Abstract

Cryptococcus neoformans 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 C. neoformans. To identify genes important for yeast infection and disease progression, we profiled the gene expression of seven C. neoformans isolates grown in five representative in vitro environmental and in vivo 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 in vivo 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 C. neoformans across natural isolates, and provides insights into genes important for in vitro and in vivo growth stages.

Highlights

  • Cryptococcus neoformans can infect the central nervous system (CNS) resulting in life-­threatening cryptococcal meningoencephalitis

  • The results suggest that these Differentially expressed genes (DEGs) might provide an advantage for VNI isolates in their survival within pigeon guano compared to VNBI isolates, as it is likely beneficial for C. neoformans to uptake and utilize uric acid in bird droppings as a nitrogen source [41, 43, 54]

  • This work built on prior studies that collected these isolates and used multilocus sequence typing to characterize the major divisions within this species and the relationship of clinical and environmental isolates [15]

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Summary

Introduction

Cryptococcus neoformans can infect the central nervous system (CNS) resulting in life-­threatening cryptococcal meningoencephalitis. Cryptococcal disease has had an enormous impact on worldwide health-­care systems in the last three decades during the AIDS pandemic. This reached a peak of over one million patients per year resulting in over 600 000 deaths [1]. In the recent era of widespread use of effective antiretroviral therapies, the incidence has been reduced, but still remains high at over 220 000 new cases per year, with mortality rates approaching 50 % [2].

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