| Autor: |
Oberkampf M; Institut Pasteur, Université Paris Cité, UMR-CNRS 6047, Laboratoire Pathogenèse des Bactéries Anaérobies, F-75015 Paris, France., Hamiot A; Institut Pasteur, Université Paris Cité, UMR-CNRS 6047, Laboratoire Pathogenèse des Bactéries Anaérobies, F-75015 Paris, France., Altamirano-Silva P; Centro de Investigación en Enfermedades Tropicales, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica., Bellés-Sancho P; Institut Pasteur, Université Paris Cité, UMR-CNRS 6047, Laboratoire Pathogenèse des Bactéries Anaérobies, F-75015 Paris, France., Tremblay YDN; Institut Pasteur, Université Paris Cité, UMR-CNRS 6047, Laboratoire Pathogenèse des Bactéries Anaérobies, F-75015 Paris, France., DiBenedetto N; Massachusetts Host-Microbiome Center, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Seifert R; Institute of Pharmacology and Research Core Unit Metabolomics, Hannover Medical School, Hannover, Germany., Soutourina O; Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198 Gif-sur-Yvette, France., Bry L; Massachusetts Host-Microbiome Center, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Clinical Microbiology Laboratory, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA., Dupuy B; Institut Pasteur, Université Paris Cité, UMR-CNRS 6047, Laboratoire Pathogenèse des Bactéries Anaérobies, F-75015 Paris, France., Peltier J; Institut Pasteur, Université Paris Cité, UMR-CNRS 6047, Laboratoire Pathogenèse des Bactéries Anaérobies, F-75015 Paris, France.; Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198 Gif-sur-Yvette, France. |
| Abstrakt: |
To colonize the host and cause disease, the human enteropathogen Clostridioides difficile must sense, respond, and adapt to the harsh environment of the gastrointestinal tract. We showed that the production and degradation of cyclic diadenosine monophosphate (c-di-AMP) were necessary during different phases of C. difficile growth, environmental adaptation, and infection. The production of this nucleotide second messenger was essential for growth because it controlled the uptake of potassium and also contributed to biofilm formation and cell wall homeostasis, whereas its degradation was required for osmotolerance and resistance to detergents and bile salts. The c-di-AMP binding transcription factor BusR repressed the expression of genes encoding the compatible solute transporter BusAA-AB. Compared with the parental strain, a mutant lacking BusR was more resistant to hyperosmotic and bile salt stresses, whereas a mutant lacking BusAA was more susceptible. A short exposure of C. difficile cells to bile salts decreased intracellular c-di-AMP concentrations, suggesting that changes in membrane properties induce alterations in the intracellular c-di-AMP concentration. A C. difficile strain that could not degrade c-di-AMP failed to persist in a mouse gut colonization model as long as the wild-type strain did. Thus, the production and degradation of c-di-AMP in C. difficile have pleiotropic effects, including the control of osmolyte uptake to confer osmotolerance and bile salt resistance, and its degradation is important for host colonization. |
