Small RNAs and extracellular vesicles: New mechanisms of cross-species communication and innovative tools for disease control

Autoři: Qiang Cai aff001;  Baoye He aff001;  Arne Weiberg aff002;  Amy H. Buck aff003;  Hailing Jin aff001
Působiště autorů: Department of Microbiology and Plant Pathology, Center for Plant Cell Biology, Institute for Integrative Genome Biology, University of California, Riverside, California, United States of America aff001;  Department of Biology, Ludwig-Maximilians University of Munich (LMU), Munich, Germany aff002;  Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom aff003;  Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom aff004
Vyšlo v časopise: Small RNAs and extracellular vesicles: New mechanisms of cross-species communication and innovative tools for disease control. PLoS Pathog 15(12): e32767. doi:10.1371/journal.ppat.1008090
Kategorie: Pearls


1. Baulcombe D. RNA silencing in plants. Nature. 2004;431: 356–363. doi: 10.1038/nature02874 15372043

2. Weiberg A, Wang M, Lin FM, Zhao H, Zhang Z, Kaloshian I, et al. Fungal small RNAs suppress plant immunity by hijacking host RNA interference pathways. Science. 2013;342: 118–123. doi: 10.1126/science.1239705 24092744

3. Wang B, Sun YF, Song N, Zhao MX, Liu R, Feng H, et al. Puccinia striiformis f. sp tritici microRNA-like RNA 1 (Pst-milR1), an important pathogenicity factor of Pst, impairs wheat resistance to Pst by suppressing the wheat pathogenesis-related 2 gene. New Phytol. 2017;215: 338–350. doi: 10.1111/nph.14577 28464281

4. Wang M, Weiberg A, Lin FM, Thomma BP, Huang HD, Jin H. Bidirectional cross-kingdom RNAi and fungal uptake of external RNAs confer plant protection. Nat Plants. 2016;2: 16151. doi: 10.1038/nplants.2016.151 27643635

5. Derbyshire M, Mbengue M, Barascud M, Navaud O, Raffaele S. Small RNAs from the plant pathogenic fungus Sclerotinia sclerotiorum highlight host candidate genes associated with quantitative disease resistance. Mol Plant Pathol. 2019;20: 1279–1297. doi: 10.1111/mpp.12841 31361080

6. Cui C, Wang Y, Liu J, Zhao J, Sun P, Wang S. A fungal pathogen deploys a small silencing RNA that attenuates mosquito immunity and facilitates infection. Nat Commun. 2019;10: 4298. doi: 10.1038/s41467-019-12323-1 31541102

7. Shahid S, Kim G, Johnson NR, Wafula E, Wang F, Coruh C, et al. MicroRNAs from the parasitic plant Cuscuta campestris target host messenger RNAs. Nature. 2018;553: 82–85. doi: 10.1038/nature25027 29300014

8. Ren B, Wang X, Duan J, Ma J. Rhizobial tRNA-derived small RNAs are signal molecules regulating plant nodulation. Science. 2019;365: 919–922. doi: 10.1126/science.aav8907 31346137

9. Shimura H, Pantaleo V, Ishihara T, Myojo N, Inaba J, Sueda K, et al. A viral satellite RNA induces yellow symptoms on tobacco by targeting a gene involved in chlorophyll biosynthesis using the RNA silencing machinery. PLoS Pathog. 2011;7: e1002021. doi: 10.1371/journal.ppat.1002021 21573143

10. Smith NA, Eamens AL, Wang MB. Viral small interfering RNAs target host genes to mediate disease symptoms in plants. PLoS Pathog. 2011;7: e1002022. doi: 10.1371/journal.ppat.1002022 21573142

11. Adkar-Purushothama CR, Brosseau C, Giguere T, Sano T, Moffett P, Perreault JP. Small RNA derived from the virulence modulating region of the Potato spindle tuber viroid silences callose synthase genes of tomato plants. Plant Cell. 2015;27: 2178–2194. doi: 10.1105/tpc.15.00523 26290537

12. Grey F, Tirabassi R, Meyers H, Wu GM, McWeeney S, Hook L, et al. A viral microRNA down-regulates multiple cell cycle genes through mRNA 5 ' UTRs. Plos Pathog. 2010;6: e1000967. doi: 10.1371/journal.ppat.1000967 20585629

13. Pfeffer S, Zavolan M, Grasser FA, Chien MC, Russo JJ, Ju JY, et al. Identification of virus-encoded microRNAs. Science. 2004;304: 734–736. doi: 10.1126/science.1096781 15118162

14. Pfeffer S. Viral miRNAs: tiny but mighty helpers for large and small DNA viruses. Future Virol. 2008;3: 291–299.

15. Yang Y, Liu T, Shen D, Wang J, Ling X, Hu Z, et al. Tomato yellow leaf curl virus intergenic siRNAs target a host long noncoding RNA to modulate disease symptoms. PLoS Pathog. 2019;15: e1007534. doi: 10.1371/journal.ppat.1007534 30668603

16. Cai Q, Qiao L, Wang M, He B, Lin FM, Palmquist J, et al. Plants send small RNAs in extracellular vesicles to fungal pathogen to silence virulence genes. Science. 2018;360: 1126–1129. doi: 10.1126/science.aar4142 29773668

17. Cai Q, Jin H. Small RNA extraction and quantification of isolated fungal cells from plant tissue by the sequential protoplastation. Methods in Molecular Biology on “RNA Abundance Analysis”, second edition, Springer Protocols. In press. 2019.

18. Zhang T, Zhao YL, Zhao JH, Wang S, Jin Y, Chen ZQ, et al. Cotton plants export microRNAs to inhibit virulence gene expression in a fungal pathogen. Nat Plants. 2016;2: 16153. doi: 10.1038/nplants.2016.153 27668926

19. Jiao J, Peng D. Wheat microRNA1023 suppresses invasion of Fusarium graminearum via targeting and silencing FGSG_03101. J Plant Interact. 2018;13: 514–521.

20. Hou YN, Zhai Y, Feng L, Karimi HZ, Rutter BD, Zeng LP, et al. A Phytophthora effector suppresses trans-kingdom RNAi to promote disease susceptibility. Cell Host Microbe. 2019;25: 153–165. doi: 10.1016/j.chom.2018.11.007 30595554

21. Buck AH, Coakley G, Simbari F, McSorley HJ, Quintana JF, Le Bihan T, et al. Exosomes secreted by nematode parasites transfer small RNAs to mammalian cells and modulate innate immunity. Nat Commun. 2014;5: 5488. doi: 10.1038/ncomms6488 25421927

22. LaMonte G, Philip N, Reardon J, Lacsina JR, Majoros W, Chapman L, et al. Translocation of sickle cell erythrocyte microRNAs into Plasmodium falciparum inhibits parasite translation and contributes to malaria resistance. Cell Host Microbe. 2012;12: 187–199. doi: 10.1016/j.chom.2012.06.007 22901539

23. Wang Z, Xi J, Hao X, Deng W, Liu J, Wei C, et al. Red blood cells release microparticles containing human argonaute 2 and miRNAs to target genes of Plasmodium falciparum. Emerg Microbes Infect. 2017;6: e75. doi: 10.1038/emi.2017.63 28831191

24. Liu SR, da Cunha AP, Rezende RM, Cialic R, Wei ZY, Bry L, et al. The host shapes the gut microbiota via fecal microRNA. Cell Host Microbe. 2016;19: 32–43. doi: 10.1016/j.chom.2015.12.005 26764595

25. Teng Y, Ren Y, Sayed M, Hu X, Lei C, Kumar A, et al. Plant-derived exosomal microRNAs shape the gut microbiota. Cell Host Microbe. 2018;24: 637–652. doi: 10.1016/j.chom.2018.10.001 30449315

26. Condon C, Putzer H. The phylogenetic distribution of bacterial ribonucleases. Nucleic Acids Res. 2002;30: 5339–5346. doi: 10.1093/nar/gkf691 12490701

27. Colombo M, Raposo G, Thery C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014;30: 255–289. doi: 10.1146/annurev-cellbio-101512-122326 25288114

28. Andreu Z, Yanez-Mo M. Tetraspanins in extracellular vesicle formation and function. Front Immunol. 2014;5: 442. doi: 10.3389/fimmu.2014.00442 25278937

29. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9: 654–659. doi: 10.1038/ncb1596 17486113

30. D’Souza-Schorey C, Clancy JW. Tumor-derived microvesicles: shedding light on novel microenvironment modulators and prospective cancer biomarkers. Genes Dev. 2012;26: 1287–1299. doi: 10.1101/gad.192351.112 22713869

31. Robbins PD, Morelli AE. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol. 2014;14: 195–208. doi: 10.1038/nri3622 24566916

32. Janas AM, Sapon K, Janas T, Stowell MHB, Janas T. Exosomes and other extracellular vesicles in neural cells and neurodegenerative diseases. Biochim Biophys Acta Biomembr. 2016;1858: 1139–1151.

33. Akers JC, Gonda D, Kim R, Carter BS, Chen CC. Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J Neurooncol. 2013;113: 1–11. doi: 10.1007/s11060-013-1084-8 23456661

34. Crescitelli R, Lasser C, Szabo TG, Kittel A, Eldh M, Dianzani I, et al. Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes. J Extracell Vesicles. 2013;2.

35. Bergsmedh A, Szeles A, Henriksson M, Bratt A, Folkman MJ, Spetz AL, et al. Horizontal transfer of oncogenes by uptake of apoptotic bodies. Proc Natl Acad Sci U S A. 2001;98: 6407–6411. doi: 10.1073/pnas.101129998 11353826

36. Zernecke A, Bidzhekov K, Noels H, Shagdarsuren E, Gan L, Denecke B, et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal. 2009;2: ra81. doi: 10.1126/scisignal.2000610 19996457

37. Coakley G, Maizels RM, Buck AH. Exosomes and other extracellular vesicles: The new communicators in parasite infections. Trends Parasitol. 2015;31: 477–489. doi: 10.1016/ 26433251

38. Chow FW, Koutsovoulos G, Ovando-Vazquez C, Neophytou K, Bermudez-Barrientos JR, Laetsch DR, et al. Secretion of an Argonaute protein by a parasitic nematode and the evolution of its siRNA guides. Nucleic Acids Res. 2019;47: 3594–3606. doi: 10.1093/nar/gkz142 30820541

39. Li J, Wu C, Wang W, He Y, Elkayam E, Joshua-Tor L, et al. Structurally modulated codelivery of siRNA and Argonaute 2 for enhanced RNA interference. Proc Natl Acad Sci U S A. 2018;115: E2696–E2705. doi: 10.1073/pnas.1719565115 29432194

40. Eichenberger RM, Ryan S, Jones L, Buitrago G, Polster R, Montes de Oca M, et al. Hookworm secreted extracellular vesicles interact with host cells and prevent inducible colitis in mice. Front Immunol. 2018;9: 850. doi: 10.3389/fimmu.2018.00850 29760697

41. Roig J, Saiz ML, Galiano A, Trelis M, Cantalapiedra F, Monteagudo C, et al. Extracellular vesicles from the helminth Fasciola hepatica prevent DSS-Induced acute ulcerative colitis in a T-lymphocyte independent mode. Front Microbiol. 2018;9: 1036. doi: 10.3389/fmicb.2018.01036 29875750

42. Halperin W, Jensen WA. Ultrastructural changes during growth and embryogenesis in carrot cell cultures. J Ultrastruct Res. 1967;18: 428–443. doi: 10.1016/s0022-5320(67)80128-x 6025110

43. Regente M, Corti-Monzon G, Maldonado AM, Pinedo M, Jorrin J, de la Canal L. Vesicular fractions of sunflower apoplastic fluids are associated with potential exosome marker proteins. FEBS Lett. 2009;583: 3363–3366. doi: 10.1016/j.febslet.2009.09.041 19796642

44. Boavida LC, Qin P, Broz M, Becker JD, McCormick S. Arabidopsis tetraspanins are confined to discrete expression domains and cell types in reproductive tissues and form homo- and heterodimers when expressed in yeast. Plant Physiol. 2013;163: 696–712. doi: 10.1104/pp.113.216598 23946353

45. Rutter BD, Innes RW. Extracellular vesicles isolated from the leaf apoplast carry stress-response proteins. Plant Physiol. 2017;173: 728–741. doi: 10.1104/pp.16.01253 27837092

46. Kwon C, Neu C, Pajonk S, Yun HS, Lipka U, Humphry M, et al. Co-option of a default secretory pathway for plant immune responses. Nature. 2008;451: 835–840. doi: 10.1038/nature06545 18273019

47. Rutter BD, Rutter K. L. and Innes R. W. Isolation and quantification of plant extracellular vesicles. Bio-protocol. 2017;7: e2533.

48. Baldrich P, Rutter BD, Zand Karimi H, Podicheti R, Meyers BC, Innes RW. Plant extracellular vesicles contain diverse small RNA species and are enriched in 10 to 17 nucleotide "Tiny" RNAs. Plant Cell. 2019;31: 315–324. doi: 10.1105/tpc.18.00872 30705133

49. Meyer D, Pajonk S, Micali C, O’Connell R, Schulze-Lefert P. Extracellular transport and integration of plant secretory proteins into pathogen-induced cell wall compartments. Plant J. 2009;57: 986–999. doi: 10.1111/j.1365-313X.2008.03743.x 19000165

50. Rutter BD, Innes RW. Extracellular vesicles as key mediators of plant-microbe interactions. Curr Opin Plant Biol. 2018;44: 16–22. doi: 10.1016/j.pbi.2018.01.008 29452903

51. Wang J, Ding Y, Wang J, Hillmer S, Miao Y, Lo SW, et al. EXPO, an exocyst-positive organelle distinct from multivesicular endosomes and autophagosomes, mediates cytosol to cell wall exocytosis in Arabidopsis and tobacco cells. Plant Cell. 2010;22: 4009–4030. doi: 10.1105/tpc.110.080697 21193573

52. Willms E, Cabanas C, Mager I, Wood MJA, Vader P. Extracellular vesicle heterogeneity: Subpopulations, isolation techniques, and diverse functions in cancer progression. Front Immunol. 2018;9: 738. doi: 10.3389/fimmu.2018.00738 29760691

53. Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF, et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A. 2011;108: 5003–5008. doi: 10.1073/pnas.1019055108 21383194

54. Michell DL, Allen RM, Landstreet SR, Zhao SL, Toth CL, Sheng QH, et al. Isolation of high-density lipoproteins for non-coding small RNA quantification. J Vis Exp. 2016;28: 54488.

55. Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol. 2011;13: 423–433. doi: 10.1038/ncb2210 21423178

56. Turchinovich A, Weiz L, Langheinz A, Burwinkel B. Characterization of extracellular circulating microRNA. Nucleic Acids Res. 2011;39: 7223–7233. doi: 10.1093/nar/gkr254 21609964

57. Zhang Q, Higginbotham JN, Jeppesen DK, Yang YP, Li W, McKinley ET, et al. Transfer of functional cargo in exomeres. Cell Rep. 2019;27: 940–954. doi: 10.1016/j.celrep.2019.01.009 30956133

58. Zhang HY, Freitas D, Kim HS, Fabijanic K, Li Z, Chen HY, et al. Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation. Nat Cell Biol. 2018;20: 332–343. doi: 10.1038/s41556-018-0040-4 29459780

59. Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006;Chapter 3: Unit 3 22. doi: 10.1002/0471143030.cb0322s30 18228490

60. Jeppesen DK, Fenix AM, Franklin JL, Higginbotham JN, Zhang Q, Zimmerman LJ, et al. Reassessment of exosome composition. Cell. 2019;177: 428–445 e18. doi: 10.1016/j.cell.2019.02.029 30951670

61. Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal-Bengtson B, et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci U S A. 2016;113: E968–E977. doi: 10.1073/pnas.1521230113 26858453

62. Rodrigues ML, Nimrichter L, Oliveira DL, Frases S, Miranda K, Zaragoza O, et al. Vesicular polysaccharide export in Cryptococcus neoformans is a eukaryotic solution to the problem of fungal trans-cell wall transport. Eukaryot Cell. 2007;6: 48–59. doi: 10.1128/EC.00318-06 17114598

63. Peres da Silva R, Puccia R, Rodrigues ML, Oliveira DL, Joffe LS, Cesar GV, et al. Extracellular vesicle-mediated export of fungal RNA. Sci Rep. 2015;5: 7763. doi: 10.1038/srep07763 25586039

64. Fisher MC, Hawkins NJ, Sanglard D, Gurr SJ. Worldwide emergence of resistance to antifungal drugs challenges human health and food security. Science. 2018;360: 739–742. doi: 10.1126/science.aap7999 29773744

65. Nunes CC, Dean RA. Host-induced gene silencing: a tool for understanding fungal host interaction and for developing novel disease control strategies. Mol Plant Pathol. 2012;13: 519–529. doi: 10.1111/j.1364-3703.2011.00766.x 22111693

66. Nowara D, Gay A, Lacomme C, Shaw J, Ridout C, Douchkov D, et al. HIGS: host-induced gene silencing in the obligate biotrophic fungal pathogen Blumeria graminis. Plant Cell. 2010;22: 3130–3141. doi: 10.1105/tpc.110.077040 20884801

67. Whangbo JS, Hunter CP. Environmental RNA interference. Trends Genet. 2008;24: 297–305. doi: 10.1016/j.tig.2008.03.007 18450316

68. Shih JD, Hunter CP. SID-1 is a dsRNA-selective dsRNA-gated channel. RNA. 2011;17: 1057–1065. doi: 10.1261/rna.2596511 21474576

69. McEwan DL, Weisman AS, Huntert CP. Uptake of extracellular double-stranded RNA by SID-2. Mol Cell. 2012;47: 746–754. doi: 10.1016/j.molcel.2012.07.014 22902558

70. Bolognesi R, Ramaseshadri P, Anderson J, Bachman P, Clinton W, Flannagan R, et al. Characterizing the mechanism of action of double-stranded RNA activity against western corn rootworm (Diabrotica virgifera virgifera LeConte). Plos One. 2012;7: e47534. doi: 10.1371/journal.pone.0047534 23071820

71. Winston WM, Sutherlin M, Wright AJ, Feinberg EH, Hunter CP. Caenorhabditis elegans SID-2 is required for environmental RNA interference. Proc Natl Acad Sci U S A. 2007;104: 10565–10570. doi: 10.1073/pnas.0611282104 17563372

72. Cai Q, He B, Kogel KH, Jin H. Cross-kingdom RNA trafficking and environmental RNAi-nature’s blueprint for modern crop protection strategies. Curr Opin Microbiol. 2018;46: 58–64. doi: 10.1016/j.mib.2018.02.003 29549797

73. Koch A, Biedenkopf D, Furch A, Weber L, Rossbach O, Abdellatef E, et al. An RNAi-based control of Fusarium graminearum infections through spraying of long dsRNAs involves a plant passage and is controlled by the fungal silencing machinery. Plos Pathog. 2016;12: e1005901. doi: 10.1371/journal.ppat.1005901 27737019

74. McLoughlin AG, Wytinck N, Walker PL, Girard IJ, Rashid KY, de Kievit T, et al. Identification and application of exogenous dsRNA confers plant protection against Sclerotinia sclerotiorum and Botrytis cinerea. Sci Rep. 2018;8: 7320. doi: 10.1038/s41598-018-25434-4 29743510

75. Mitter N, Worrall EA, Robinson KE, Li P, Jain RG, Taochy C, et al. Clay nanosheets for topical delivery of RNAi for sustained protection against plant viruses. Nat Plants. 2017;3: 16207. doi: 10.1038/nplants.2016.207 28067898

76. Regente M, Pinedo M, San Clemente H, Balliau T, Jamet E, de la Canal L. Plant extracellular vesicles are incorporated by a fungal pathogen and inhibit its growth. J Exp Bot. 2017;68: 5485–5495. doi: 10.1093/jxb/erx355 29145622

77. Tatiparti K, Sau S, Kashaw SK, Iyer AK. siRNA delivery strategies: A comprehensive review of recent developments. Nanomaterials (Basel). 2017;7: E77.

78. Groll AH, Rijnders BJA, Walsh TJ, Adler-Moore J, Lewis RE, Bruggemann RJM. Clinical pharmacokinetics, pharmacodynamics, safety and efficacy of liposomal amphotericin B. Clin Infect Dis. 2019;68: S260–S274. doi: 10.1093/cid/ciz076 31222253

79. Walker L, Sood P, Lenardon MD. The viscoelastic properties of the fungal cell wall allow traffic of AmBisome as intact liposome vesicles. mBio. 2018;9: e02383–17. doi: 10.1128/mBio.02383-17 29437927

80. Mullard A. FDA approves landmark RNAi drug. Nat Rev Drug Discov. 2018;17: 613.

81. Garcia-Solache MA, Casadevall A. Global warming will bring new fungal diseases for mammals. Mbio. 2010;1: e00061–10. doi: 10.1128/mBio.00061-10 20689745

82. Srinivasan S, Yeri A, Cheah PS, Chung A, Danielson K, De Hoff P, et al. Small RNA sequencing across diverse biofluids identifies optimal methods for exRNA isolation. Cell. 2019;177: 446–462. doi: 10.1016/j.cell.2019.03.024 30951671

83. Murillo OD, Thistlethwaite W, Rozowsky J, Subramanian SL, Lucero R, Shah N, et al. exRNA Atlas analysis reveals distinct extracellular RNA cargo types and their carriers present across human biofluids. Cell. 2019;177: 463–477 doi: 10.1016/j.cell.2019.02.018 30951672

84. Das S, Ansel KM, Bitzer M, Breakefield XO, Charest A, Galas DJ, et al. The extracellular RNA communication consortium: Establishing foundational knowledge and technologies for extracellular RNA research. Cell. 2019;177: 231–242. doi: 10.1016/j.cell.2019.03.023 30951667

85. Shurtleff MJ, Temoche-Diaz MM, Karfilis KV, Ri S, Schekman R. Y-box protein 1 is required to sort microRNAs into exosomes in cells and in a cell-free reaction. Elife. 2016;5: e19276. doi: 10.7554/eLife.19276 27559612

Hygiena a epidemiologie Infekční lékařství Laboratoř

Článek vyšel v časopise

PLOS Pathogens

2019 Číslo 12
Nejčtenější tento týden
Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Hypertenze a hypercholesterolémie – synergický efekt léčby
nový kurz
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Úloha kombinovaných preparátů v léčbě arteriální hypertenze
Autoři: prof. MUDr. Martin Haluzík, DrSc.

Autoři: MUDr. Ladislav Korábek, CSc., MBA

Terapie roztroušené sklerózy v kostce
Autoři: MUDr. Dominika Šťastná, Ph.D.

Všechny kurzy
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se