Dataset Information

Network-assisted genetic dissection of pathogenicity and drug resistance in the opportunistic human pathogenic fungus Cryptococcus neoformans.

ABSTRACT: Cryptococcus neoformans is an opportunistic human pathogenic fungus that causes meningoencephalitis. Due to the increasing global risk of cryptococcosis and the emergence of drug-resistant strains, the development of predictive genetics platforms for the rapid identification of novel genes governing pathogenicity and drug resistance of C. neoformans is imperative. The analysis of functional genomics data and genome-scale mutant libraries may facilitate the genetic dissection of such complex phenotypes but with limited efficiency. Here, we present a genome-scale co-functional network for C. neoformans, CryptoNet, which covers ~81% of the coding genome and provides an efficient intermediary between functional genomics data and reverse-genetics resources for the genetic dissection of C. neoformans phenotypes. CryptoNet is the first genome-scale co-functional network for any fungal pathogen. CryptoNet effectively identified novel genes for pathogenicity and drug resistance using guilt-by-association and context-associated hub algorithms. CryptoNet is also the first genome-scale co-functional network for fungi in the basidiomycota phylum, as Saccharomyces cerevisiae belongs to the ascomycota phylum. CryptoNet may therefore provide insights into pathway evolution between two distinct phyla of the fungal kingdom. The CryptoNet web server (www.inetbio.org/cryptonet) is a public resource that provides an interactive environment of network-assisted predictive genetics for C. neoformans.

SUBMITTER: Kim H

PROVIDER: S-EPMC4350084 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Network-assisted genetic dissection of pathogenicity and drug resistance in the opportunistic human pathogenic fungus Cryptococcus neoformans.

Kim Hanhae H Jung Kwang-Woo KW Maeng Shinae S Chen Ying-Lien YL Shin Junha J Shim Jung Eun JE Hwang Sohyun S Janbon Guilhem G Kim Taeyup T Heitman Joseph J Bahn Yong-Sun YS Lee Insuk I

Scientific reports 20150305

Cryptococcus neoformans is an opportunistic human pathogenic fungus that causes meningoencephalitis. Due to the increasing global risk of cryptococcosis and the emergence of drug-resistant strains, the development of predictive genetics platforms for the rapid identification of novel genes governing pathogenicity and drug resistance of C. neoformans is imperative. The analysis of functional genomics data and genome-scale mutant libraries may facilitate the genetic dissection of such complex phen ...[more]

PMID: 25739925

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Project description:The Cryptococcus complex consists of at least seven evolutionary divergent lineages and causes ?200,000 fatal human infections each year worldwide. The dominant lineage is Cryptococcus neoformans which consists of three haploid clades VNI, VNII, and VNB, their haploid hybrids, and various diploids derived from intra- and inter-clade mating events. In this study, we analyzed the mitogenomes of 184 strains of C. neoformans. Our analyses revealed that all 184 mitogenomes contained the same 15 protein-coding genes in the same gene order. However, their mitogenome sizes varied between 24,740 and 31,327 bp, primarily due to differences in the number and size of mitochondrial introns. Twelve nucleotide sites within five mitochondrial genes were found to contain introns in at least one of the 184 strains, ranging from 2 to 7 introns within each mitogenome. The concatenated mitochondrial exon sequences of the 15 protein-coding genes and two rRNA genes showed that VNI, VNII, and VNB strains were separated into distinct clades or sub-clades, largely consistent with results based on nuclear genome SNPs. However, several novel findings were observed. First, one strain of the VNB clade contained mitogenome exon sequences identical to the main VNI mitogenome type but was distant to other VNB mitogenomes. Second, hybrids among clades VNI, VNII, and VNB identified based on their nuclear genome SNPs contained mitogenomes from different clades, with evidence of their mitogenomes inherited from either the MAT a or the MAT ? parents. Third, the eight diploid VNB (C. neoformans) × VNIV (C. deneoformans) hybrids contained recombinant mitogenomes. Fourth, analyses of intron distribution and the paired exon-intron phylogenies for each of the 12 exon-intron pairs suggested frequent gains and losses of mitochondrial introns during the evolution of C. neoformans. The combined mitogenome exon-based phylogeny and intron distributions suggested that clades VNI, VNII and VNB could be further divided into sub-clades. Together, our results revealed a dynamic evolution of mitochondrial genomes in this important human fungal pathogen.

Project description:The opportunistic pathogen Cryptococcus neoformans causes fungal meningoencephalitis in immunocompromised individuals. In previous studies, we found that the Hap complex in this pathogen represses genes encoding mitochondrial respiratory functions and tricarboxylic acid (TCA) cycle components under low-iron conditions. The orthologous Hap2/3/4/5 complex in Saccharomyces cerevisiae exerts a regulatory influence on mitochondrial functions, and Hap4 is subject to glucose repression via the carbon catabolite repressor Mig1. In this study, we explored the regulatory link between a candidate ortholog of the Mig1 protein and the HapX component of the Hap complex in C. neoformans. This analysis revealed repression of MIG1 by HapX and activation of HAPX by Mig1 under low-iron conditions and Mig1 regulation of mitochondrial functions, including respiration, tolerance for reactive oxygen species, and expression of genes for iron consumption and iron acquisition functions. Consistently with these regulatory functions, a mig1? mutant had impaired growth on inhibitors of mitochondrial respiration and inducers of ROS. Furthermore, deletion of MIG1 provoked a dysregulation in nutrient sensing via the TOR pathway and impacted the pathway for cell wall remodeling. Importantly, loss of Mig1 increased susceptibility to fluconazole, thus further establishing a link between azole antifungal drugs and mitochondrial function. Mig1 and HapX were also required together for survival in macrophages, but Mig1 alone had a minimal impact on virulence in mice. Overall, these studies provide novel insights into a HapX/Mig1 regulatory network and reinforce an association between mitochondrial dysfunction and drug susceptibility that may provide new targets for the development of antifungal drugs. IMPORTANCE Fungal pathogens of humans are difficult to treat, and there is a pressing need to identify new targets for antifungal drugs and to obtain a detailed understanding of fungal proliferation in vertebrate hosts. In this study, we examined the roles of the regulatory proteins Mig1 and HapX in mitochondrial function and antifungal drug susceptibility in the fungus Cryptococcus neoformans. This pathogen is a particular threat to the large population of individuals infected with human immunodeficiency virus (HIV). Our analysis revealed regulatory interactions between Mig1 and HapX, and a role for Mig1 in mitochondrial functions, including respiration, tolerance for reactive oxygen species, and expression of genes for iron consumption and iron acquisition functions. Importantly, loss of Mig1 increased susceptibility to the antifungal drug fluconazole, which is commonly used to treat cryptococcal disease. These studies highlight an association between mitochondrial dysfunction and drug susceptibility that may provide new targets for the development of antifungal drugs.

Dataset Information

Network-assisted genetic dissection of pathogenicity and drug resistance in the opportunistic human pathogenic fungus Cryptococcus neoformans.

Publications

Network-assisted genetic dissection of pathogenicity and drug resistance in the opportunistic human pathogenic fungus Cryptococcus neoformans.

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