A Novel Metal Transporter Mediating Manganese Export (MntX) Regulates the Mn to Fe Intracellular Ratio and Virulence
Neisseria meningitidis (Nm) and N. gonorrhoeae (Ng) are adapted to different environments within their human host. If the basis of this difference has not yet been fully understood, previous studies (including our own data) have reported that, unlike Ng, Nm tolerates high manganese concentrations. As transition metals are essential regulators of cell growth and host pathogen interactions, we aimed to address mechanisms of Nm Mn2+ tolerance and its pathogenic consequences. Using bioinformatics, gene deletion and heterologous expression we identified a conserved bacterial manganese resistance factor MntX (formerly YebN). The predicted structure suggests that MntX represents a new family of transporters exporting Mn. In the Neisseria genus, this exporter is present and functional in all Nm isolates but it is mutated in a majority of Ng strains and commonly absent in nonpathogenic species. In Nm, Mn2+ export via MntX regulates the intracellular Mn/Fe ratio and protects against manganese toxicity that is exacerbated in low iron conditions. MntX is also important for N. meningitidis to resist killing by human serum and for survival in mice blood during septicemia. The present work thus points to new clues about Mn homeostasis, its interplay with Fe metabolism and the influence on N. meningitidis physiology and pathogenicity.
Vyšlo v časopise:
A Novel Metal Transporter Mediating Manganese Export (MntX) Regulates the Mn to Fe Intracellular Ratio and Virulence. PLoS Pathog 7(9): e32767. doi:10.1371/journal.ppat.1002261
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002261
Souhrn
Neisseria meningitidis (Nm) and N. gonorrhoeae (Ng) are adapted to different environments within their human host. If the basis of this difference has not yet been fully understood, previous studies (including our own data) have reported that, unlike Ng, Nm tolerates high manganese concentrations. As transition metals are essential regulators of cell growth and host pathogen interactions, we aimed to address mechanisms of Nm Mn2+ tolerance and its pathogenic consequences. Using bioinformatics, gene deletion and heterologous expression we identified a conserved bacterial manganese resistance factor MntX (formerly YebN). The predicted structure suggests that MntX represents a new family of transporters exporting Mn. In the Neisseria genus, this exporter is present and functional in all Nm isolates but it is mutated in a majority of Ng strains and commonly absent in nonpathogenic species. In Nm, Mn2+ export via MntX regulates the intracellular Mn/Fe ratio and protects against manganese toxicity that is exacerbated in low iron conditions. MntX is also important for N. meningitidis to resist killing by human serum and for survival in mice blood during septicemia. The present work thus points to new clues about Mn homeostasis, its interplay with Fe metabolism and the influence on N. meningitidis physiology and pathogenicity.
Zdroje
1. FinkelsteinRASciortinoCVMcIntoshMA 1983 Role of iron in microbe-host interactions. Rev Infect Dis 5 Suppl 4 S759 777
2. WeinbergED 1971 Role of iron in host-parasite interactions. J Infect Dis 124 401 410
3. SchaibleUEKaufmannSH 2005 A nutritive view on the host-pathogen interplay. Trends Microbiol 13 373 380
4. BarondeauDPGetzoffED 2004 Structural insights into protein-metal ion partnerships. Curr Opin Struct Biol 14 765 774
5. StadtmanER 1990 Metal ion-catalyzed oxidation of proteins: biochemical mechanism and biological consequences. Free Radic Biol Med 9 315 325
6. CellierMFCourvillePCampionC 2007 Nramp1 phagocyte intracellular metal withdrawal defense. Microbes Infect 9 1662 1670
7. CorbinBDSeeleyEHRaabAFeldmannJMillerMR 2008 Metal chelation and inhibition of bacterial growth in tissue abscesses. Science 319 962 965
8. JakubovicsNSValentineRA 2009 A new direction for manganese homeostasis in bacteria: identification of a novel efflux system in Streptococcus pneumoniae. Mol Microbiol 72 1 4
9. Kehl-FieTESkaarEP 2010 Nutritional immunity beyond iron: a role for manganese and zinc. Curr Opin Chem Biol 14 218 224
10. RoschJWGaoGRidoutGWangYDTuomanenEI 2009 Role of the manganese efflux system mntE for signalling and pathogenesis in Streptococcus pneumoniae. Mol Microbiol 72 12 25
11. ArchibaldFSFridovichI 1981 Manganese and defenses against oxygen toxicity in Lactobacillus plantarum. J Bacteriol 145 442 451
12. SeibKLWuHJKiddSPApicellaMAJenningsMP 2006 Defenses against oxidative stress in Neisseria gonorrhoeae: a system tailored for a challenging environment. Microbiol Mol Biol Rev 70 344 361
13. ChampionOLKarlyshevAVCooperIAFordDCWrenBW 2011 Yersinia pseudotuberculosis mntH functions in intracellular manganese accumulation that is essential for virulence and survival in cells expressing functional Nramp1. Microbiology 157 Pt 4 1115 22
14. AndersonESPaulleyJTGainesJMValderasMWMartinDW 2009 The manganese transporter MntH is a critical virulence determinant for Brucella abortus 2308 in experimentally infected mice. Infect Immun 77 3466 3474
15. ZaharikMLCullenVLFungAMLibbySJKujat ChoySL 2004 The Salmonella enterica serovar typhimurium divalent cation transport systems MntH and SitABCD are essential for virulence in an Nramp1G169 murine typhoid model. Infect Immun 72 5522 5525
16. BoyerEBergevinIMaloDGrosPCellierMF 2002 Acquisition of Mn(II) in addition to Fe(II) is required for full virulence of Salmonella enterica serovar Typhimurium. Infect Immun 70 6032 6042
17. PuriSHohleTHO'BrianMR 2010 Control of bacterial iron homeostasis by manganese. Proc Natl Acad Sci U S A 107 23 10691 10695
18. DalyMJGaidamakovaEKMatrosovaVYVasilenkoAZhaiM 2004 Accumulation of Mn(II) in Deinococcus radiodurans facilitates gamma-radiation resistance. Science 306 1025 1028
19. AnjemAVargheseSImlayJA 2009 Manganese import is a key element of the OxyR response to hydrogen peroxide in Escherichia coli. Mol Microbiol 72 844 858
20. McEwanAG 2009 New insights into the protective effect of manganese against oxidative stress. Mol Microbiol 72 812 814
21. Renauld-MongenieGPoncetDMignonMFraysseSChabanelC 2004 Role of transferrin receptor from a Neisseria meningitidis tbpB isotype II strain in human transferrin binding and virulence. Infect Immun 72 3461 3470
22. HagenTACornelissenCN 2006 Neisseria gonorrhoeae requires expression of TonB and the putative transporter TdfF to replicate within cervical epithelial cells. Mol Microbiol 62 1144 1157
23. LarsonJAHigashiDLStojiljkovicISoM 2002 Replication of Neisseria meningitidis within epithelial cells requires TonB-dependent acquisition of host cell iron. Infect Immun 70 1461 1467
24. GencoCADesaiPJ 1996 Iron acquisition in the pathogenic Neisseria. Trends Microbiol 4 179 184
25. GencoCAChenCYArkoRJKapczynskiDRMorseSA 1991 Isolation and characterization of a mutant of Neisseria gonorrhoeae that is defective in the uptake of iron from transferrin and haemoglobin and is avirulent in mouse subcutaneous chambers. J Gen Microbiol 137 1313 1321
26. ZarantonelliMLSzatanikMGiorginiDHongEHuerreM 2007 Transgenic mice expressing human transferrin as a model for meningococcal infection. Infect Immun 75 5609 5614
27. OftungFLovikMAndersenSRFroholmLOBjuneG 1999 A mouse model utilising human transferrin to study protection against Neisseria meningitidis serogroup B induced by outer membrane vesicle vaccination. FEMS Immunol Med Microbiol 26 75 82
28. OdugbemiTMcEntegartMHafizS 1978 Effects of various divalent cations on the survival of Neisseria gonorrhoeae in liquid media. Br J Vener Dis 54 239 242
29. OdugbemiTOMcEntegartMGHafizS 1978 A simple manganous chloride and Congo red disc method for differentiating Neisseria gonorrhoeae from Neisseria meningitidis. J Clin Pathol 31 936 938
30. SeibKLTsengHJMcEwanAGApicellaMAJenningsMP 2004 Defenses against oxidative stress in Neisseria gonorrhoeae and Neisseria meningitidis: distinctive systems for different lifestyles. J Infect Dis 190 136 147
31. QueQHelmannJD 2000 Manganese homeostasis in Bacillus subtilis is regulated by MntR, a bifunctional regulator related to the diphtheria toxin repressor family of proteins. Mol Microbiol 35 1454 1468
32. RodionovDAGelfandMSToddJDCursonARJohnstonAW 2006 Computational reconstruction of iron- and manganese-responsive transcriptional networks in alpha-proteobacteria. PLoS Comput Biol 2 e163
33. PatzerSIHantkeK 2001 Dual repression by Fe(2+)-Fur and Mn(2+)-MntR of the mntH gene, encoding an NRAMP-like Mn(2+) transporter in Escherichia coli. J Bacteriol 183 4806 4813
34. KehresDGJanakiramanASlauchJMMaguireME 2002 Regulation of Salmonella enterica serovar Typhimurium mntH transcription by H(2)O(2), Fe(2+), and Mn(2+). J Bacteriol 184 3151 3158
35. IkedaJSJanakiramanAKehresDGMaguireMESlauchJM 2005 Transcriptional regulation of sitABCD of Salmonella enterica serovar Typhimurium by MntR and Fur. J Bacteriol 187 912 922
36. TamuraKDudleyJNeiMKumarS 2007 MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol 24 1596 1599
37. ShihACLeeDTPengCLWuYW 2007 Phylo-mLogo: an interactive and hierarchical multiple-logo visualization tool for alignment of many sequences. BMC Bioinformatics 8 63
38. CellierM 2011 Nutritional Immunity: Homology Modeling of Nramp Metal Import. Current Topics in Innate Immunity II. LambrisJDHajishengallisGN Advances in Experimental Medicine and Biology 946
39. Marchler-BauerALuSAndersonJBChitsazFDerbyshireMK CDD: a Conserved Domain Database for the functional annotation of proteins. Nucleic Acids Res 39 D225 229
40. NamHJJeonJKimS 2009 Bioinformatic approaches for the structure and function of membrane proteins. BMB Rep 42 697 704
41. BoudkerOVerdonG 2010 Structural perspectives on secondary active transporters. Trends Pharmacol Sci 31 418 426
42. KuntalBKAparoyPReddannaP 2010 Development of tools and database for analysis of metal binding sites in protein. Protein Pept Lett 17 765 773
43. MakuiHRoigEColeSTHelmannJDGrosP 2000 Identification of the Escherichia coli K-12 Nramp orthologue (MntH) as a selective divalent metal ion transporter. Mol Microbiol 35 1065 1078
44. BreuerWEpsztejnSCabantchikZI 1995 Iron acquired from transferrin by K562 cells is delivered into a cytoplasmic pool of chelatable iron(II). J Biol Chem 270 24209 24215
45. KehresDGMaguireME 2003 Emerging themes in manganese transport, biochemistry and pathogenesis in bacteria. FEMS Microbiol Rev 27 263 290
46. TsengHJSrikhantaYMcEwanAGJenningsMP 2001 Accumulation of manganese in Neisseria gonorrhoeae correlates with resistance to oxidative killing by superoxide anion and is independent of superoxide dismutase activity. Mol Microbiol 40 1175 1186
47. SchryversABGonzalezGC 1989 Comparison of the abilities of different protein sources of iron to enhance Neisseria meningitidis infection in mice. Infect Immun 57 2425 2429
48. KorkhovVMTateCG 2009 An emerging consensus for the structure of EmrE. Acta Crystallogr D Biol Crystallogr 65 186 192
49. KhafizovKStaritzbichlerRStammMForrestLR 2010 A study of the evolution of inverted-topology repeats from LeuT-fold transporters using AlignMe. Biochemistry 49 10702 10713
50. ForrestLRRudnickG 2009 The rocking bundle: a mechanism for ion-coupled solute flux by symmetrical transporters. Physiology (Bethesda) 24 377 386
51. RadestockSForrestLR 2011 The alternating-access mechanism of MFS transporters arises from inverted-topology repeats. J Mol Biol 407 5 698 715
52. ZhengHYAlcornTMCohenMS 1994 Effects of H2O2-producing lactobacilli on Neisseria gonorrhoeae growth and catalase activity. J Infect Dis 170 1209 1215
53. FaulknerMJHelmannJD 2011 Peroxide stress elicits adaptive changes in bacterial metal ion homeostasis. Antioxid Redox Signal 15 1 175 189
54. GrootMNKlaassensEde VosWMDelcourJHolsP 2005 Genome-based in silico detection of putative manganese transport systems in Lactobacillus plantarum and their genetic analysis. Microbiology 151 1229 1238
55. SchaferATauchAJagerWKalinowskiJThierbachG 1994 Small mobilizable multi-purpose cloning vectors derived from the Escherichia coli plasmids pK18 and pK19: selection of defined deletions in the chromosome of Corynebacterium glutamicum. Gene 145 69 73
56. DennisJJZylstraGJ 1998 Plasposons: modular self-cloning minitransposon derivatives for rapid genetic analysis of gram-negative bacterial genomes. Appl Environ Microbiol 64 2710 2715
57. DeShazerDWoodsDE 1996 Broad-host-range cloning and cassette vectors based on the R388 trimethoprim resistance gene. Biotechniques 20 762 764
58. SlaterHAlvarez-MoralesABarberCEDanielsMJDowJM 2000 A two-component system involving an HD-GYP domain protein links cell-cell signalling to pathogenicity gene expression in Xanthomonas campestris. Mol Microbiol 38 986 1003
59. McQuillenDPGulatiSRicePA 1994 Complement-mediated bacterial killing assays. Methods Enzymol 236 137 147
60. YellaboinaSSeshadriJKumarMSRanjanA 2004 PredictRegulon: a web server for the prediction of the regulatory protein binding sites and operons in prokaryote genomes. Nucleic Acids Res 32 W318 320
61. HiardSMareeRColsonSHoskissonPATitgemeyerF 2007 PREDetector: a new tool to identify regulatory elements in bacterial genomes. Biochem Biophys Res Commun 357 861 864
62. ClarosMGvon HeijneG 1994 TopPred II: an improved software for membrane protein structure predictions. Comput Appl Biosci 10 685 686
63. NugentTJonesDT 2009 Transmembrane protein topology prediction using support vector machines. BMC Bioinformatics 10 159
64. FrickeyTLupasA 2004 CLANS: a Java application for visualizing protein families based on pairwise similarity. Bioinformatics 20 3702 3704
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Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
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