Abstract
Systemic dimorphic fungi cause more than one million new infections each year, ranking them among the significant public health challenges currently encountered. Penicillium marneffei is a systemic dimorphic fungus endemic to Southeast Asia. The temperature-dependent dimorphic phase transition between mycelium and yeast is considered crucial for the pathogenicity and transmission of P. marneffei, but the underlying mechanisms are still poorly understood. Here, we re-sequenced P. marneffei strain PM1 using multiple sequencing platforms and assembled the genome using hybrid genome assembly. We determined gene expression levels using RNA sequencing at the mycelial and yeast phases of P. marneffei, as well as during phase transition. We classified 2,718 genes with variable expression across conditions into 14 distinct groups, each marked by a signature expression pattern implicated at a certain stage in the dimorphic life cycle. Genes with the same expression patterns tend to be clustered together on the genome, suggesting orchestrated regulations of the transcriptional activities of neighboring genes. Using qRT-PCR, we validated expression levels of all genes in one of clusters highly expressed during the yeast-to-mycelium transition. These included madsA, a gene encoding MADS-box transcription factor whose gene family is exclusively expanded in P. marneffei. Over-expression of madsA drove P. marneffei to undergo mycelial growth at 37°C, a condition that restricts the wild-type in the yeast phase. Furthermore, analyses of signature expression patterns suggested diverse roles of secreted proteins at different developmental stages and the potential importance of non-coding RNAs in mycelium-to-yeast transition. We also showed that RNA structural transition in response to temperature changes may be related to the control of thermal dimorphism. Together, our findings have revealed multiple molecular mechanisms that may underlie the dimorphic transition in P. marneffei, providing a powerful foundation for identifying molecular targets for mechanism-based interventions.
Highlights
Systemic dimorphic fungi are a group of phylogenetically diverse fungal pathogens which are often geographically restricted but pose an increasing threat to the general population, for immunosuppressed hosts
The mycelium-to-yeast (M-Y) transition is believed to be critical for the pathogenicity of systemic dimorphic fungi because the yeast form is the in vivo cellular form that is capable of evading the host immune system [3], while the yeast-to-mycelium (Y-M)
Over forty genes have been functionally characterized in P. marneffei, yet genetic mechanisms underlying dimorphism remain elusive
Summary
Systemic dimorphic fungi are a group of phylogenetically diverse fungal pathogens which are often geographically restricted but pose an increasing threat to the general population, for immunosuppressed hosts. When transferring between their inhabited environments and human body, morphologic shifts seem necessary for dimorphic fungi to adapt to new circumstance [1]. The phase transitions are regulated by temperature in systemic dimorphic fungi, which take the saprotrophic mycelial form at the lower ambient temperature and the pathogenic yeast form at the higher host body temperature [2]. The recent advent of high-throughput approaches has brought new promise for the utilization of genomic and systematic
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