Constraint-based analysis of metabolic capacity of Salmonella typhimurium during host-pathogen interaction

We have developed and validated a genome-scale metabolic network of Salmonella typhimurium LT2 (iRR1083). This model accounts for 1,083 genes that encode proteins catalyzing 1,087 unique metabolic and transport reactions in the bacterium. We employed flux balance analysis and in silico gene essentiality analysis to investigate growth under a wide range of conditions that mimic in vitro and host cell environments. Gene expression profiling of S. typhimurium isolated from macrophage cell lines was used to constrain the model to predict metabolic pathways that are likely to be operational during infection.Our analysis suggests that there is a robust minimal set of metabolic pathways that is required for successful replication of Salmonella inside the host cell. This model also serves as platform for the integration of high-throughput data. Its computational power allows identification of networked metabolic pathways and generation of hypotheses about metabolism during infection, which might be used for the rational design of novel antibiotics or vaccine strains.Salmonellae are Gram-negative bacterial pathogens with a wide host range. The ability of Salmonella enterica to cause disease is closely correlated with its ability to survive inside its host cells, which include epithelial cells and macrophages [1]. Infection of mice with Salmonella enterica serovar Typhimurium (S. typhimurium) serves as model for the systemic disease typhoid fever. Salmonella strains that are deficient for intra-macrophage survival cannot elicit disease in the mouse model. Many genomic and proteomic datasets exist for Salmonella as a pathogen [2-6]. Most experiments have focused on identifying 'virulence' factors that might drive the disease process, such as surface structures or secreted products. Differential expression of metabolic gene-products has largely been left unexplored in terms of their role in pathogenesis. However, it has now gained more attention that the metabolism of intracell