ArticleJournal of bacteriology2013
The second messenger cyclic Di-GMP regulates Clostridium difficile toxin production by controlling expression of sigD.
Article in Journal of bacteriology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers.
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Who cites it
91 citing papers in PubMed, 130 citations in OpenAlex.
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- Naturally Occurring CodY Variants Alter Ligand Binding, DNA Target Affinity, and Virulence in Clostridioides difficile.Molecular microbiology · 2026Article
- Dissecting the role of flagellar subunits inJournal of bacteriology · 2025Article
- Characterization of two co-regulated response regulators inJournal of bacteriology · 2025Article
- Biofilm Dispersal inMicroorganisms · 2025Article
- Regulatory networks: Linking toxin production and sporulation in Clostridioides difficile.Anaerobe · 2025Review
- The conserved noncoding RNA ModT coordinates growth and virulence in Clostridioides difficile.PLoS biology · 2024Article
- The current riboswitch landscape inMicrobiology (Reading, England) · 2024Review
- Spores of Clostridioides difficile are toxin delivery vehicles.Communications biology · 2024Article
- A conserved switch controls virulence, sporulation, and motility in C. difficile.PLoS pathogens · 2024Article
- Phase Variation of Flagella and Toxins in Clostridioides difficile is Mediated by Selective Rho-dependent Termination.Journal of molecular biology · 2024Article
- Fight or flee, a vital choice formLife · 2024Article
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- Butyrate enhancesJournal of bacteriology · 2023Article
- Biofilm Formation ofMicroorganisms · 2023Review
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- Regulatory transcription factors ofCritical reviews in microbiology · 2023Review
- Network analysis of toxin production in Clostridioides difficile identifies key metabolic dependencies.PLoS computational biology · 2023Article
- Anti-Virulence Strategy of Novel Dehydroabietic Acid Derivatives: Design, Synthesis, and Antibacterial Evaluation.International journal of molecular sciences · 2023Article
31 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The Gram-positive obligate anaerobe Clostridium difficile causes potentially fatal intestinal diseases. How this organism regulates virulence gene expression is poorly understood. In many bacterial species, the second messenger cyclic di-GMP (c-di-GMP) negatively regulates flagellar motility and, in some cases, virulence. c-di-GMP was previously shown to repress motility of C. difficile. Recent evidence indicates that flagellar gene expression is tightly linked with expression of the genes encoding the two C. difficile toxins TcdA and TcdB, which are key virulence factors for this pathogen. Here, the effect of c-di-GMP on expression of the toxin genes tcdA and tcdB was determined, and the mechanism connecting flagellar and toxin gene expressions was examined. In C. difficile, increasing c-di-GMP levels reduced the expression levels of tcdA and tcdB, as well as that of tcdR, which encodes an alternative sigma factor that activates tcdA and tcdB expression. We hypothesized that the C. difficile orthologue of the flagellar alternative sigma factor SigD (FliA; σ(28)) mediates regulation of toxin gene expression in response to c-di-GMP. Indeed, ectopic expression of sigD in C. difficile resulted in increased expression levels of tcdR, tcdA, and tcdB. Furthermore, sigD expression enhanced toxin production and increased the cytopathic effect of C. difficile on cultured fibroblasts. Finally, evidence is provided that SigD directly activates tcdR expression and that SigD cannot activate tcdA or tcdB expression independent of TcdR. Taken together, these data suggest that SigD positively regulates toxin genes in C. difficile and that c-di-GMP can inhibit both motility and toxin production via SigD, making this signaling molecule a key virulence gene regulator in C. difficile.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.