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Principal Investigator: Sebastian E Winter
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2024
Award: $430,673
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Infection with the bacterial pathogen Salmonella enterica serovar Typhimurium (S. Tm) is a common cause of
inflammatory diarrhea. Intriguingly, intestinal inflammation drives an expansion of the S. Tm population in the
gut lumen. The molecular mechanisms that support S. Tm colonization of the intestinal tract remain
incompletely understood. Our central hypothesis is that the inflamed gut constitutes a peculiar nutritional
environment that enables S. Tm to outgrow obligate anaerobic commensal bacteria. We have recently
demonstrated that during the acute phase of the infection, neutrophil-derived electron acceptors facilitate an
oxidative central metabolism in S. Tm. In this application, we hypothesize that S. Tm relies on a branched TCA
cycle for initial gut colonization. In particular, tartaric acid, produced through oxidation of microbiota-liberated
sugars, supports fumarate reduction in the branched TCA cycle. We will test key aspects of our hypothesis by
pursuing the following specific aims: 1.) determine how utilization of D- and L-tartrate contributes to growth of
S. Tm in the lumen of the mammalian large intestine, 2.) determine the origin of tartrate during S. Tm infection,
and 3.) investigate the regulation of tartrate utilization genes in vitro and in vivo. This work will advance our
understanding of how intestinal pathogens, such as S. Tm, adapt their carbon and energy metabolism to
colonize the mammalian intestinal tract. We envision that a better understanding of the mechanisms by which
S. Tm outgrows competing microbes during inflammation will aid the development of new and innovative
approaches for treatment.
Terms: <Abnormal Assessment of Metabolism><Acids><Acute><Address><Animal Disease Models><Animal Model><Animal Models and Related Studies><Bacterial Model><Biochemical><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Carbon><Cell Function><Cell Physiology><Cell Process><Cellular Function><Cellular Physiology><Cellular Process><Citric Acid Cycle><Colitis><Development><Diarrhea><Disease><Disorder><Energy Expenditure><Energy Metabolism><Environment><Epithelium><Equilibrium><Fumarates><GI colonization><GI microbiota><Gastroenteritis><Gastrointestinal microbiota><Generalized Growth><Genes><Genetic><Goals><Growth><Gut Mucosa><Immune response><Immunocompetent><Immunological response><In Vitro><Individual><Infection><Inflammation><Inflammatory><Inflammatory Response><Intermediary Metabolism><Intervention><Intervention Strategies><Intestinal><Intestines><Isomerism><Krebs Cycle><Large Intestine><Lead><Marrow Neutrophil><Medical Care Costs><Metabolic><Metabolic Processes><Metabolic Studies><Metabolism><Metabolism Studies><Methods><Microbe><Modeling><Molecular><Mucosa><Mucosal Tissue><Mucous Membrane><Nature><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Nitrogen><Nutritional><O element><O2 element><Operon><Organism><Oxidants><Oxidizing Agents><Oxygen><Pathogenesis><Pathogenicity Factors><Pathway interactions><Pb element><Phase><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Productivity><Regulation><Repression><Research><Respiration><S enterica><S enterica serovar Typhimurium><S typhimurium><S. enterica><S. enterica Typhimurium><S. enterica serovar Typhimurium><S. typhimurium><Salmonella><Salmonella enterica><Salmonella enterica Typhimurium><Salmonella enterica serovar Typhimurium><Salmonella typhimurium><Serotyping><Subcellular Process><Symptoms><TCA cycle><Tartrates><Testing><Time><Tissue Growth><Toxin><Tricarboxylic Acid Cycle><United States><Variant><Variation><Virulence><Virulence Factors><Work><bacteria metabolism><bacteria pathogen><bacterial metabolism><bacterial pathogen><balance><balance function><bowel><bowel inflammation><colitis mouse model><colitis murine model><commensal bacteria><commensal bacterial species><cost><developmental><diarrheal disease><diarrheal illness><electron acceptor><enteral pathogen><enteric microbial community><enteric microbiota><enteric pathogen><enteropathogen><gastrointestinal microbial flora><gastrointestinal tract colonization><gut colonization><gut commensal><gut community><gut flora><gut inflammation><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiota><gut microbiotic><gut microflora><heavy metal Pb><heavy metal lead><host response><immune competent><immune system response><immunoresponse><in vivo><inflamed bowel><inflamed gut><inflamed intestine><innovate><innovation><innovative><interventional strategy><intestinal colonization><intestinal flora><intestinal inflammation><intestinal microbiota><intestinal microflora><intestinal pathogen><intestinal tract microflora><intestine pathogen><isomer><large bowel><living system><medical costs><medical expenses><metabolic abnormality assessment><microbe pathogen><microbial><microbial consortia><microbial flora><microbial pathogen><microbiota><microbiota composition><microflora><migration><model of animal><mouse colitis><multispecies consortia><murine colitis><neutrophil><non-typhoid Salmonella><non-typhoidal Salmonella><novel><nutritious><ontogeny><oxidation><pathogen><pathogenic bacteria><pathogenic microbe><pathway><rational design><respiratory mechanism><sugar>