title: Glutathione provides a source of cysteine essential for intracellular multiplication of Francisella tularensis.
abstract: Francisella tularensis is a highly infectious bacterium causing the zoonotic disease tularemia. Its ability to multiply and survive in macrophages is critical for its virulence. By screening a bank of HimarFT transposon mutants of the F. tularensis live vaccine strain (LVS) to isolate intracellular growth-deficient mutants, we selected one mutant in a gene encoding a putative gamma-glutamyl transpeptidase (GGT). This gene (FTL_0766) was hence designated ggt. The mutant strain showed impaired intracellular multiplication and was strongly attenuated for virulence in mice. Here we present evidence that the GGT activity of F. tularensis allows utilization of glutathione (GSH, gamma-glutamyl-cysteinyl-glycine) and gamma-glutamyl-cysteine dipeptide as cysteine sources to ensure intracellular growth. This is the first demonstration of the essential role of a nutrient acquisition system in the intracellular multiplication of F. tularensis. GSH is the most abundant source of cysteine in the host cytosol. Thus, the capacity this intracellular bacterial pathogen has evolved to utilize the available GSH, as a source of cysteine in the host cytosol, constitutes a paradigm of bacteria-host adaptation.
authors.affiliation: Université Paris Descartes, France.
authors.forename: Khaled
authors.initials: K
authors.lastname: Alkhuder
authors.forename: Karin L
authors.initials: KL
authors.lastname: Meibom
authors.forename: Iharilalao
authors.initials: I
authors.lastname: Dubail
authors.forename: Marion
authors.initials: M
authors.lastname: Dupuis
authors.forename: Alain
authors.initials: A
authors.lastname: Charbit
mesh_terms: D000818:Animals; D002460:Cell Line; D003545:Cysteine / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004151:Dipeptides / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics; D005260:Female; D005604:Francisella tularensis / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D005798:Genes, Bacterial; D005816:Genetic Complementation Test; D005978:Glutathione / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D050296:Microbial Viability; D009154:Mutation; D010957:Plasmids; D014774:Virulence; D005723:gamma-Glutamyltransferase / Q000235:genetics / Q000378:metabolism
chemical_list: D004151:Dipeptides; D005723:gamma-Glutamyltransferase; D005978:Glutathione; D003545:Cysteine; C017341:gamma-glutamylcysteine