glutathione provides a source of cysteine essential for intracellular multiplication of francisella tularensis谷胱甘肽提供了一种半胱氨酸必不可少的土拉杆菌内的细胞内增殖.pdfVIP

Glutathione Provides a Source of Cysteine Essential for Intracellular Multiplication of Francisella tularensis Khaled Alkhuder1,2, Karin L. Meibom1,2, Iharilalao Dubail1,2, Marion Dupuis1,2, Alain Charbit1,2* ´ ´ ´ ´ ´ ´ 1 Universite Paris Descartes, Faculte de Medecine Necker-Enfants Malades, Paris, France, 2 INSERM, U570, Unite de Pathogenie des Infections Systemiques, Paris, France 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 c-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, c-glutamyl-cysteinyl-glycine) and c-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. Citation: Alkhuder K, Meibom KL, Dubail I, Dupuis M, Charbit A (2009) Glutathione Provides a