-
Články
- Časopisy
- Kurzy
- Témy
- Kongresy
- Videa
- Podcasty
Age-Dependent Enterocyte Invasion and Microcolony Formation by
Non-typhoidal Salmonella are among of the most prevalent causative agents of infectious diarrheal disease worldwide but also very significantly contribute to infant sepsis and meningitis particularly in developing countries. The underlying mechanisms of the elevated susceptibility of the infant host to systemic Salmonella infection have not been investigated. Here we analyzed age-dependent differences in the colonization, mucosal translocation and systemic spread in a murine oral infection model. We observed efficient entry of Salmonella in intestinal epithelial cells of newborn mice. Enterocyte invasion was followed by massive bacterial proliferation and the formation of large intraepithelial bacterial colonies. Intraepithelial, but not non-invasive, extracellular Salmonella induced a potent immune stimulation. Also, enterocyte invasion was required for translocation through the mucosal barrier and spread of Salmonella to systemic organs. This requirement was due to the absence of M cells, specialized epithelial cells that forward luminal antigen to the underlying immune cells, in the neonate host. Our results identify age-dependent factors of host susceptibility and illustrate the initial phase of Salmonella infection. They further present a new small animal model amenable to genetic manipulation to investigate the interaction of this pathogen with epithelial cells and characterize the early steps in Salmonella pathogenesis.
Vyšlo v časopise: Age-Dependent Enterocyte Invasion and Microcolony Formation by. PLoS Pathog 10(9): e32767. doi:10.1371/journal.ppat.1004385
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004385Souhrn
Non-typhoidal Salmonella are among of the most prevalent causative agents of infectious diarrheal disease worldwide but also very significantly contribute to infant sepsis and meningitis particularly in developing countries. The underlying mechanisms of the elevated susceptibility of the infant host to systemic Salmonella infection have not been investigated. Here we analyzed age-dependent differences in the colonization, mucosal translocation and systemic spread in a murine oral infection model. We observed efficient entry of Salmonella in intestinal epithelial cells of newborn mice. Enterocyte invasion was followed by massive bacterial proliferation and the formation of large intraepithelial bacterial colonies. Intraepithelial, but not non-invasive, extracellular Salmonella induced a potent immune stimulation. Also, enterocyte invasion was required for translocation through the mucosal barrier and spread of Salmonella to systemic organs. This requirement was due to the absence of M cells, specialized epithelial cells that forward luminal antigen to the underlying immune cells, in the neonate host. Our results identify age-dependent factors of host susceptibility and illustrate the initial phase of Salmonella infection. They further present a new small animal model amenable to genetic manipulation to investigate the interaction of this pathogen with epithelial cells and characterize the early steps in Salmonella pathogenesis.
Zdroje
1. MolyneuxE, WalshA, PhiriA, MolyneuxM (1998) Acute bacterial meningitis in children admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi in 1996–97. Trop Med Int Health 3 : 610–618.
2. MilledgeJ, CalisJC, GrahamSM, PhiriA, WilsonLK, et al. (2005) Aetiology of neonatal sepsis in Blantyre, Malawi: 1996–2001. Ann Trop Paediatr 25 : 101–110.
3. SigaúqueB, RocaA, MandomandoI, MoraisL, QuintóL, et al. (2009) Community-acquired bacteremia among children admitted to a rural hospital in Mozambique. Pediatr Infect Dis J 28 : 108–113.
4. MakokaMH, MillerWC, HoffmanIF, CholeraR, GilliganPH, et al. (2012) Bacterial infections in Lilongwe, Malawi: aetiology and antibiotic resistance. BMC Infect Dis 12 : 67 doi: 10.1186/1471-2334-12-67
5. McCormickDW, WilsonML, MankhamboL, PhiriA, ChimalizeniY, et al. (2013) Risk factors for death and severe sequelae in Malawian children with bacterial meningitis, 1997–2010. Pediatr Infect Dis J 32: e54–61.
6. QueF, WuS, HuangR (2013) Salmonella pathogenicity island 1(SPI-1) at work. Curr Microbiol 66 : 582–587.
7. HapfelmeierS, StecherB, BarthelM, KremerM, MüllerAJ, et al. (2005) The Salmonella pathogenicity island (SPI)-2 and SPI-1 type III secretion systems allow Salmonella serovar typhimurium to trigger colitis via MyD88-dependent and MyD88-independent mechanisms. J Immunol 174 : 1675–1685.
8. García-Del PortilloF, PucciarelliMG, CasadesúsJ (1999) DNA adenine methylase mutants of Salmonella typhimurium show defects in protein secretion, cell invasion, and M cell cytotoxicity. Proc Natl Acad Sci U S A 96 : 11578–11583.
9. AnjumMF, MarooneyC, FookesM, BakerS, DouganG, et al. (2005) Identification of core and variable components of the Salmonella enterica subspecies I genome by microarray. Infect Immun 73 : 7894–7905.
10. FigueiraR, WatsonKG, HoldenDW, HelaineS (2013) Identification of salmonella pathogenicity island-2 type III secretion system effectors involved in intramacrophage replication of S. enterica serovar typhimurium: implications for rational vaccine design. MBio 4: e00065 doi: 10.1128/mBio.00065-13
11. HapfelmeierS, MüllerAJ, StecherB, KaiserP, BarthelM, et al. (2008) Microbe sampling by mucosal dendritic cells is a discrete, MyD88-independent step in DeltainvG S. Typhimurium colitis. J Exp Med 205 : 437–450.
12. FelmyB, SonghetP, SlackEM, MüllerAJ, KremerM, et al. (2013) NADPH oxidase deficient mice develop colitis and bacteremia upon infection with normally avirulent, TTSS-1 - and TTSS-2-deficient Salmonella Typhimurium. PLoS One 8: e77204.
13. SonghetP, BarthelM, StecherB, MüllerAJ, KremerM, et al. (2011) Stromal IFN-γR-signaling modulates goblet cell function during Salmonella Typhimurium infection. PLoS One 6: e22459.
14. MüllerAJ, HoffmannC, GalleM, Van Den BroekeA, HeikenwalderM, et al. (2009) The S. Typhimurium effector SopE induces caspase-1 activation in stromal cells to initiate gut inflammation. Cell Host Microbe 6 : 125–136.
15. MüllerAJ, KaiserP, DittmarKE, WeberTC, HaueterS, et al. (2012) Salmonella gut invasion involves TTSS-2-dependent epithelial traversal, basolateral exit, and uptake by epithelium-sampling lamina propria phagocytes. Cell Host Microbe 11 : 19–32.
16. JonesBD, GhoriN, FalkowS (1994) Salmonella typhimurium initiates murine infection by penetrating and destroying the specialized epithelial M cells of the Peyer's patches. J Exp Med 180 : 15–23.
17. JangMH, KweonMN, IwataniK, YamamotoM, TeraharaK, et al. (2004) Intestinal villous M cells: an antigen entry site in the mucosal epithelium. Proc. Natl. Acad. Sci. USA 101 : 6110–6115.
18. KanayaT, HaseK, TakahashiD, FukudaS, HoshinoK, et al. (2012) The Ets transcription factor Spi-B is essential for the differentiation of intestinal microfold cells. Nat Immunol 13 : 729–736.
19. FaracheJ, KorenI, MiloI, GurevichI, KimKW, et al. (2013) Luminal bacteria recruit CD103+ dendritic cells into the intestinal epithelium to sample bacterial antigens for presentation. Immunity 38 : 581–595.
20. HaseK, KawanoK, NochiT, PontesGS, FukudaS, et al. (2009) Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response. Nature 462 : 226–230.
21. TahounA, MahajanS, PaxtonE, MaltererG, DonaldsonDS, et al. (2012) Salmonella transforms follicle-associated epithelial cells into M cells to promote intestinal invasion. Cell Host Microbe 12 : 645–656.
22. de Santa BarbaraP, van den BrinkGR, RobertsDJ (2003) Development and differentiation of the intestinal epithelium. Cell Mol Life Sci 60 : 1322–1332.
23. MuncanV, HeijmansJ, KrasinskiSD, BüllerNV, WildenbergME, et al. (2011) Blimp1 regulates the transition of neonatal to adult intestinal epithelium. Nat Commun 2 : 452 doi: 10.1038/ncomms1463
24. MénardS, FörsterV, LotzM, GütleD, DuerrCU, et al. (2008) Developmental switch of intestinal antimicrobial peptide expression. J Exp Med 205 : 183–193.
25. BarthelM, HapfelmeierS, Quintanilla-MartínezL, KremerM, RohdeM, et al. (2003) Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host. Infect Immun 71 : 2839–2858.
26. TakeuchiA (1967) Electron microscope studies of experimental Salmonella infection. I. Penetration into the intestinal epithelium by Salmonella typhimurium. Am J Pathol 50 : 109–136.
27. NietfeldJC, TylerDE, HarrisonLR, ColeJR, LatimerKS, et al. (1992) Invasion of enterocytes in cultured porcine small intestinal mucosal explants by Salmonella choleraesuis. Am J Vet Res 53 : 1493–1499.
28. GiannellaRA, FormalSB, DamminGJ, CollinsH (1972) Pathogenesis of salmonellosis. Studies of fluid secretion, mucosal invasion, and morphologic reaction in the rabbit ileum. J Clin Invest 52 : 441–453.
29. FrostAJ, BlandAP, WallisTS (1997) The early dynamic response of the calf ileal epithelium to Salmonella typhimurium. Vet Pathol 34 : 369–386.
30. LaughlinRC, KnodlerLA, BarhoumiR, PayneHR, WuJ, et al. (2014) Spatial segregation of virulence gene expression during acute enteric infection with Salmonella enterica serovar Typhimurium. MBio 5: e00946-13 doi: 10.1128/mBio.00946-13
31. BoltonAJ, OsborneMP, WallisTS, StephenJ (1999) Interaction of Salmonella choleraesuis, Salmonella dublin and Salmonella typhimurium with porcine and bovine terminal ileum in vivo. Microbiology 145 : 2431–2441.
32. SantosRL, ZhangS, TsolisRM, BäumlerAJ, AdamsLG (2002) Morphologic and molecular characterization of Salmonella typhimurium infection in neonatal calves. Vet Pathol 39 : 200–215.
33. OchmanH, GroismanEA (1996) Distribution of pathogenicity islands in Salmonella spp. Infect Immun 64 : 5410–5412.
34. ZhangS, SantosRL, TsolisRM, StenderS, HardtWD, et al. (2002) The Salmonella enterica serotype typhimurium effector proteins SipA, SopA, SopB, SopD, and SopE2 act in concert to induce diarrhea in calves. Infect Immun 70 : 3843–3855.
35. TsolisRM, AdamsLG, FichtTA, BäumlerAJ (1999) Contribution of Salmonella typhimurium virulence factors to diarrheal disease in calves. Infect Immun 67 : 4879–4885.
36. HapfelmeierS, EhrbarK, StecherB, BarthelM, KremerM, et al. (2004) Role of the Salmonella pathogenicity island 1 effector proteins SipA, SopB, SopE, and SopE2 in Salmonella enterica subspecies 1 serovar Typhimurium colitis in streptomycin-pretreated mice. Infect Immun 72 : 795–809.
37. ConwayKL, KuballaP, SongJH, PatelKK, CastorenoAB, et al. (2013) Atg16l1 is required for autophagy in intestinal epithelial cells and protection of mice from Salmonella infection. Gastroenterology 145 : 1347–1357.
38. BenjaminJL, SumpterRJr, LevineB, HooperLV (2013) Intestinal epithelial autophagy is essential for host defense against invasive bacteria. Cell Host Microbe 13 : 723–734.
39. ThurstonTL, WandelMP, von MuhlinenN, FoegleinA, RandowF (2012) Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 482 : 414–418.
40. ZarepourM, BhullarK, MonteroM, MaC, HuangT, et al. (2013) The mucin Muc2 limits pathogen burdens and epithelial barrier dysfunction during Salmonella enterica serovar Typhimurium colitis. Infect Immun 81 : 3672–3683.
41. WilsonCL, OuelletteAJ, SatchellDP, AyabeT, López-BoadoYS, et al. (1999) Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286 : 113–117.
42. SalzmanNH, GhoshD, HuttnerKM, PatersonY, BevinsCL (2003) Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 422 : 522–526.
43. DupontA, KaconisY, YangI, AlbersT, WoltemateS, et al. (2014) Intestinal mucus affinity and biological activity of an orally administered antibacterial and anti-inflammatory peptide. Gut [epub ahead of print] doi: 10.1136/gutjnl-2014-307150
44. SchauserK, OlsenJE, LarssonLI (2005) Salmonella typhimurium infection in the porcine intestine: evidence for caspase-3-dependent and -independent programmed cell death. Histochem Cell Biol 123 : 43–50.
45. KunisawaJ, KiyonoH (2012) Alcaligenes is commensal bacteria habituating in the gut-associated lymphoid tissue for the regulation of intestinal IgA responses. Front Immunol 3 : 65 doi: 10.3389/fimmu.2012.0006.
46. EcheverryA, SchesserK, AdkinsB (2007) Murine neonates are highly resistant to Yersinia enterocolitica following orogastric exposure. Infect Immun 75 : 2234–2243.
47. ClarkMA, HirstBH, JepsonMA (1998) M-cell surface beta1 integrin expression and invasin-mediated targeting of Yersinia pseudotuberculosis to mouse Peyer's patch M cells. Infect Immun 66 : 1237–1243.
48. GodinezI, HanedaT, RaffatelluM, GeorgeMD, PaixãoTA, et al. (2008) T cells help to amplify inflammatory responses induced by Salmonella enterica serotype Typhimurium in the intestinal mucosa. Infect Immun 76 : 2008–2017.
49. LawhonSD, KhareS, RossettiCA, EvertsRE, GalindoCL, et al. (2011) Role of SPI-1 secreted effectors in acute bovine response to Salmonella enterica Serovar Typhimurium: a systems biology analysis approach. PLoS One 6: e26869.
50. WeissDS, RaupachB, TakedaK, AkiraS, ZychlinskyA (2004) Toll-like receptors are temporally involved in host defense. J Immunol 172 : 4463–4439.
51. RoyMF, LarivièreL, WilkinsonR, TamM, StevensonMM, et al. (2006) Incremental expression of Tlr4 correlates with mouse resistance to Salmonella infection and fine regulation of relevant immune genes. Genes Immun 7 : 372–383.
52. BrinkmannMM, SpoonerE, HoebeK, BeutlerB, PloeghHL, et al. (2007) The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling. J Cell Biol 177 : 265–275.
53. ArpaiaN, GodecJ, LauL, SivickKE, McLaughlinLM, et al. (2011) TLR signaling is required for Salmonella typhimurium virulence. Cell 144 : 675–688.
54. ZengH, CarlsonAQ, GuoY, YuY, Collier-HyamsLS, et al. (2003) Flagellin is the major proinflammatory determinant of enteropathogenic Salmonella. J Immunol 171 : 3668–3674.
55. WinterSE, WinterMG, XavierMN, ThiennimitrP, PoonV, et al. (2013) Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 339 : 708–711.
56. AntunesLC, FinlayBB (2011) A comparative analysis of the effect of antibiotic treatment and enteric infection on intestinal homeostasis. Gut Microbes 2 : 105–108.
57. RaffatelluM, SantosRL, VerhoevenDE, GeorgeMD, WilsonRP, et al. (2008) Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nat Med 14 : 421–428.
58. GerlachRG, CláudioN, RohdeM, JäckelD, WagnerC, et al. (2008) Cooperation of Salmonella pathogenicity islands 1 and 4 is required to breach epithelial barriers. Cell Microbiol 10 : 2364–2376.
59. TabetaK, HoebeK, JanssenEM, DuX, GeorgelP, et al. (2006) The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat Immunol 7 : 156–164.
60. HemmiH, TakeuchiO, KawaiT, KaishoT, SatoS, et al. (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408 : 740–745.
61. ReynoldsES (1963) The use of lead citrate at high pH as an electron-opaque stain in electron microscopy. J Cell Biol 17 : 208–213.
62. LotzM, GütleD, WaltherS, MénardS, BogdanC, et al. (2006) Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J Exp Med 203 : 973–984.
Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium
Článek Out-of-Sequence Signal 3 as a Mechanism for Virus-Induced Immune Suppression of CD8 T Cell ResponsesČlánek RNF26 Temporally Regulates Virus-Triggered Type I Interferon Induction by Two Distinct MechanismsČlánek Mouse, but Not Human, ApoB-100 Lipoprotein Cholesterol Is a Potent Innate Inhibitor of Pneumolysin
Článok vyšiel v časopisePLOS Pathogens
Najčítanejšie tento týždeň
2014 Číslo 9- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
-
Všetky články tohto čísla
- Virus Control Goes Epigenetic
- The Role of Iron in Prion Disease and Other Neurodegenerative Diseases
- The Ins and Outs of Rust Haustoria
- Prion Strains and Amyloid Polymorphism Influence Phenotypic Variation
- Teaching Fido New ModiFICation Tricks
- Can Enhance Infection in Mosquitoes: Implications for Malaria Control?
- MIF Contributes to Associated Immunopathogenicity Development
- Persistence of Virus Reservoirs in ART-Treated SHIV-Infected Rhesus Macaques after Autologous Hematopoietic Stem Cell Transplant
- Bacillus Calmette-Guerin Infection in NADPH Oxidase Deficiency: Defective Mycobacterial Sequestration and Granuloma Formation
- EhCoactosin Stabilizes Actin Filaments in the Protist Parasite
- Molecular Insights Into the Evolutionary Pathway of O1 Atypical El Tor Variants
- LprG-Mediated Surface Expression of Lipoarabinomannan Is Essential for Virulence of
- Structural Correlates of Rotavirus Cell Entry
- Multivalent Adhesion Molecule 7 Clusters Act as Signaling Platform for Host Cellular GTPase Activation and Facilitate Epithelial Barrier Dysfunction
- The Effects of Vaccination and Immunity on Bacterial Infection Dynamics
- Myeloid Derived Hypoxia Inducible Factor 1-alpha Is Required for Protection against Pulmonary Infection
- Functional Characterisation of Germinant Receptors in and Presents Novel Insights into Spore Germination Systems
- Global Analysis of Neutrophil Responses to Reveals a Self-Propagating Inflammatory Program
- Host Cell Invasion by Apicomplexan Parasites: The Junction Conundrum
- Comparative Phenotypic Analysis of the Major Fungal Pathogens and
- Unravelling the Multiple Functions of the Architecturally Intricate β-galactosidase, BgaA
- Sialylation of Prion Protein Controls the Rate of Prion Amplification, the Cross-Species Barrier, the Ratio of PrP Glycoform and Prion Infectivity
- Symbionts Commonly Provide Broad Spectrum Resistance to Viruses in Insects: A Comparative Analysis of Strains
- Ontogeny of Recognition Specificity and Functionality for the Broadly Neutralizing Anti-HIV Antibody 4E10
- Identification and Characterisation of a Hyper-Variable Apoplastic Effector Gene Family of the Potato Cyst Nematodes
- Crimean-Congo Hemorrhagic Fever Virus Entry into Host Cells Occurs through the Multivesicular Body and Requires ESCRT Regulators
- Age-Dependent Enterocyte Invasion and Microcolony Formation by
- CD160-Associated CD8 T-Cell Functional Impairment Is Independent of PD-1 Expression
- Functional Fluorescent Protein Insertions in Herpes Simplex Virus gB Report on gB Conformation before and after Execution of Membrane Fusion
- The Tudor Domain Protein Spindlin1 Is Involved in Intrinsic Antiviral Defense against Incoming Hepatitis B Virus and Herpes Simplex Virus Type 1
- Transgenic Analysis of the MAP Kinase MPK10 Reveals an Auto-inhibitory Mechanism Crucial for Stage-Regulated Activity and Parasite Viability
- Evidence for a Transketolase-Mediated Metabolic Checkpoint Governing Biotrophic Growth in Rice Cells by the Blast Fungus
- Incomplete Deletion of IL-4Rα by LysM Reveals Distinct Subsets of M2 Macrophages Controlling Inflammation and Fibrosis in Chronic Schistosomiasis
- Identification and Functional Expression of a Glutamate- and Avermectin-Gated Chloride Channel from , a Southern Hemisphere Sea Louse Affecting Farmed Fish
- Out-of-Sequence Signal 3 as a Mechanism for Virus-Induced Immune Suppression of CD8 T Cell Responses
- Strong Epistatic Selection on the RNA Secondary Structure of HIV
- Hematopoietic but Not Endothelial Cell MyD88 Contributes to Host Defense during Gram-negative Pneumonia Derived Sepsis
- Delineation of Interfaces on Human Alpha-Defensins Critical for Human Adenovirus and Human Papillomavirus Inhibition
- Exploitation of Reporter Strains to Probe the Impact of Vaccination at Sites of Infection
- RNF26 Temporally Regulates Virus-Triggered Type I Interferon Induction by Two Distinct Mechanisms
- Helminth Infections Coincident with Active Pulmonary Tuberculosis Inhibit Mono- and Multifunctional CD4 and CD8 T Cell Responses in a Process Dependent on IL-10
- MHC Class II Restricted Innate-Like Double Negative T Cells Contribute to Optimal Primary and Secondary Immunity to
- Reactive Oxygen Species Regulate Caspase-11 Expression and Activation of the Non-canonical NLRP3 Inflammasome during Enteric Pathogen Infection
- Evolution of Plastic Transmission Strategies in Avian Malaria
- A New Human 3D-Liver Model Unravels the Role of Galectins in Liver Infection by the Parasite
- Translocates into the Myocardium and Forms Unique Microlesions That Disrupt Cardiac Function
- Mouse, but Not Human, ApoB-100 Lipoprotein Cholesterol Is a Potent Innate Inhibitor of Pneumolysin
- The Cofilin Phosphatase Slingshot Homolog 1 (SSH1) Links NOD1 Signaling to Actin Remodeling
- Kaposi's Sarcoma Herpesvirus MicroRNAs Induce Metabolic Transformation of Infected Cells
- Reorganization of the Endosomal System in -Infected Cells: The Ultrastructure of -Induced Tubular Compartments
- Distinct Dictation of Japanese Encephalitis Virus-Induced Neuroinflammation and Lethality via Triggering TLR3 and TLR4 Signal Pathways
- Exploitation of the Complement System by Oncogenic Kaposi's Sarcoma-Associated Herpesvirus for Cell Survival and Persistent Infection
- The Secreted Peptide PIP1 Amplifies Immunity through Receptor-Like Kinase 7
- Structural Insight into Host Recognition by Aggregative Adherence Fimbriae of Enteroaggregative
- The CD14CD16 Inflammatory Monocyte Subset Displays Increased Mitochondrial Activity and Effector Function During Acute Malaria
- Infection Induces Expression of a Mosquito Salivary Protein (Agaphelin) That Targets Neutrophil Function and Inhibits Thrombosis without Impairing Hemostasis
- PLOS Pathogens
- Archív čísel
- Aktuálne číslo
- Informácie o časopise
Najčítanejšie v tomto čísle- The Secreted Peptide PIP1 Amplifies Immunity through Receptor-Like Kinase 7
- Symbionts Commonly Provide Broad Spectrum Resistance to Viruses in Insects: A Comparative Analysis of Strains
- MIF Contributes to Associated Immunopathogenicity Development
- The Ins and Outs of Rust Haustoria
Prihlásenie#ADS_BOTTOM_SCRIPTS#Zabudnuté hesloZadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
- Časopisy