Landscape of gene expression variation of natural isolates of Cryptococcus neoformans in response to biologically relevant stresses

Abstract

<i>Cryptococcus neoformans</i> is an opportunistic fungal pathogen that at its peak epidemic levels caused an estimated million cases of cryptococcal meningitis per year worldwide. This species can grow in diverse environmental (trees, soil and bird excreta) and host niches (intracellular microenvironments of phagocytes and free-living in host tissues). The genetic basic for adaptation to these different conditions is not well characterized, as most experimental work has relied on a single reference strain of <i>C. neoformans</i>. To identify genes important for yeast infection and disease progression, we profiled the gene expression of seven <i>C. neoformans</i> isolates grown in five representative <i>in vitro</i> environmental and <i>in vivo</i> conditions. We characterized gene expression differences using RNA-Seq (RNA sequencing), comparing clinical and environmental isolates from two of the major lineages of this species, VNI and VNBI. These comparisons highlighted genes showing lineage-specific expression that are enriched in subtelomeric regions and in lineage-specific gene clusters. By contrast, we find few expression differences between clinical and environmental isolates from the same lineage. Gene expression specific to <i>in vivo</i> stages reflects available nutrients and stresses, with an increase in fungal metabolism within macrophages, and an induction of ribosomal and heat-shock gene expression within the subarachnoid space. This study provides the widest view to date of the transcriptome variation of <i>C. neoformans</i> across natural isolates, and provides insights into genes important for <i>in vitro</i> and <i>in vivo</i> growth stages.