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

Abstract

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.

Host restriction, pathogenesis and chronic carriage of typhoidalSalmonella

“…Within monocyte-derived dendritic cells, S. Typhi switches from carbohydrate to lipid consumption (Xu et al 2019). The significance of this is not yet understood, although for S. Typhimurium lipid metabolism is necessary for replication within pro-inflammatory macrophages (Reens, Nagy and Detweiler 2020).…”

Salmonella finds a way: Metabolic versatility of Salmonella enterica serovar Typhimurium in diverse host environments

“…Despite their antibacterial function, M1 macrophages can also provide a site for S. Typhimurium replication [12] (Fig 1). M1 macrophages, also known as "pro-inflammatory" macrophages, produce large quantities of antimicrobials, such as reactive nitrogen species [3].…”

“…The other author SJT has declared that no competing interests exist. the host's glycolytic metabolic program by oxidizing lipids [12]. Lipid transport, β-oxidation, and glyoxylate shunt genes are required for S. Typhimurium to effectively replicate in M1 macrophages and spread to systemic sites [12].…”

“…the host's glycolytic metabolic program by oxidizing lipids [12]. Lipid transport, β-oxidation, and glyoxylate shunt genes are required for S. Typhimurium to effectively replicate in M1 macrophages and spread to systemic sites [12]. Though S. Typhimurium counteracts many of the host's defenses, exposure to NO in infected M1 macrophages still alters S. Typhimurium metabolism.…”

An Oral Fluorouracil Prodrug, Capecitabine, Mitigates a Gram-Positive Systemic Infection in Mice

“…However, prior to rapid replication, bacterial pathogens need to overcome nutritional immunity, a host defense mechanism that restricts microbial access to metabolic building blocks ( 7 ). For example, growth of the human Gram-negative bacterial pathogen S. enterica serovar Typhimurium in mammalian cells is limited by access to amino acids ( 8 , 9 ) and to carbohydrates or lipids ( 10 , 11 ). Bacteria respond to nutritional restrictions by reprograming gene expression and activating diverse metabolic and catabolic pathways that enable virulence ( 12 – 14 ).…”