chemotherapy or radiotherapy. Fungal infections are caused by yeasts and filamentous fungi. The yeasts species that have higher prevalence in humans belong to the genera Candida and Cryptococcus. Infections by filamentous fungi are mainly caused by Aspergillus spp. In addition, there are primary dimorphic fungi (mainly Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum and Paracoccidioides brasiliensis) that may affect immunocompetent individuals. One of the main features of the majority of pathogenic fungi is their ability to change their morphology. These morphological changes occur during infection and play a key role in the development of the disease. Morphological changes in fungi may happen in two different ways: by changing the shape of the cells (such as the formation of hyphae and pseudohyphae), or by changing the size of the cells (i.e., inducing a massive growth of the blastoconidia). The best example of this last change is induced by Cryptococcus neoformans, which is a pathogenic yeast whose main phenotypic feature is the presence of a polysaccharide capsule around the cell body. During infection, this fungus can increase its size in two different ways: by enlarging the size of the capsule without changing the size of the cell body or by increasing both structures resulting in the appearance of blastoconidia of an abnormal enlarged size denominated as “titan cells” (diameter larger than 30 microns). Both changes are very characteristic and contribute to evade the attacks of the immune system. The main objective of this work is to investigate the mechanisms that regulate morphogenesis in C. neoformans, and to delve deeper into the host factors that induce these changes...
Pathogenic fungi represent a risk to public health because they are a common cause of superficial and invasive diseases. Topical infections, such as colonization of the skin and mucosae affect millons of people. However, in the last decades there has also been an increase in the incidence of invasive fungal infections associated with an increase in the proportion of immunocompromised patients, such as transplant recipients, cancer patients with chemotherapy or radiotherapy. Fungal infections are caused by yeasts and filamentous fungi. The yeasts species that have higher prevalence in humans belong to the genera Candida and Cryptococcus. Infections by filamentous fungi are mainly caused by Aspergillus spp. In addition, there are primary dimorphic fungi (mainly Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum and Paracoccidioides brasiliensis) that may affect immunocompetent individuals. One of the main features of the majority of pathogenic fungi is their ability to change their morphology. These morphological changes occur during infection and play a key role in the development of the disease. Morphological changes in fungi may happen in two different ways: by changing the shape of the cells (such as the formation of hyphae and pseudohyphae), or by changing the size of the cells (i.e., inducing a massive growth of the blastoconidia). The best example of this last change is induced by Cryptococcus neoformans, which is a pathogenic yeast whose main phenotypic feature is the presence of a polysaccharide capsule around the cell body. During infection, this fungus can increase its size in two different ways: by enlarging the size of the capsule without changing the size of the cell body or by increasing both structures resulting in the appearance of blastoconidia of an abnormal enlarged size denominated as “titan cells” (diameter larger than 30 microns). Both changes are very characteristic and contribute to evade the attacks of the immune system. The main objective of this work is to investigate the mechanisms that regulate morphogenesis in C. neoformans, and to delve deeper into the host factors that induce these changes...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Microbiología II, leída el 02-02-2017