BioProject

Cryptococcal meningitis (CM) accounts for nearly 50% of AIDS-related mortality in sub-Saharan Africa (Armstrong-James et al. 2014). Its main aetiological agent, Cryptococcus neoformans var. grubii (Cng), is subdivided into three molecular type, namely VNI, VNII and VNB. The latter remains mostly uncharacterised, although recent studies suggests that Cng VNB infection is more severe (Beale et al. 2015). The present study recovers environmental isolates of this molecular type from southern Africa and explores its relationship with clinical VNB isolates. The population structure was partitioned into four genetically different clusters. Then, a RNA-Seq-based analysis compared environmental and clinical VNB transcriptomes in response to a heat shock highlighting 130 differentially-expressed genes in clinical isolates. In vitro phenotypic experiments supported the hypothesis (p < 0.03) that clinical Cryptococcus neoformans isolates acquired a selective advantage leading to an increased thermotolerance affecting their success inside the human host. Gene network analyses emphasised the role of the cell wall integrity pathway in response to the heat shock as well as other related biological mechanisms including cellular response to oxidative stress, fatty acid-beta oxidation, Golgi apparatus-derived secretory pathway and protein biosynthesis. Selection analyses within the cryptococcal genome identified 19 genes under positive selection which were also upregulated only among clinical VNB isolates. Finally, the study argues that changes in ploidy is a critical asset for the establishment of VNB infection with 70% of clinical isolates presenting with a Chromosomal Copy Number Variations (CCNV) potentially explaining the critical pathogenicity of this highly genetically-divers molecular type.