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Passage through the mammalian gut triggers a phenotypic switch required for Candida albicans commensalism

ABSTRACT: Among ~5,000,000 fungal species on Earth, Candida albicans is exceptional in its lifelong association with humans, where it exists either as a benign component of the gastrointestinal microbiome or as an invasive pathogen. Although it is generally assumed that invasiveness results from a breakdown of host immunity , it is also possible that specific fungal programs control the transition between these divergent lifestyles. Here, we report that exposure of C. albicans to the mammalian gut triggers a developmental switch, driven by the Wor1 transcription factor, to a commensal cell type. Wor1 has been thought to occur only in unique genetic backgrounds, but we show that WOR1 expression is triggered when wild-type cells are propagated in a murine gastrointestinal infection model. Similar to Wor1’s role in a white-opaque switch for mating, WOR1 overexpression within the host induces a novel switch affecting cell and colony morphology and conferring commensal fitness. However, these hyperfit GUT (Gastrointestinally-IndUced Transition) cells lack the functional hallmarks of opaque cells, which they resemble morphologically, whereas bona fide opaque cells are defective for commensalism. Instead, the GUT cell transcriptome is optimized for the environment of the distal mammalian digestive tract. The GUT cell type switch illuminates how a single organism can utilize distinct genetic programs to transition between commensalism and invasive tissue pathogenesis

ORGANISM(S): Candida albicans

PROVIDER: GSE43972 | GEO | 2013/07/28

SECONDARY ACCESSION(S): PRJNA188306

REPOSITORIES: GEO

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Project description:The differentiation of cells into distinct cell types, each of which is heritable for many generations, underlies many biological phenomena. White and opaque cells of the fungal pathogen Candida albicans are two such heritable cell types, each thought to be adapted to unique niches within their human host. To systematically investigate the differences between the two cell types, we performed strand-specific massively-parallel sequencing of RNA from C. albicans white and opaque cells. Combining the resulting data from both cell types, we first substantially re-annotated the C. albicans transcriptome, finding 1443 novel coding and non-coding transcriptionally active regions. Using the new annotation, we compared differences in transcript abundance between the two cell types with the genomic regions bound by the master regulator of the white-opaque switch (Wor1). We found that the revised transcriptional landscape considerably alters our understanding of the circuit governing differentiation. In particular, we can now resolve the poor concordance between binding of the master regulator and the differential expression of adjacent genes, a discrepancy observed in many other studies of cell differentiation. More than one third of the Wor1-bound differentially-expressed transcripts were previously unannotated, which explains the formerly puzzling presence of Wor1 at these positions along the genome. Indeed, many of these newly identified Wor1-regulated genes are non-coding and transcribed antisense to coding transcripts. We also found that 5' and 3' untranslated regions (UTRs) of mRNAs in the circuit are unusually long and that 5' UTRs often differ in length between white and opaque cells. These observations suggest that the use of alternative promoters is widespread in the circuit and that important regulatory information is carried in the long UTRs. Further analysis revealed that the revised Wor1 circuit bears several striking similarities to the Oct4 circuit that specifies the pluripotency of mammalian embryonic stem cells. Additional characteristics shared with the Oct4 circuit suggest a set of general hallmarks characteristic of heritable differentiation states in eukaryotes. RNA-Seq was applied to Candida albicans white and opaque cells to identify novel transcripts and UTRs that are differentially regulated between the two cell types. Two biological replicates each of white and opaque cell cultures. One of the white cell RNA samples was split just after isolation to allow a comparison of the poly(A)-selection and ribo-depletion sample preparation strategies.

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Passage through the mammalian gut triggers a phenotypic switch required for Candida albicans commensalism

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