title: Salmonella require the fatty acid regulator PPARδ for the establishment of a metabolic environment essential for long-term persistence.
abstract: Host-adapted Salmonella strains are responsible for a number of disease manifestations in mammals, including an asymptomatic chronic infection in which bacteria survive within macrophages located in systemic sites. However, the host cell physiology and metabolic requirements supporting bacterial persistence are poorly understood. In a mouse model of long-term infection, we found that S. typhimurium preferentially associates with anti-inflammatory/M2 macrophages at later stages of infection. Further, PPARδ, a eukaryotic transcription factor involved in sustaining fatty acid metabolism, is upregulated in Salmonella-infected macrophages. PPARδ deficiency dramatically inhibits Salmonella replication, which is linked to the metabolic state of macrophages and the level of intracellular glucose available to bacteria. Pharmacological activation of PPARδ increases glucose availability and enhances bacterial replication in macrophages and mice, while Salmonella fail to persist in Pparδ null mice. These data suggest that M2 macrophages represent a unique niche for long-term intracellular bacterial survival and link the PPARδ-regulated metabolic state of the host cell to persistent bacterial infection.
authors: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Nicholas A
authors: NA
authors: Eisele
authors: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Thomas
authors: T
authors: Ruby
authors: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Amanda
authors: A
authors: Jacobson
authors: Department of Microbiology and Immunology, Program in Microbial Pathogenesis and Host Defense. University of California San Francisco, San Francisco, CA 94143, USA.
authors: Paolo S
authors: PS
authors: Manzanillo
authors: Department of Microbiology and Immunology, Program in Microbial Pathogenesis and Host Defense. University of California San Francisco, San Francisco, CA 94143, USA.
authors: Jeffery S
authors: JS
authors: Cox
authors: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Lilian
authors: L
authors: Lam
authors: Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143, USA.
authors: Lata
authors: L
authors: Mukundan
authors: Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143, USA.
authors: Ajay
authors: A
authors: Chawla
authors: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Denise M
authors: DM
authors: Monack
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D054884:Host-Pathogen Interactions; D008264:Macrophages / Q000382:microbiology*; D051379:Mice; D050296:Microbial Viability; D047494:PPAR delta / Q000378:metabolism*; D012481:Salmonella Infections, Animal; D012486:Salmonella typhimurium / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*
chemical_list: D047494:PPAR delta; D005947:Glucose
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