title: L-glutamine Induces Expression of Listeria monocytogenes Virulence Genes.
abstract: The high environmental adaptability of bacteria is contingent upon their ability to sense changes in their surroundings. Bacterial pathogen entry into host poses an abrupt and dramatic environmental change, during which successful pathogens gauge multiple parameters that signal host localization. The facultative human pathogen Listeria monocytogenes flourishes in soil, water and food, and in ~50 different animals, and serves as a model for intracellular infection. L. monocytogenes identifies host entry by sensing both physical (e.g., temperature) and chemical (e.g., metabolite concentrations) factors. We report here that L-glutamine, an abundant nitrogen source in host serum and cells, serves as an environmental indicator and inducer of virulence gene expression. In contrast, ammonia, which is the most abundant nitrogen source in soil and water, fully supports growth, but fails to activate virulence gene transcription. We demonstrate that induction of virulence genes only occurs when the Listerial intracellular concentration of L-glutamine crosses a certain threshold, acting as an on/off switch: off when L-glutamine concentrations are below the threshold, and fully on when the threshold is crossed. To turn on the switch, L-glutamine must be present, and the L-glutamine high affinity ABC transporter, GlnPQ, must be active. Inactivation of GlnPQ led to complete arrest of L-glutamine uptake, reduced type I interferon response in infected macrophages, dramatic reduction in expression of virulence genes, and attenuated virulence in a mouse infection model. These results may explain observations made with other pathogens correlating nitrogen metabolism and virulence, and suggest that gauging of L-glutamine as a means of ascertaining host localization may be a general mechanism.
authors.affiliation: Department of Biochemistry, The Bruce and Ruth Rappaport Faculty of Medicine, the Rappaport Institute for Biomedical research, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Haber
authors.affiliation: The Department of Molecular Microbiology and Biotechnology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Sivan
authors.identifier: 0000-0002-5170-808X
authors.initials: S
authors.lastname: Friedman
authors.affiliation: The Department of Molecular Microbiology and Biotechnology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Lobel
authors.affiliation: The Department of Molecular Microbiology and Biotechnology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Burg-Golani
authors.affiliation: The Department of Molecular Microbiology and Biotechnology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Nadejda
authors.initials: N
authors.lastname: Sigal
authors.affiliation: Department of Biochemistry, The Bruce and Ruth Rappaport Faculty of Medicine, the Rappaport Institute for Biomedical research, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Jessica
authors.initials: J
authors.lastname: Rose
authors.affiliation: Department of Biochemistry, The Bruce and Ruth Rappaport Faculty of Medicine, the Rappaport Institute for Biomedical research, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Nurit
authors.initials: N
authors.lastname: Livnat-Levanon
authors.affiliation: Department of Biochemistry, The Bruce and Ruth Rappaport Faculty of Medicine, the Rappaport Institute for Biomedical research, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Oded
authors.initials: O
authors.lastname: Lewinson
authors.affiliation: The Department of Molecular Microbiology and Biotechnology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Anat A
authors.initials: AA
authors.lastname: Herskovits
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology*; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D008089:Listeria monocytogenes / Q000472:pathogenicity*; D008088:Listeriosis / Q000382:microbiology*; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D016297:Mutagenesis, Site-Directed; D016133:Polymerase Chain Reaction; D014774:Virulence / Q000502:physiology*
chemical_list: D005973:Glutamine