Glutathione provides a source of cysteine essential for intracellular multiplication of Francisella tularensis
| Autor: | Marion Dupuis, Alain Charbit, Karin L. Meibom, Iharilalao Dubail, Khaled Alkhuder |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
lcsh:Immunologic diseases. Allergy
Immunology Mutant Virulence Biology Microbiology Cell Line Infectious Diseases/Bacterial Infections Tularemia Mice chemistry.chemical_compound Cytosol Virology Escherichia coli Genetics medicine Animals Cysteine Francisella tularensis Molecular Biology lcsh:QH301-705.5 Cysteine metabolism Mice Inbred BALB C Microbial Viability Macrophages Intracellular parasite Genetic Complementation Test Dipeptides gamma-Glutamyltransferase Glutathione medicine.disease biology.organism_classification chemistry lcsh:Biology (General) Genes Bacterial Mutation Female Parasitology lcsh:RC581-607 Intracellular Research Article Plasmids |
| Zdroj: | PLoS Pathogens, Vol 5, Iss 1, p e1000284 (2009) PLoS Pathogens |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | 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 γ-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, γ-glutamyl-cysteinyl-glycine) and γ-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. Author Summary The role of nutrient acquisition systems in survival and multiplication of intracellular bacterial pathogens within infected cells is yet poorly understood. The data presented here suggest that Francisella tularensis, a highly infectious facultative intracellular bacterium, is capable of utilizing glutathione (GSH) and γ–glutamyl-cysteine peptides present in the cytosol of infected host cells. An in vitro negative selection method, based on the use of a bacteriostatic antibiotic, to recover intracellular growth mutants directly from a pool of mutants, allowed us to select one mutant in a gene encoding a γ-glutamyl transpeptidase (GGT). The mutant strain showed impaired intracellular multiplication and was strongly attenuated for virulence in mice. The cleavage of these cysteine-containing peptides by GGT activity provides thus the essential source of cysteine required for intracellular multiplication. The capacity F. tularensis has evolved to utilize GSH, the most abundant source of cysteine in the host cytosol, constitutes a model of bacterial adaptation to intracellular lifestyle. |
| Databáze: | OpenAIRE |
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