title: Host-pathogen interactions: Host resistance factor Nramp1 up-regulates the expression of Salmonella pathogenicity island-2 virulence genes.
abstract: Nramp1 (Natural resistance-associated macrophage protein-1; also known as Slc11a1) is a host resistance gene that provides protection against several intracellular pathogens, including Salmonella enterica serovar Typhimurium. Little is known about the dynamic interplay that occurs between mammalian host resistance determinants such as Nramp1 and pathogens during infection. To explore these interactions, we examined the effect of Nramp1 on expression of Salmonella typhimurium (STM) virulence factors. We demonstrate that Salmonella pathogenicity island 2 (SPI2) is essential for replication of STM in spleens of infected Nramp1(+/+) mice. Furthermore, the presence of Nramp1 in transfected cell lines and congenic knockout mice resulted in the up-regulation of STM SPI2-associated virulence genes critical for intramacrophage survival. This Nramp1-dependent up-regulation of SPI2 was mimicked in vitro by chelation of iron, demonstrating the iron-responsive nature of expression of STM SPI2-associated virulence genes. We propose that acquisition of SPI2 by S. enterica not only enabled this bacterium to become an effective intracellular pathogen but also allowed the bacterium to withstand the effects of macrophage defense mechanisms such as Nramp1 early in the evolution of its pathogenic character. These dynamic Nramp1-pathogen interactions may be essential for regulating the course of an infection. This study demonstrates the presence of a previously undescribed direct influence of a mammalian innate host resistance locus on a pathogen at the genetic level.
authors.affiliation: Biotechnology Laboratory and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada V6T 1Z3.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Zaharik
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Vallance
authors.forename: Jose L
authors.initials: JL
authors.lastname: Puente
authors.forename: Philippe
authors.initials: P
authors.lastname: Gros
authors.forename: B Brett
authors.initials: BB
authors.lastname: Finlay
mesh_terms: D015082:2,2'-Dipyridyl / Q000494:pharmacology; D000818:Animals; D020296:Animals, Congenic; D001426:Bacterial Proteins / Q000096:biosynthesis* / Q000235:genetics; D027682:Cation Transport Proteins / Q000502:physiology*; D002460:Cell Line; D004492:Edetic Acid / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D005786:Gene Expression Regulation; D015964:Gene Expression Regulation, Bacterial; D007113:Immunity, Innate; D007501:Iron / Q000502:physiology; D007502:Iron Chelating Agents / Q000494:pharmacology; D008264:Macrophages / Q000382:microbiology* / Q000502:physiology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012481:Salmonella Infections, Animal / Q000276:immunology* / Q000382:microbiology; D019779:Salmonella enterica / Q000235:genetics / Q000472:pathogenicity*; D012486:Salmonella typhimurium / Q000235:genetics / Q000472:pathogenicity*; D013154:Spleen / Q000382:microbiology; D014162:Transfection; D014617:Vacuoles / Q000382:microbiology; D014774:Virulence / Q000235:genetics; D000099173:Natural Resistance-associated Macrophage Protein 1
chemical_list: D015082:2,2'-Dipyridyl; D001426:Bacterial Proteins; D027682:Cation Transport Proteins; D004492:Edetic Acid; D004533:Egtazic Acid; D007501:Iron; D007502:Iron Chelating Agents; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D000099173:Natural Resistance-associated Macrophage Protein 1; C440638:SPI-2 protein, Salmonella