RESUMEN
Pathogen access to host nutrients in infected tissues is fundamental for pathogen growth and virulence, disease progression, and infection control. However, our understanding of this crucial process is still rather limited because of experimental and conceptual challenges. Here, we used proteomics, microbial genetics, competitive infections, and computational approaches to obtain a comprehensive overview of Salmonella nutrition and growth in a mouse typhoid fever model. The data revealed that Salmonella accessed an unexpectedly diverse set of at least 31 different host nutrients in infected tissues but the individual nutrients were available in only scarce amounts. Salmonella adapted to this situation by expressing versatile catabolic pathways to simultaneously exploit multiple host nutrients. A genome-scale computational model of Salmonella in vivo metabolism based on these data was fully consistent with independent large-scale experimental data on Salmonella enzyme quantities, and correctly predicted 92% of 738 reported experimental mutant virulence phenotypes, suggesting that our analysis provided a comprehensive overview of host nutrient supply, Salmonella metabolism, and Salmonella growth during infection. Comparison of metabolic networks of other pathogens suggested that complex host/pathogen nutritional interfaces are a common feature underlying many infectious diseases.
Asunto(s)
Salmonella enterica/patogenicidad , Fiebre Tifoidea/microbiología , Animales , Línea Celular , Modelos Animales de Enfermedad , Femenino , Interacciones Huésped-Patógeno , Redes y Vías Metabólicas , Ratones , Ratones Endogámicos BALB C , Proteómica , Salmonella enterica/genética , Salmonella enterica/metabolismo , Fiebre Tifoidea/metabolismoRESUMEN
Chronic infections caused by persistent pathogens represent an important health problem. Here, we establish a simple practical mouse Salmonella infection model for identifying bacterial maintenance functions that are essential for persistency. In this model, a substantial fraction of Salmonella survived even several days of treatment with a potent fluoroquinolone antibiotic indicating stringency of the model. Evaluation of twelve metabolic defects revealed dramatically different requirements for Salmonella during persistency as compared to acute infections. Disrupted synthesis of unsaturated/cyclopropane fatty acids was the only defect that resulted in rapid Salmonella clearance suggesting that this pathway might contain suitable targets for antimicrobial chemotherapy of chronic infection.
Asunto(s)
Salmonelosis Animal/microbiología , Salmonella/fisiología , 3-Oxoacil-(Proteína Transportadora de Acil) Sintasa/genética , Animales , Recuento de Colonia Microbiana , Modelos Animales de Enfermedad , Femenino , Genes Bacterianos/genética , Cinética , Hígado/microbiología , Hígado/patología , Ratones , Ratones Endogámicos BALB C , Mutación/genética , Fenotipo , Salmonella/enzimología , Salmonella/genética , Salmonella/crecimiento & desarrollo , Salmonelosis Animal/patología , Bazo/microbiología , Bazo/patologíaRESUMEN
BACKGROUND: Metabolic reconstructions (MRs) are common denominators in systems biology and represent biochemical, genetic, and genomic (BiGG) knowledge-bases for target organisms by capturing currently available information in a consistent, structured manner. Salmonella enterica subspecies I serovar Typhimurium is a human pathogen, causes various diseases and its increasing antibiotic resistance poses a public health problem. RESULTS: Here, we describe a community-driven effort, in which more than 20 experts in S. Typhimurium biology and systems biology collaborated to reconcile and expand the S. Typhimurium BiGG knowledge-base. The consensus MR was obtained starting from two independently developed MRs for S. Typhimurium. Key results of this reconstruction jamboree include i) development and implementation of a community-based workflow for MR annotation and reconciliation; ii) incorporation of thermodynamic information; and iii) use of the consensus MR to identify potential multi-target drug therapy approaches. CONCLUSION: Taken together, with the growing number of parallel MRs a structured, community-driven approach will be necessary to maximize quality while increasing adoption of MRs in experimental design and interpretation.