Salmonella enterica Requires Lipid Metabolism Genes To Replicate in Proinflammatory Macrophages and Mice

To survive and replicate during infection, pathogens utilize different carbon and energy sources depending on the nutritional landscape of their host microenvironment. Salmonella enterica serovar Typhimurium is an intracellular bacterial pathogen that occupies diverse cellular niches. While it is clear that Salmonella Typhimurium requires access to glucose during systemic infection, data on the need for lipid metabolism are mixed. We report that Salmonella Typhimurium strains lacking lipid metabolism genes were defective for systemic infection of mice. Bacterial lipid import, β-oxidation, and glyoxylate shunt genes were required for tissue colonization upon oral or intraperitoneal inoculation. In cultured macrophages, lipid import and β-oxidation genes were required for bacterial replication and/or survival only when the cell culture medium was supplemented with nonessential amino acids. Removal of glucose from tissue culture medium further enhanced these phenotypes and, in addition, conferred a requirement for glyoxylate shunt genes. We also observed that Salmonella Typhimurium needs lipid metabolism genes in proinflammatory but not anti-inflammatory macrophages. These results suggest that during systemic infection, the Salmonella Typhimurium that relies upon host lipids to replicate is within proinflammatory macrophages that have access to amino acids but not glucose. An improved understanding of the host microenvironments in which pathogens have specific metabolic requirements may facilitate the development of targeted approaches to treatment.