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Eukaryotic Cell, December 2005, p. 2115-2128, Vol. 4, No. 12
1535-9778/05/$08.00+0     doi:10.1128/EC.4.12.2115-2128.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Transcriptome Analysis of Paracoccidioides brasiliensis Cells Undergoing Mycelium-to-Yeast Transition

Luiz R. Nunes,¹ Regina Costa de Oliveira,¹ Daniela Batista Leite,¹ Vivian Schmidt da Silva,¹ Everaldo dos Reis Marques,² Márcia Eliana da Silva Ferreira,² Diógenes Custódio Duarte Ribeiro,⁵ Luciano Ângelo de Souza Bernardes,² Maria Helena S. Goldman,³ Rosana Puccia,⁴ Luiz R. Travassos,⁴ Wagner L. Batista,⁴ Marina Pasetto Nóbrega,⁵ Francisco G. Nobrega,⁵ Ding-Yah Yang,⁶ Carlos A. de Bragança Pereira,⁷ and Gustavo H. Goldman^2*

Núcleo Integrado de Biotecnologia, Universidade de Mogi das Cruzes, Mogi das Cruzes, Brazil,¹ Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil,² Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil,³ Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, São Paulo, Brazil,⁴ Universidade do Vale do Paraiba, Sao Jose dos Campos, SP, 12244-000, São Paulo, Brazil,⁵ Department of Chemistry, Tunghai University, Taichung, Taiwan,⁶ Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, Brazil⁷

Received 29 June 2005/ Accepted 23 September 2005

Paracoccidioides brasiliensis is a thermodimorphic fungus associated with paracoccidioidomycosis (PCM), a systemic mycosis prevalent in South America. In humans, infection starts by inhalation of fungal propagules, which reach the pulmonary epithelium and transform into the yeast parasitic form. Thus, the mycelium-to-yeast transition is of particular interest because conversion to yeast is essential for infection. We have used a P. brasiliensis biochip carrying sequences of 4,692 genes from this fungus to monitor gene expression at several time points of the mycelium-to-yeast morphological shift (from 5 to 120 h). The results revealed a total of 2,583 genes that displayed statistically significant modulation in at least one experimental time point. Among the identified gene homologues, some encoded enzymes involved in amino acid catabolism, signal transduction, protein synthesis, cell wall metabolism, genome structure, oxidative stress response, growth control, and development. The expression pattern of 20 genes was independently verified by real-time reverse transcription-PCR, revealing a high degree of correlation between the data obtained with the two methodologies. One gene, encoding 4-hydroxyl-phenyl pyruvate dioxygenase (4-HPPD), was highly overexpressed during the mycelium-to-yeast differentiation, and the use of NTBC [2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione], a specific inhibitor of 4-HPPD activity, as well as that of NTBC derivatives, was able to inhibit growth and differentiation of the pathogenic yeast phase of the fungus in vitro. These data set the stage for further studies involving NTBC and its derivatives as new chemotherapeutic agents against PCM and confirm the potential of array-based approaches to identify new targets for the development of alternative treatments against pathogenic microorganisms.

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* Corresponding author. Mailing address: Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café S/N, CEP 14040-903, Ribeirão Preto, São Paulo, Brazil. Phone: 55-16-36024280. Fax: 55-16-36024879. E-mail: ggoldman{at}usp.br.

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Eukaryotic Cell, December 2005, p. 2115-2128, Vol. 4, No. 12
1535-9778/05/$08.00+0     doi:10.1128/EC.4.12.2115-2128.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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