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Relative roles of Stp1 and Stp2 in amino acid and peptide utilization in Candida albicans

ABSTRACT: Candida albicans is a member of the normal commensal flora with the ability to cause disease in susceptible individuals. Nutrient acquisition is of central importance for C. albicans to colonize and thrive in the host. We have previously assessed the role of amino acid utilization for growth and manipulation of pH, triggering the filamentation program and promoting immune evasion. While the role of amino acids has been largely studied, protein utilization has remained less well understood. We investigated the utilization of peptides as a source of carbon and to support the neutralization phenomena. We found that both transcription factors Stp1 and Stp2 are required for proper peptide utilization in a manner dependent of amino acid sensing signaling involving the SPS system. However, we found that Stp2 is the major contributor for this process. Epistasis experiments shown that Stp1 partially restores the ability to utilize peptides in the absence of amino acid signaling, whilst Stp2 is sufficient to fully restore this phenotype. Transcriptomic analysis revealed that the response to amino acids and peptides is very similar, but peptides represent a more difficult carbon source to utilize. It is known that the Stp1/Stp2 duet has divergent roles in C. albicans, however the specific set of genes controlled by each TF remained unclear. We showed that the Stp1 regulon is limited to two oligopeptide transporters (OPT1, OPT9), and iron-acquisition oxidoreductase (CFL2), a nucleoside transporter (NUP) and a leucine aminopeptidase (APE2), whereas Stp2 is responsible for the regulation of amino acid uptake and catabolic genes, in a manner dependent of amino acid sensing. Surprisingly, Stp2 affects expression of genes involved in the filamentation response (e.g. UME6, SFL2) that have been associated with host colonization. In a GI tract competition experiment, mutants lacking the amino acid sensor Ssy1 or the TF Stp2 exhibited decreased colonization, while an stp1Δ/Δ mutant showed increase colonization. Taken together, these results highlight the importance of peptide and amino acid utilization for colonization of the host, a prerequisite for disseminated disease.

ORGANISM(S): Candida albicans SC5314

PROVIDER: GSE145576 | GEO | 2020/02/20

REPOSITORIES: GEO

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Project description:Carbapenem-resistantKlebsiella pneumoniae(CR-Kp) is significant threat to public health worldwide. The primary reservoir for CR-Kp is the intestinal tract, where the bacterium is usually present at low density, but can bloom following antibiotic treatment, mostly in hospital settings. The impact of disturbances in the intestinal environment on the fitness, survival, expansion, and drug susceptibility of this pathogen is not well-understood. Nevertheless, gaining such knowledge could lead to innovative intervention strategies for addressing colonization and infection. Here, we adopted anin vivomodel to examine the transcriptional adaptation of a CR-Kp clinical isolate to immune activation in the intestine. We report that as early as 6 hours following host treatment with anti-CD3 antibody, CR-Kp underwent rapid transcriptional changes including downregulation of genes involved in sugar utilization and amino acid biosynthesis, and upregulation of genes involved in amino acid uptake and catabolism, antibiotic resistance, and stress response. In agreement with these findings, the concentration of oxidative species and amino acids was increased in the mouse intestine following treatment. Genes encoding for proteins containing the domain of unknown function (DUF) 1471 were particularly upregulated, however their deletion did not impair CR-Kp fitness in vivoupon immune activation. Transcription factor enrichment analysis identified the global regulator cAMP-Receptor Protein CRP as a potential orchestrator of the observed transcriptional signature. In keeping with the recognized role of CRP in regulating utilization of alternative carbon sources, CRP deletion in CR-Kp resulted in strongly impaired gut colonization, but this effect was not amplified by immune activation. Thus, following intestinal colonization, which occurs in a CRP-dependent manner, CR-Kp can rapidly respond to immune cues by implementing a well-defined and complex transcriptional program whose direct relevance towards bacterial fitness remains cryptic. Further analyses utilizing this model may identify key factors to tackle the intestinal stage of CR-Kp colonization.

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Relative roles of Stp1 and Stp2 in amino acid and peptide utilization in Candida albicans

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