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Integration of the tricarboxylic acid (TCA) cycle with cAMP signaling and Sfl2 pathways in the regulation of CO2 sensing, filamentation, and virulence in Candida albicans

ABSTRACT: Candida albicans is the most common opportunistic fungal pathogen of humans and is also a benign member of the gastrointestinal (GI) tract microbiota. Morphological transitions and metabolic regulation are critical for C. albicans to adapt to the changing host environment. We generated a library of central metabolic pathway mutants in the tricarboxylic acid (TCA) cycle, and investigated the functional consequences of these gene deletions on C. albicans biology. Inactivation of the TCA cycle impairs the ability of C. ablicans to utilize non-fermentable carbon sources and dramatically attenuates cell growth rates under several culture conditions. Through integrations with the Ras1-cAMP signaling pathway and the heat shock factor-type transcription regulator Sfl2, we found that the TCA cycle plays fundamental roles in the regulation of CO2 sensing and filamentation. The TCA cycle and cAMP signaling pathways form a regulatory feedback loop, in which ATP and CO2 may function as molecular linkers. We further demonstrate that inactivation of the TCA cycle leads to lowered intracellular ATP and cAMP levels and thus affects the activation of the Ras1-regulated cAMP signaling pathway. In turn, the Ras1-cAMP signaling pathway controls the TCA cycle through both Efg1- and Sfl2-mediated transcriptional regulation in response to elevated CO2 levels. The protein kinase A (PKA) catalytic subunit Tpk1, but not Tpk2, may play a major role in this regulation. Sfl2 specifically binds to several TCA cycle and filamentation-associated genes under high CO2 conditions. Global transcriptional profiling experiments indicate that Sfl2 is indeed required for the gene expression changes occurring in response to these elevated CO2 levels. Finally, we also demonstrate that several key genes of the TCA cycle are essential for virulence and successful colonization of the GI tract in two mouse infection models.

ORGANISM(S): Candida albicans

PROVIDER: GSE102039 | GEO | 2017/10/04

SECONDARY ACCESSION(S): PRJNA396454

REPOSITORIES: GEO

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Project description:Candida albicans and Candida dubliniensis are closely related species displaying differences in virulence and genome content, therefore providing potential opportunities to identify novel C. albicans virulence genes. C. albicans gene arrays were used for comparative analysis of global gene expression in the two species in reconstituted human oral epithelium (RHE). C. albicans (SC5314) showed upregulation of hypha-specific and virulence genes within 30 min postinoculation, coinciding with rapid induction of filamentation and increased RHE damage. C. dubliniensis (CD36) showed no detectable upregulation of hypha-specific genes, grew as yeast, and caused limited RHE damage. Several genes absent or highly divergent in C. dubliniensis were upregulated in C. albicans. One such gene, SFL2 (orf19.3969), encoding a putative heat shock factor, was deleted in C. albicans. ÎÎsfl2 cells failed to filament under a range of hypha-inducing conditions and exhibited greatly reduced RHE damage, reversed by reintroduction of SFL2 into the ÎÎsfl2 strain. Moreover, SFL2 overexpression in C. albicans triggered hyphal morphogenesis. Although SFL2 deletion had no apparent effect on host survival in the murine model of systemic infection, ÎÎsfl2 strain-infected kidney tissues contained only yeast cells. These results suggest a role for SFL2 in morphogenesis and an indirect role in C. albicans pathogenesis in epithelial tissues. Global gene expression in Candida albicans SC5314 or Candida dubliniensis CD36 on reconstituted human oral epithelium (RHE) 90 min postinoculation. Gene expression on RHE was compared to gene expression on polycarbonate filter (PCF; used as RHE support matrix) 90 min postinoculation. Performed in two biological replicates with reciprocal dye swaps for each biological replicate. Gene expression of Candida cells on RHE was normalized to gene expression in reference control (PCF); log2 ratios were calculated by dividing spot intensity of experimental by that of the reference control.

Project description:Candida albicans and Candida dubliniensis are closely related species displaying differences in virulence and genome content, therefore providing potential opportunities to identify novel C. albicans virulence genes. C. albicans gene arrays were used for comparative analysis of global gene expression in the two species in reconstituted human oral epithelium (RHE). C. albicans (SC5314) showed upregulation of hypha-specific and virulence genes within 30 min postinoculation, coinciding with rapid induction of filamentation and increased RHE damage. C. dubliniensis (CD36) showed no detectable upregulation of hypha-specific genes, grew as yeast, and caused limited RHE damage. Several genes absent or highly divergent in C. dubliniensis were upregulated in C. albicans. One such gene, SFL2 (orf19.3969), encoding a putative heat shock factor, was deleted in C. albicans. ÎÎsfl2 cells failed to filament under a range of hypha-inducing conditions and exhibited greatly reduced RHE damage, reversed by reintroduction of SFL2 into the ÎÎsfl2 strain. Moreover, SFL2 overexpression in C. albicans triggered hyphal morphogenesis. Although SFL2 deletion had no apparent effect on host survival in the murine model of systemic infection, ÎÎsfl2 strain-infected kidney tissues contained only yeast cells. These results suggest a role for SFL2 in morphogenesis and an indirect role in C. albicans pathogenesis in epithelial tissues. Global gene expression in Candida albicans SC5314 or Candida dubliniensis CD36 on reconstituted human oral epithelium (RHE) 30 min postinoculation. Gene expression on RHE was compared to gene expression in cells used as inoculum (0 min). Performed in three biological replicates with dye swaps across the biological replicates. Gene expression of Candida cells on RHE was normalized to gene expression in reference control (0 min); log2 ratios were calculated by dividing spot intensity of experimental by that of the reference control.

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Integration of the tricarboxylic acid (TCA) cycle with cAMP signaling and Sfl2 pathways in the regulation of CO2 sensing, filamentation, and virulence in Candida albicans

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