Dataset Information

Importance of arginine trasporter ArgP in Francisella by comparative proteomics.

ABSTRACT: Metabolic adaptation has recently been recognized as a key component of the intracellular life cycle of pathogenic microorganisms. Upon entry into mammalian host cells, Francisella tularensis, a pathogenic bacterium responsible for the zoonotic disease tularemia, rapidly escapes from the phagosome to multiply actively in the cytosolic compartment. Francisella is auxotroph for several amino acids, including arginine, and thus relies exclusively on their import from the host to survive in infected cells. We identified an arginine transporter (hereafter designated ArgP) whose inactivation considerably delayed bacterial phagosomal escape and intracellular multiplication. Remarkably, this defect could be totally suppressed in macrophages and dendritic cells from IRAP-KO mice. Wild-type cytosolic multiplication of the mutant bacteria was restored in these cells, indicating that the ArgP transporter is mainly required for arginine uptake in the phagosomal compartment. Proteomic analyses showed that arginine deprivation in the ∆argP mutant rapidly affected the expression of a numerous proteins, and in particular reduced expression of most of the ribosomal proteins. We propose that regulation of ribosomal protein biogenesis may contribute to the sensing of the intracellular stage of the pathogen and to phagosomal membrane disruption.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Francisella Tularensis Subsp. Novicida (strain U112)

DISEASE(S): Tularemia

SUBMITTER: Chiara guerrera

LAB HEAD: Ida Chiara GUERRERA

PROVIDER: PXD001584 | Pride | 2015-01-28

REPOSITORIES: Pride

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			Action	DRS
	20141119_AlCH_1WT_20_2h_n3_1_1200.raw	Raw
	20141119_AlCH_1WT_20_2h_n3_2_1201.raw	Raw
	20141119_AlCH_1WT_20_2h_n3_3_1202.raw	Raw
	20141119_AlCH_1WT_20_2h_n4_1_1212.raw	Raw
	20141119_AlCH_1WT_20_2h_n4_2_1213.raw	Raw

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Publications

Importance of host cell arginine uptake in Francisella phagosomal escape and ribosomal protein amounts.

Ramond Elodie E Gesbert Gael G Guerrera Ida Chiara IC Chhuon Cerina C Dupuis Marion M Rigard Mélanie M Henry Thomas T Barel Monique M Charbit Alain A

Molecular & cellular proteomics : MCP 20150123 4

Upon entry into mammalian host cells, the pathogenic bacterium Francisella must import host cell arginine to multiply actively in the host cytoplasm. We identified and functionally characterized an arginine transporter (hereafter designated ArgP) whose inactivation considerably delayed bacterial phagosomal escape and intracellular multiplication. Intramacrophagic growth of the ΔargP mutant was fully restored upon supplementation of the growth medium with excess arginine, in both F. tularensis su ...[more]

PMID: 25616868

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Project description:The highly infectious bacterium Francisella tularensis is a facultative intracellular pathogen, whose virulence requires proliferation inside host cells, including macrophages. Although some Francisella determinants of intracellular growth have been identified, much remains to be understood about the pathogenesis of this organism. In particular, how Francisella responds to its intracellular environment could provide clues about its intracellular biology and reveal pathogenic determinants based on their intracellular expression profiles. Here we have performed a global transcriptional profiling of the highly virulent F. tularensis subsp. tularensis Schu S4 strain during its intracellular cycle within primary murine macrophages. Phagocytosed bacteria rapidly responded to their intracellular environment and progressively altered their transcriptional profile over time. Differential gene expression profiles were revealed that correlated with specific intracellular locations of the bacteria. Upregulation of general and oxidative stress response genes was a hallmark of the early phagosomal and late endosomal stages, while induction of a subset of transport and metabolic genes characterized the cytosolic replication stages. Expression of the Francisella Pathogenicity Island (FPI) genes, the functions of which are associated with intracellular proliferation, increased during the intracellular cycle. Similarly, 27 chromosomal loci putatively encoding hypothetical, secreted, outer membrane proteins or transcriptional regulators were identified as upregulated during the intracellular cycle. In-frame deletion of FTT0383, the Schu S4 ortholog of fevR, of FTT0369c or FTT1676 abolished the ability of Schu S4 to either survive or proliferate intracellularly, demonstrating that bacterial factors of intracellular pathogenesis can be identified based on their intracellular expression profile. In conclusion, establishing the intracellular transcriptome of Francisella has revealed important aspects of its intracellular biology and identified novel virulence determinants of this pathogen. Keywords: Time series Intracellular cycle within primary murine macrophages using the time series of zero, one, two, four, eight, twelve, sixteen and twenty-four hours