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ERG6 AFFECTS MEMBRANE COMPOSITION AND VIRULENCE OF THE HUMAN FUNGAL PATHOGEN CRYPTOCOCCUS NEOFORMANS
Ergosterol
Virulence
Membrane sterol composition
Autor(es)
Oliveira, Fabiana Freire M.
Paes, Hugo Costa
Peconick, Luísa Defranco F.
Fonseca, Fernanda L.
Marina, Clara Luna Freitas
Bocca, Anamélia Lorenzetti
Homem-de-Mello, Mauricio
Rodrigues, Marcio Lourenço
Albuquerque, Patricia
Nicola, André Moraes
Alspaugh, J. Andrew
Felipe, Maria Sueli S.
Fernandes, Larissa
Paes, Hugo Costa
Peconick, Luísa Defranco F.
Fonseca, Fernanda L.
Marina, Clara Luna Freitas
Bocca, Anamélia Lorenzetti
Homem-de-Mello, Mauricio
Rodrigues, Marcio Lourenço
Albuquerque, Patricia
Nicola, André Moraes
Alspaugh, J. Andrew
Felipe, Maria Sueli S.
Fernandes, Larissa
Afiliação
University of Brasília, Brasília. Faculty of Medicine. Campus Darcy Ribeiro. Federal District, DF, Brazil.
University of Brasília, Brasília. Faculty of Medicine. Campus Darcy Ribeiro. Federal District, DF, Brazil.
University of Brasília. Faculty of Ceilândia. Campus UnB Ceilândia. Federal District, DF, Brazil.
Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil.
Institute of Biology. Laboratory of Applied Immunology. Federal District, DF, Brazil.
Institute of Biology. Laboratory of Applied Immunology. Federal District, DF, Brazil.
University of Brasília, Brasília. Faculty of Medicine. Campus Darcy Ribeiro. Federal District, DF, Brazil.
Oswaldo Cruz Foundation. Carlos Chagas Institute. Curitiba, PR, Brazil / Federal University of Rio de Janeiro. Microbiology Institute. Rio de Janeiro, RJ, Brazil.
University of Brasília. Faculty of Ceilândia. Campus UnB Ceilândia. Federal District, DF, Brazil.
University of Brasília, Brasília. Faculty of Medicine. Campus Darcy Ribeiro. Federal District, DF, Brazil.
Duke University School of Medicine. Dept. of Medicine Durham. Durham, USA.
Catolic University of Brasilia, Campus Asa Norte, Brasília, Federal District, Brazil
University of Brasília. Faculty of Ceilândia. Campus UnB Ceilândia. Federal District, DF, Brazil / University of Brasília, Brasília. Faculty of Medicine, Campus Darcy Ribeiro. Federal District, DF, Brazil.
University of Brasília, Brasília. Faculty of Medicine. Campus Darcy Ribeiro. Federal District, DF, Brazil.
University of Brasília. Faculty of Ceilândia. Campus UnB Ceilândia. Federal District, DF, Brazil.
Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil.
Institute of Biology. Laboratory of Applied Immunology. Federal District, DF, Brazil.
Institute of Biology. Laboratory of Applied Immunology. Federal District, DF, Brazil.
University of Brasília, Brasília. Faculty of Medicine. Campus Darcy Ribeiro. Federal District, DF, Brazil.
Oswaldo Cruz Foundation. Carlos Chagas Institute. Curitiba, PR, Brazil / Federal University of Rio de Janeiro. Microbiology Institute. Rio de Janeiro, RJ, Brazil.
University of Brasília. Faculty of Ceilândia. Campus UnB Ceilândia. Federal District, DF, Brazil.
University of Brasília, Brasília. Faculty of Medicine. Campus Darcy Ribeiro. Federal District, DF, Brazil.
Duke University School of Medicine. Dept. of Medicine Durham. Durham, USA.
Catolic University of Brasilia, Campus Asa Norte, Brasília, Federal District, Brazil
University of Brasília. Faculty of Ceilândia. Campus UnB Ceilândia. Federal District, DF, Brazil / University of Brasília, Brasília. Faculty of Medicine, Campus Darcy Ribeiro. Federal District, DF, Brazil.
Resumo em Inglês
Ergosterol is the most important membrane sterol in fungal cells and a component not found in the membranes of human cells. We identified the ERG6 gene in the AIDS-associated fungal pathogen, Cryptococcus neoformans, encoding the sterol C-24 methyltransferase of fungal ergosterol biosynthesis. In this work, we have explored its relationship with high-temperature growth and virulence of C. neoformans by the construction of a loss-of-function mutant. In contrast to other genes involved in ergosterol biosynthesis, C. neoformans ERG6 is not essential for growth under permissive conditions in vitro. However, the erg6 mutant displayed impaired thermotolerance and increased susceptibility to osmotic and oxidative stress, as well as to different antifungal drugs. Total lipid analysis demonstrated a decrease in the erg6Δ strain membrane ergosterol content. In addition, this mutant strain was avirulent in an invertebrate model of C. neoformans infection. C. neoformans Erg6 was cyto-localized in the endoplasmic reticulum and Golgi complex. Our results demonstrate that Erg6 is crucial for growth at high temperature and virulence, likely due to its effects on C. neoformans membrane integrity and dynamics. These pathogen-focused investigations into ergosterol biosynthetic pathway components reinforce the multiple roles of ergosterol in the response of diverse fungal species to alterations in the environment, especially that of the infected host. These studies open perspectives to understand the participation of ergosterol in mechanism of resistance to azole and polyene drugs. Observed synergistic growth defects with co-inhibition of Erg6 and other components of the ergosterol biosynthesis pathway suggests novel approaches to treatment in human fungal infections.
Palavras-chave em inglês
Sterol C-24 methyltransferaseErgosterol
Virulence
Membrane sterol composition
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