Effects of Argentilactone on the Transcriptional Profile, Cell Wall and Oxidative Stress of Paracoccidioides spp.

Felipe Souto Araújo,Juliana Alves Parente-Rocha,Maristela Pereira,Alexandre Melo Bailão,Orville Hernández,Cecília Maria Alves De Oliveira,Luciene Melo Coelho,Benedito Rodrigues Da Silva Neto,Gabriel Da Rocha Fernandes,Célia Maria De Almeida Soares,Juan Guillermo Mcewen Ochoa,Lívia Do Carmo Silva,Joseph M Vinetz

doi:10.1371/journal.pntd.0004309

Abstract

Paracoccidioides spp., a dimorphic pathogenic fungus, is the etiologic agent of paracoccidioidomycosis (PCM). PCM is an endemic disease that affects at least 10 million people in Latin America, causing severe public health problems. The drugs used against pathogenic fungi have various side effects and limited efficacy; therefore, there is an inevitable and urgent medical need for the development of new antifungal drugs. In the present study, we evaluated the transcriptional profile of Paracoccidioides lutzii exposed to argentilactone, a constituent of the essential oil of Hyptis ovalifolia. A total of 1,058 genes were identified, of which 208 were up-regulated and 850 were down-regulated. Cell rescue, defense and virulence, with a total of 26 genes, was a functional category with a large number of genes induced, including heat shock protein 90 (hsp90), cytochrome c peroxidase (ccp), the hemoglobin ligand RBT5 (rbt5) and superoxide dismutase (sod). Quantitative real-time PCR revealed an increase in the expression level of all of those genes. An enzymatic assay showed a significant increase in SOD activity. The reduced growth of Pbhsp90-aRNA, Pbccp-aRNA, Pbsod-aRNA and Pbrbt5-aRNA isolates in the presence of argentilactone indicates the importance of these genes in the response of Paracoccidioides spp. to argentilactone. The response of the P. lutzii cell wall to argentilactone treatment was also evaluated. The results showed that argentilactone caused a decrease in the levels of polymers in the cell wall. These results suggest that argentilactone is a potential candidate for antifungal therapy.

Highlights

The genus Paracoccidioides, which comprises the species lutzii and brasiliensis, is the etiological agent of paracoccidioidomycosis (PCM), an important systemic mycosis in Latin America
As part of a continuing search for diverse chemicals from plants, we have examined argentilactone, a bioactive metabolite isolated from Hyptis ovalifolia, which is renowned for its wide range of anticancer, insecticidal and antimicrobial activities [17,18], including those against P. lutzii
We investigated the transcriptional profile of P. lutzii yeast cells grown in the presence of argentilactone using the Illumina/HiseqTM2000 platform (Illumina, San Diego, CA, USA)

Summary

Introduction

The genus Paracoccidioides, which comprises the species lutzii and brasiliensis, is the etiological agent of paracoccidioidomycosis (PCM), an important systemic mycosis in Latin America. PCM has been reported to affect individuals from northern Argentina to southern Mexico, with prevalence in Brazil, Colombia, Venezuela and Argentina. In Brazil, PCM is responsible for over 50% of deaths caused by fungal infections [3]. PCM treatment is a slow process that extends over months or years depending on the severity of the disease and the site of injury [6]. Given these facts, it is important to search for and identify novel antifungals

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Discussion

Conclusion