Time- and position-specific analysis of S. Typhimurium metabolism in the infection process of mice

• Applicant: Dr. Christopher Schubert
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Metabolism, Biochemistry and Genetics of Microorganisms
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 495839694

• Final Report Year: 2024

Final Report Abstract

The carbohydrates that fuel gut colonization by S. Typhimurium are not fully known. To investigate this, we designed a quality-controlled mutant pool to probe the metabolic capabilities of this enteric pathogen. Using WISH-barcoding, we tested 35 metabolic mutants across five different mouse models, allowing us to differentiate between context-dependent and context-independent nutrient sources. Results showed that S. Typhimurium uses D- glucose, D-mannose, D-fructose, and D-galactose as context-independent carbohydrates across all models. The utilization of N-acetylglucosamine and hexuronates, on the other hand, was context-dependent. Furthermore, we showed that D-fructose is important in strainto-strain competition between Salmonella serovars. Complementary experiments confirmed that D-glucose, D-fructose, and D-galactose are excellent niches for S. Typhimurium to exploit during colonization. Quantitative measurements revealed sufficient amounts of D-glucose and D-galactose in the murine cecum to drive S. Typhimurium colonization. Understanding these key substrates and their context-dependent use by enteric pathogens will inform the future design of probiotics and therapeutics to prevent diarrheal infections such as non-typhoidal salmonellosis.

Publications

• Fumarate, a central electron acceptor for Enterobacteriaceae beyond fumarate respiration and energy conservation. Advances in Microbial Physiology, 267-299. Elsevier.
  Schubert, Christopher & Unden, Gottfried
  
• VAAM 2023, Göttingen, Germany. Poster: Carbon utilization of Salmonella Typhimurium in different mouse models
  Schubert, Christopher
  
• Assessing microbiome population dynamics using wild-type isogenic standardized hybrid (WISH)-tags. Nature Microbiology, 9(4), 1103-1116.
  Daniel, Benjamin B. J.; Steiger, Yves; Sintsova, Anna; Field, Christopher M.; Nguyen, Bidong D.; Schubert, Christopher; Cherrak, Yassine; Sunagawa, Shinichi; Hardt, Wolf-Dietrich & Vorholt, Julia A.
  
• IHMC Rome 2024, Rome, Italy. Poster: Carbon utilization of Salmonella Typhimurium in different mouse models and on the family level of Enterobacteriaceae
  Schubert, Christopher
  
• Non-canonical start codons confer context-dependent advantages in carbohydrate utilization for commensal E. coli in the murine gut. Nature Microbiology, 9(10), 2696-2709.
  Cherrak, Yassine; Salazar, Miguel Angel; Näpflin, Nicolas; Malfertheiner, Lukas; Herzog, Mathias K.-M.; Schubert, Christopher; von Mering, Christian & Hardt, Wolf-Dietrich
  
• Regulation of Aerobic Succinate Transporter dctA of E. coli by cAMP-CRP, DcuS-DcuR, and EIIAGlc: Succinate as a Carbon Substrate and Signaling Molecule. Microbial Physiology, 34(1), 108-120.
  Schubert, Christopher & Unden, Gottfried
  
• Salmonella Typhimurium screen identifies shifts in mixed-acid fermentation during gut colonization. Cell Host & Microbe, 32(10), 1758-1773.e4.
  Nguyen, Bidong D.; Sintsova, Anna; Schubert, Christopher; Sichert, Andreas; Scheidegger, Clio; Näf, Jana; Huttman, Julien; Lentsch, Verena; Keys, Tim; Rutschmann, Christoph; Christen, Philipp; Kiefer, Patrick; Keller, Philipp; Barthel, Manja; Cuenca, Miguelangel; Christen, Beat; Sauer, Uwe; Slack, Emma; Vorholt, Julia A. ... & Hardt, Wolf-Dietrich
  
• VAAM 2024, Würzburg, Germany. Talk: Carbon utilization of Salmonella Typhimurium in different mouse models and on the family level of Enterobacteriaceae
  Schubert, Christopher