#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

A New Family of Secreted Toxins in Pathogenic Neisseria Species


Many bacteria are able to secrete toxins targeted against neighboring cells. In order to protect themselves against their own toxin, they also express an “immunity” protein. In silico analysis of bacterial genomes predicts that numerous genes could encode potential new toxin-immunity systems. The recently described CDI system is involved in contact-dependent inhibition of growth and confers to its host strain a significant advantage in competitive ecosystems such as the gastro-intestinal tract. Indeed, an Escherichia coli CDI+ strain is able to outcompete CDI- strains and to become predominant. Here, we show that a large family of genes called “maf”, found in pathogenic Neisseria species, encodes a toxin-immunity system. We demonstrate that a toxin named MafBMGI-1NEM8013 inhibits the growth of E. coli by degrading RNA and show that the immunity protein MafIMGI-1NEM8013 is able to abolish the toxicity. MafB toxins exhibit highly variable toxic domains. This variability of secreted toxins could be important to compete against bacteria of different species sharing the same reservoir. Since a strain may contain numerous toxin-immunity systems that can all play a role in interbacterial competition, deciphering interactions between these systems will allow a better understanding of complex bacterial communities.


Vyšlo v časopise: A New Family of Secreted Toxins in Pathogenic Neisseria Species. PLoS Pathog 11(1): e32767. doi:10.1371/journal.ppat.1004592
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004592

Souhrn

Many bacteria are able to secrete toxins targeted against neighboring cells. In order to protect themselves against their own toxin, they also express an “immunity” protein. In silico analysis of bacterial genomes predicts that numerous genes could encode potential new toxin-immunity systems. The recently described CDI system is involved in contact-dependent inhibition of growth and confers to its host strain a significant advantage in competitive ecosystems such as the gastro-intestinal tract. Indeed, an Escherichia coli CDI+ strain is able to outcompete CDI- strains and to become predominant. Here, we show that a large family of genes called “maf”, found in pathogenic Neisseria species, encodes a toxin-immunity system. We demonstrate that a toxin named MafBMGI-1NEM8013 inhibits the growth of E. coli by degrading RNA and show that the immunity protein MafIMGI-1NEM8013 is able to abolish the toxicity. MafB toxins exhibit highly variable toxic domains. This variability of secreted toxins could be important to compete against bacteria of different species sharing the same reservoir. Since a strain may contain numerous toxin-immunity systems that can all play a role in interbacterial competition, deciphering interactions between these systems will allow a better understanding of complex bacterial communities.


Zdroje

1. ZhangD, de SouzaRF, AnantharamanV, IyerLM, AravindL (2012) Polymorphic toxin systems: Comprehensive characterization of trafficking modes, processing, mechanisms of action, immunity and ecology using comparative genomics. Biol Direct 7: 18.

2. ZhangD, IyerLM, AravindL (2011) A novel immunity system for bacterial nucleic acid degrading toxins and its recruitment in various eukaryotic and DNA viral systems. Nucleic Acids Res 39: 4532–4552.

3. IyerLM, ZhangD, RogozinIB, AravindL (2011) Evolution of the deaminase fold and multiple origins of eukaryotic editing and mutagenic nucleic acid deaminases from bacterial toxin systems. Nucleic Acids Res 39: 9473–9497.

4. PooleSJ, DinerEJ, AokiSK, BraatenBA, t'Kint de RoodenbekeC, et al. (2011) Identification of functional toxin/immunity genes linked to contact-dependent growth inhibition (CDI) and rearrangement hotspot (Rhs) systems. PLoS Genet 7: e1002217.

5. AokiSK, DinerEJ, de RoodenbekeCT, BurgessBR, PooleSJ, et al. (2010) A widespread family of polymorphic contact-dependent toxin delivery systems in bacteria. Nature 468: 439–442.

6. KoskiniemiS, LamoureuxJG, NikolakakisKC, t'Kint de RoodenbekeC, KaplanMD, et al. (2013) Rhs proteins from diverse bacteria mediate intercellular competition. Proc Natl Acad Sci U S A 110: 7032–7037.

7. BeddoeT, PatonAW, Le NoursJ, RossjohnJ, PatonJC (2010) Structure, biological functions and applications of the AB5 toxins. Trends Biochem Sci 35: 411–418.

8. HayesCS, KoskiniemiS, RuheZC, PooleSJ, LowDA (2014) Mechanisms and biological roles of contact-dependent growth inhibition systems. Cold Spring Harb Persp Med 4 (2).

9. AokiSK, PooleSJ, HayesCS, LowDA (2011) Toxin on a stick: modular CDI toxin delivery systems play roles in bacterial competition. Virulence 2: 356–359.

10. KoskiniemiS, Garza-SanchezF, SandegrenL, WebbJS, BraatenBA, et al. (2014) Selection of orphan Rhs toxin expression in evolved Salmonella enterica serovar Typhimurium. PLoS Genet 10: e1004255.

11. AokiSK, PammaR, HerndayAD, BickhamJE, BraatenBA, et al. (2005) Contact-dependent inhibition of growth in Escherichia coli. Science 309: 1245–1248.

12. ur RahmanS, van UlsenP (2013) System specificity of the TpsB transporters of coexpressed two-partner secretion systems of Neisseria meningitidis. J Bacteriol 195: 788–797.

13. AndersonMS, GarciaEC, CotterPA (2012) The Burkholderia bcpAIOB genes define unique classes of two-partner secretion and contact dependent growth inhibition systems. PLoS Genet 8: e1002877.

14. ArenasJ, SchipperK, van UlsenP, van der EndeA, TommassenJ (2013) Domain exchange at the 3′ end of the gene encoding the fratricide meningococcal two-partner secretion protein A. BMC Genomics 14: 622.

15. UnemoM, ShipitsynaE, DomeikaM, Eastern EuropeanS (2011) Reproductive Health Network Antimicrobial Resistance G (2011) Gonorrhoea surveillance, laboratory diagnosis and antimicrobial susceptibility testing of Neisseria gonorrhoeae in 11 countries of the eastern part of the WHO European region. APMIS 119: 643–649.

16. CarbonnelleE, HillDJ, MorandP, GriffithsNJ, BourdoulousS, et al. (2009) Meningococcal interactions with the host. Vaccine 27 Suppl 2: B78–89.

17. CaugantDA, TzanakakiG, KrizP (2007) Lessons from meningococcal carriage studies. FEMS Microbiol Rev 31: 52–63.

18. BennettJS, BentleySD, VernikosGS, QuailMA, CherevachI, et al. (2010) Independent evolution of the core and accessory gene sets in the genus Neisseria: insights gained from the genome of Neisseria lactamica isolate 020-06. BMC Genomics 11: 652.

19. BentleySD, VernikosGS, SnyderLA, ChurcherC, ArrowsmithC, et al. (2007) Meningococcal genetic variation mechanisms viewed through comparative analysis of serogroup C strain FAM18. PLoS Genet 3: e23.

20. PengJ, YangL, YangF, YangJ, YanY, et al. (2008) Characterization of ST-4821 complex, a unique Neisseria meningitidis clone. Genomics 91: 78–87.

21. SchoenC, BlomJ, ClausH, Schramm-GluckA, BrandtP, et al. (2008) Whole-genome comparison of disease and carriage strains provides insights into virulence evolution in Neisseria meningitidis. Proc Natl Acad Sci U S A 105: 3473–3478.

22. SnyderLA, ButcherSA, SaundersNJ (2001) Comparative whole-genome analyses reveal over 100 putative phase-variable genes in the pathogenic Neisseria spp. Microbiology 147: 2321–2332.

23. Dunning HotoppJC, GrifantiniR, KumarN, TzengYL, FoutsD, et al. (2006) Comparative genomics of Neisseria meningitidis: core genome, islands of horizontal transfer and pathogen-specific genes. Microbiology 152: 3733–3749.

24. SunYH, BakshiS, ChalmersR, TangCM (2000) Functional genomics of Neisseria meningitidis pathogenesis. Nat Med 6: 1269–1273.

25. SnyderLA, SaundersNJ (2006) The majority of genes in the pathogenic Neisseria species are present in non-pathogenic Neisseria lactamica, including those designated as ‘virulence genes’. BMC Genomics 7: 128.

26. DobrindtU, HochhutB, HentschelU, HackerJ (2004) Genomic islands in pathogenic and environmental microorganisms. Nat Rev Microbiol 2: 414–424.

27. JuhasM, van der MeerJR, GaillardM, HardingRM, HoodDW, et al. (2009) Genomic islands: tools of bacterial horizontal gene transfer and evolution. FEMS Microbiol Rev 33: 376–393.

28. BilleE, ZaharJR, PerrinA, MorelleS, KrizP, et al. (2005) A chromosomally integrated bacteriophage in invasive meningococci. J Exp Med 201: 1905–1913.

29. KleeSR, NassifX, KusecekB, MerkerP, BerettiJL, et al. (2000) Molecular and biological analysis of eight genetic islands that distinguish Neisseria meningitidis from the closely related pathogen Neisseria gonorrhoeae. Infect Immun 68: 2082–2095.

30. PerrinA, BonacorsiS, CarbonnelleE, TalibiD, DessenP, et al. (2002) Comparative genomics identifies the genetic islands that distinguish Neisseria meningitidis, the agent of cerebrospinal meningitis, from other Neisseria species. Infect Immun 70: 7063–7072.

31. SnyderLA, DaviesJK, RyanCS, SaundersNJ (2005) Comparative overview of the genomic and genetic differences between the pathogenic Neisseria strains and species. Plasmid 54: 191–218.

32. PiekarowiczA, KlyzA, MajchrzakM, Adamczyk-PoplawskaM, MaugelTK, et al. (2007) Characterization of the dsDNA prophage sequences in the genome of Neisseria gonorrhoeae and visualization of productive bacteriophage. BMC Microbiol 7: 66.

33. DillardJP, SeifertHS (2001) A variable genetic island specific for Neisseria gonorrhoeae is involved in providing DNA for natural transformation and is found more often in disseminated infection isolates. Mol Microbiol 41: 263–277.

34. SnyderLA, JarvisSA, SaundersNJ (2005) Complete and variant forms of the ‘gonococcal genetic island’ in Neisseria meningitidis. Microbiology 151: 4005–4013.

35. ParuchuriDK, SeifertHS, AjiokaRS, KarlssonKA, SoM (1990) Identification and characterization of a Neisseria gonorrhoeae gene encoding a glycolipid-binding adhesin. Proc Natl Acad Sci U S A 87: 333–337.

36. PetersenTN, BrunakS, von HeijneG, NielsenH (2011) SignalP 4.0: discriminating signal peptides from transmembrane regions. Nat Methods 8: 785–786.

37. BagosPG, NikolaouEP, LiakopoulosTD, TsirigosKD (2010) Combined prediction of Tat and Sec signal peptides with hidden Markov models. Bioinformatics 26: 2811–2817.

38. BendtsenJD, KiemerL, FausbollA, BrunakS (2005) Non-classical protein secretion in bacteria. BMC Microbiol 5: 58.

39. RoseRW, BruserT, KissingerJC, PohlschroderM (2002) Adaptation of protein secretion to extremely high-salt conditions by extensive use of the twin-arginine translocation pathway. Mol Microbiol 45: 943–950.

40. JunckerAS, WillenbrockH, Von HeijneG, BrunakS, NielsenH, et al. (2003) Prediction of lipoprotein signal peptides in Gram-negative bacteria. Protein Sci 12: 1652–1662.

41. VipondC, WheelerJX, JonesC, FeaversIM, SukerJ (2005) Characterization of the protein content of a meningococcal outer membrane vesicle vaccine by polyacrylamide gel electrophoresis and mass spectrometry. Hum Vaccin 1: 80–84.

42. WuHJ, SeibKL, SrikhantaYN, EdwardsJ, KiddSP, et al. (2010) Manganese regulation of virulence factors and oxidative stress resistance in Neisseria gonorrhoeae. J Proteomics 73: 899–916.

43. ZielkeRA, WierzbickiIH, WeberJV, GafkenPR, SikoraAE (2014) Quantitative proteomics of the Neisseria gonorrhoeae cell envelope and membrane vesicles for the discovery of potential therapeutic targets. Mol Cell Proteomics 13: 1299–1317.

44. Marchler-BauerA, LuS, AndersonJB, ChitsazF, DerbyshireMK, et al. (2011) CDD: a Conserved Domain Database for the functional annotation of proteins. Nucleic Acids Res 39: D225–229.

45. GuzmanLM, BelinD, CarsonMJ, BeckwithJ (1995) Tight regulation, modulation, and high-level expression by vectors containing the arabinose PBAD promoter. J Bacteriol 177: 4121–4130.

46. MehrIJ, LongCD, SerkinCD, SeifertHS (2000) A homologue of the recombination-dependent growth gene, rdgC, is involved in gonococcal pilin antigenic variation. Genetics 154: 523–532.

47. AokiSK, MalinverniJC, JacobyK, ThomasB, PammaR, et al. (2008) Contact-dependent growth inhibition requires the essential outer membrane protein BamA (YaeT) as the receptor and the inner membrane transport protein AcrB. Mol Microbiol 70: 323–340.

48. HolbergerLE, Garza-SanchezF, LamoureuxJ, LowDA, HayesCS (2012) A novel family of toxin/antitoxin proteins in Bacillus species. FEBS Lett 586: 132–136.

49. WebbJS, NikolakakisKC, WillettJL, AokiSK, HayesCS, et al. (2013) Delivery of CdiA nuclease toxins into target cells during contact-dependent growth inhibition. PLoS One 8: e57609.

50. SchielkeS, FroschM, KurzaiO (2010) Virulence determinants involved in differential host niche adaptation of Neisseria meningitidis and Neisseria gonorrhoeae. Med Microbiol Immunol 199: 185–196.

51. van UlsenP, RuttenL, FellerM, TommassenJ, van der EndeA (2008) Two-partner secretion systems of Neisseria meningitidis associated with invasive clonal complexes. Infect Immun 76: 4649–4658.

52. ur RahmanS, ArenasJ, OzturkH, DekkerN, van UlsenP (2014) The polypeptide transport-associated (POTRA) domains of TpsB transporters determine the system specificity of two-partner secretion systems. J Biol Chem 289: 19799–19809.

53. RemautH, WaksmanG (2004) Structural biology of bacterial pathogenesis. Curr Opin Struct Biol 14: 161–170.

54. DesvauxM, HebraudM, TalonR, HendersonIR (2009) Secretion and subcellular localizations of bacterial proteins: a semantic awareness issue. Trends Microbiol 17: 139–145.

55. SilvermanJM, BrunetYR, CascalesE, MougousJD (2012) Structure and regulation of the type VI secretion system. Annu Rev Microbiol 66: 453–472.

56. van UlsenP, TommassenJ (2006) Protein secretion and secreted proteins in pathogenic Neisseriaceae. FEMS Microbiol Rev 30: 292–319.

57. DesvauxM, ParhamNJ, HendersonIR (2004) Type V protein secretion: simplicity gone awry? Curr Issues Mol Biol 6: 111–124.

58. KoomeyJM, GillRE, FalkowS (1982) Genetic and biochemical analysis of gonococcal IgA1 protease: cloning in Escherichia coli and construction of mutants of gonococci that fail to produce the activity. Proc Natl Acad Sci U S A 79: 7881–7885.

59. NattNK, KaurH, RaghavaGP (2004) Prediction of transmembrane regions of beta-barrel proteins using ANN- and SVM-based methods. Proteins 56: 11–18.

60. BagosPG, LiakopoulosTD, HamodrakasSJ (2006) Algorithms for incorporating prior topological information in HMMs: application to transmembrane proteins. BMC Bioinformatics 7: 189.

61. HodakH, Jacob-DubuissonF (2007) Current challenges in autotransport and two-partner protein secretion pathways. Res Microbiol 158: 631–637.

62. DevoeIW, GilchristJE (1973) Release of endotoxin in the form of cell wall blebs during in vitro growth of Neisseria meningitidis. J Exp Med 138: 1156–1167.

63. LloubesR, BernadacA, HouotL, PommierS (2013) Non classical secretion systems. Res Microbiol 164: 655–663.

64. KadurugamuwaJL, BeveridgeTJ (1996) Bacteriolytic effect of membrane vesicles from Pseudomonas aeruginosa on other bacteria including pathogens: conceptually new antibiotics. J Bacteriol 178: 2767–2774.

65. MacDonaldIA, KuehnMJ (2012) Offense and defense: microbial membrane vesicles play both ways. Res Microbiol 163: 607–618.

66. KestyNC, MasonKM, ReedyM, MillerSE, KuehnMJ (2004) Enterotoxigenic Escherichia coli vesicles target toxin delivery into mammalian cells. EMBO J 23: 4538–4549.

67. BombergerJM, MaceachranDP, CoutermarshBA, YeS, O'TooleGA, et al. (2009) Long-distance delivery of bacterial virulence factors by Pseudomonas aeruginosa outer membrane vesicles. PLoS Pathog 5: e1000382.

68. HolstJ, OsterP, ArnoldR, TatleyMV, NaessLM, et al. (2013) Vaccines against meningococcal serogroup B disease containing outer membrane vesicles (OMV): lessons from past programs and implications for the future. Hum Vaccin Immunother 9: 1241–1253.

69. HammerschmidtS, HilseR, van PuttenJP, Gerardy-SchahnR, UnkmeirA, et al. (1996) Modulation of cell surface sialic acid expression in Neisseria meningitidis via a transposable genetic element. EMBO J 15: 192–198.

70. HammerschmidtS, MullerA, SillmannH, MuhlenhoffM, BorrowR, et al. (1996) Capsule phase variation in Neisseria meningitidis serogroup B by slipped-strand mispairing in the polysialyltransferase gene (siaD): correlation with bacterial invasion and the outbreak of meningococcal disease. Mol Microbiol 20: 1211–1220.

71. HeyA, LiMS, HudsonMJ, LangfordPR, KrollJS (2013) Transcriptional profiling of Neisseria meningitidis interacting with human epithelial cells in a long-term in vitro colonization model. Infect Immun 81: 4149–4159.

72. DeghmaneAE, GiorginiD, LarribeM, AlonsoJM, TahaMK (2002) Down-regulation of pili and capsule of Neisseria meningitidis upon contact with epithelial cells is mediated by CrgA regulatory protein. Mol Microbiol 43: 1555–1564.

73. FagnocchiL, PigozziE, ScarlatoV, DelanyI (2012) In the NadR regulon, adhesins and diverse meningococcal functions are regulated in response to signals in human saliva. J Bacteriol 194: 460–474.

74. GarciaEC, AndersonMS, HagarJA, CotterPA (2013) Burkholderia BcpA mediates biofilm formation independently of interbacterial contact-dependent growth inhibition. Mol Microbiol 89: 1213–1225.

75. AndersonMS, GarciaEC, CotterPA (2014) Kind discrimination and competitive exclusion mediated by contact-dependent growth inhibition systems shape biofilm community structure. PLoS Pathog 10: e1004076.

76. ParkhillJ, AchtmanM, JamesKD, BentleySD, ChurcherC, et al. (2000) Complete DNA sequence of a serogroup A strain of Neisseria meningitidis Z2491. Nature 404: 502–506.

77. TettelinH, SaundersNJ, HeidelbergJ, JeffriesAC, NelsonKE, et al. (2000) Complete genome sequence of Neisseria meningitidis serogroup B strain MC58. Science 287: 1809–1815.

78. VallenetD, LabarreL, RouyZ, BarbeV, BocsS, et al. (2006) MaGe: a microbial genome annotation system supported by synteny results. Nucleic Acids Res 34: 53–65.

79. ChungGT, YooJS, OhHB, LeeYS, ChaSH, et al. (2008) Complete genome sequence of Neisseria gonorrhoeae NCCP11945. J Bacteriol 190: 6035–6036.

80. RusniokC, VallenetD, FloquetS, EwlesH, Mouze-SoulamaC, et al. (2009) NeMeSys: a biological resource for narrowing the gap between sequence and function in the human pathogen Neisseria meningitidis. Genome Biol 10: R110.

81. PietJR, Huis in 't VeldRA, van SchaikBD, van KampenAH, BaasF, et al. (2011) Genome sequence of Neisseria meningitidis serogroup B strain H44/76. J Bacteriol 193: 2371–2372.

82. BudroniS, SienaE, Dunning HotoppJC, SeibKL, SerrutoD, et al. (2011) Neisseria meningitidis is structured in clades associated with restriction modification systems that modulate homologous recombination. Proc Natl Acad Sci U S A 108: 4494–4499.

83. SchoenC, Weber-LehmannJ, BlomJ, JosephB, GoesmannA, et al. (2011) Whole-genome sequence of the transformable Neisseria meningitidis serogroup A strain WUE2594. J Bacteriol 193: 2064–2065.

84. FinnRD, BatemanA, ClementsJ, CoggillP, EberhardtRY, et al. (2014) Pfam: the protein families database. Nucleic Acids Res 42: D222–230.

85. KanehisaM (1997) Linking databases and organisms: GenomeNet resources in Japan. Trends Biochem Sci 22: 442–444.

86. LarkinMA, BlackshieldsG, BrownNP, ChennaR, McGettiganPA, et al. (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23: 2947–2948.

87. EdgarRC (2004) MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 32: 1792–1797.

88. SieversF, HigginsDG (2014) Clustal Omega, accurate alignment of very large numbers of sequences. Methods Mol Biol 1079: 105–116.

89. SullivanMJ, PettyNK, BeatsonSA (2011) Easyfig: a genome comparison visualizer. Bioinformatics 27: 1009–1010.

90. HelaineS, CarbonnelleE, ProuvensierL, BerettiJL, NassifX, et al. (2005) PilX, a pilus-associated protein essential for bacterial aggregation, is a key to pilus-facilitated attachment of Neisseria meningitidis to human cells. Mol Microbiol 55: 65–77.

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2015 Číslo 1
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#