Comparative Genomic Analysis of Human Fungal Pathogens Causing Paracoccidioidomycosis

Abstract

Paracoccidioides is a fungal pathogen and the cause of paracoccidioidomycosis, a health-threatening human systemic mycosis endemic to Latin America. Infection by Paracoccidioides, a dimorphic fungus in the order Onygenales, is coupled with a thermally regulated transition from a soil-dwelling filamentous form to a yeast-like pathogenic form. To better understand the genetic basis of growth and pathogenicity in Paracoccidioides, we sequenced the genomes of two strains of Paracoccidioides brasiliensis (Pb03 and Pb18) and one strain of Paracoccidioides lutzii (Pb01). These genomes range in size from 29.1 Mb to 32.9 Mb and encode 7,610 to 8,130 genes. To enable genetic studies, we mapped 94% of the P. brasiliensis Pb18 assembly onto five chromosomes. We characterized gene family content across Onygenales and related fungi, and within Paracoccidioides we found expansions of the fungal-specific kinase family FunK1. Additionally, the Onygenales have lost many genes involved in carbohydrate metabolism and fewer genes involved in protein metabolism, resulting in a higher ratio of proteases to carbohydrate active enzymes in the Onygenales than their relatives. To determine if gene content correlated with growth on different substrates, we screened the non-pathogenic onygenale Uncinocarpus reesii, which has orthologs for 91% of Paracoccidioides metabolic genes, for growth on 190 carbon sources. U. reesii showed growth on a limited range of carbohydrates, primarily basic plant sugars and cell wall components; this suggests that Onygenales, including dimorphic fungi, can degrade cellulosic plant material in the soil. In addition, U. reesii grew on gelatin and a wide range of dipeptides and amino acids, indicating a preference for proteinaceous growth substrates over carbohydrates, which may enable these fungi to also degrade animal biomass. These capabilities for degrading plant and animal substrates suggest a duality in lifestyle that could enable pathogenic species of Onygenales to transfer from soil to animal hosts.

Latent homology and convergent regulatory evolution underlies the repeated emergence of yeasts

“…On the basis of the previously reported roles of Zn-cluster TFs, we hypothesize that the expansion of this gene family contributes to the suppression of filamentous forms throughout the life cycle and under different conditions. In support of this, Zn-binding protein families (including Zn-cluster TFs) have been found to have expanded independently in Paracoccidioides immitis also, another dimorphic fungus 23 with a well-developed yeast phase.…”

Snake fungal disease: an emerging threat to wild snakes

“…Fungi within Onygenales show significant genomic adaptations for using animal substrates [27]. The virulence factors possessed by O. ophiodiicola have not been fully characterized, but Allender et al [11] demonstrated that O. ophiodiicola has gelatinase, b-glucosidase, lipase, esterase, urease and keratinase activities in vitro.…”

Evolutionary Perspectives on Human Fungal Pathogens

“…When genomes of three Paracoccidioides strains became available, they were added to the analyses, again finding a loss of genes involved in metabolizing carbohydrates in these species (Desjardins et al 2011). These authors also experimented with the growth of U. reesii on 190 carbon substrates, including carbohydrates and proteins.…”