Prion Uptake in the Gut: Identification of the First Uptake and Replication Sites

English version České info

After oral exposure, prions are thought to enter Peyer's patches via M cells and accumulate first upon follicular dendritic cells (FDCs) before spreading to the nervous system. How prions are actually initially acquired from the gut lumen is not known. Using high-resolution immunofluorescence and cryo-immunogold electron microscopy, we report the trafficking of the prion protein (PrP) toward Peyer's patches of wild-type and PrP-deficient mice. PrP was transiently detectable at 1 day post feeding (dpf) within large multivesicular LAMP1-positive endosomes of enterocytes in the follicle-associated epithelium (FAE) and at much lower levels within M cells. Subsequently, PrP was detected on vesicles in the late endosomal compartments of macrophages in the subepithelial dome. At 7–21 dpf, increased PrP labelling was observed on the plasma membranes of FDCs in germinal centres of Peyer's patches from wild-type mice only, identifying FDCs as the first sites of PrP conversion and replication. Detection of PrP on extracellular vesicles displaying FAE enterocyte-derived A33 protein implied transport towards FDCs in association with FAE-derived vesicles. By 21 dpf, PrP was observed on the plasma membranes of neurons within neighbouring myenteric plexi. Together, these data identify a novel potential M cell-independent mechanism for prion transport, mediated by FAE enterocytes, which acts to initiate conversion and replication upon FDCs and subsequent infection of enteric nerves.

Vyšlo v časopise: Prion Uptake in the Gut: Identification of the First Uptake and Replication Sites. PLoS Pathog 7(12): e32767. doi:10.1371/journal.ppat.1002449
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002449

Souhrn

Zdroje

1. PrusinerSB 2007 KnipeDMHowleyPM Fields Virology Philadelphia Lippincott Williams & Wilkins 3359 3091

2. BlattlerTBrandnerSRaeberAJKleinMAVoigtlanderT 1997 PrP-expressing tissue required for transfer of scrapie infectivity from spleen to brain. Nature 389 69 73

3. BrandnerSIsenmannSRaeberAFischerMSailerA 1996 Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature 379 339 43

4. BuelerHAguzziASailerAGreinerRAAutenriedP 1993 Mice devoid of PrP are resistant to scrapie. Cell 73 1339 47

5. PeretzDWilliamsonRAMatsunagaYSerbanHPinillaC 1997 A conformational transition at the N terminus of the prion protein features in formation of the scrapie isoform. J Mol Biol 273 614 22

6. KrügerDThomzigALenzGKampfKMcBrideP 2009 Faecal shedding, alimentary clearance and intestinal spread of prions in hamsters fed with scrapie. Vet Res 40 4

7. AndreolettiOBerthonPMarcDSarradinPGrosclaudeJ 2000 Early accumulation of PrP(Sc) in gut-associated lymphoid and nervous tissues of susceptible sheep from a Romanov flock with natural scrapie. J Gen Virol 81 3115 26

8. BeekesMMcBridePA 2000 Early accumulation of pathological PrP in the enteric nervous system and gut-associated lymphoid tissue of hamsters orally infected with scrapie. Neurosci Lett 278 181 4

9. GlaysherBRMabbottNA 2007 Role of the GALT in scrapie agent neuroinvasion from the intestine. J Immunol 178 3757 66

10. HeggeboRPressCMGunnesGUlvundMJTranulisMA 2003 Detection of PrPSc in lymphoid tissues of lambs experimentally exposed to the scrapie agent. J Comp Pathol 128 172 81

11. JeffreyMMcGovernGGoodsirCMBrownKLBruceME 2000 Sites of prion protein accumulation in scrapie-infected mouse spleen revealed by immuno-electron microscopy. J Pathol 191 323 32

12. PrinzMHuberGMacPhersonAJSHeppnerFLGlatzelM 2003 Oral prion infection requires normal numbers of Peyer's patches but not of enteric lymphocytes. Am J Pathol 162 1103 11

13. SigurdsonCJBarillas-MuryCMillerMWOeschBvan KeulenLJ 2002 PrP(CWD) lymphoid cell targets in early and advanced chronic wasting disease of mule deer. J Gen Virol 83 2617 28

14. MabbottNAYoungJMcConnellIBruceME 2003 Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphotoxin pathway dramatically reduces scrapie susceptibility. J Virol 77 6845 54

15. AguzziA 2003 Prions and the immune system: a journey through gut, spleen, and nerves. Adv Immunol 81 123 71

16. MabbottNAMacPhersonGG 2006 Prions and their lethal journey to the brain. Nat Rev Microbiol 4 201 11

17. AnoYSakudoANakayamaHOnoderaT 2009 Uptake and dynamics of infectious prion protein in the intestine. Protein Pept Lett 16 247 55

18. KraehenbuhlJPNeutraMR 2000 Epithelial M cells: differentiation and function. Annu Rev Cell Dev Biol 16 301 32

19. HeppnerFLChristADKleinMAPrinzMFriedM 2001 Transepithelial prion transport by M cells. Nat Med 7 976 7

20. MiyazawaKKanayaTTakakuraITanakaSHondoT 2010 Transcytosis of murine-adapted BSE agents in an in vitro bovine M cell model. J Virol 84 12285 12291

21. FosterNMacphersonGG 2010 Murine cecal patch M cells transport infectious prions in vivo. J Infect Dis 202 1916 1919

22. JeffreyMGonzálezLEspenesAPressCMMartinS 2006 Transportation of prion protein across the intestinal mucosa of scrapie-susceptible and scrapie-resistant sheep. J Pathol 209 4 14

23. MishraRSBasuSGuYLuoXZouW-Q 2004 Protease-resistant human prion protein and ferritin are cotransported across Caco-2 epithelial cells: Implications for species barrier in prion uptake from the intestine. J Neurosci 24 11280 90

24. RescignoMUrbanoMValzasinaBFrancoliniMRottaG 2001 Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol 2 361 367

25. RaymondCRAucouturierPMabbottNA 2007 In vivo depletion of CD11c+ cells impairs scrapie agent neuroinvasion from the intestine. J Immunol 179 7758 66

26. MabbottNAKenneth BaillieJKobayashiADonaldsonDSOhmoriH 2011 Expression of mesenchyme-specific gene signatures by follicular dendritic cells: insights from the meta-analysis of microarray data from multiple mouse cell populations. Immunology 133 482 498

27. BrownKLStewartKRitchieDLMabbottNAWilliamsA 1999 Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells. Nat Med 5 1308 12

28. KitamotoTMuramotoTMohriSDoh-UraKTateishiJ 1991 Abnormal isoform of prion protein accumulates in follicular dendritic cells in mice with Creutzfeldt-Jakob disease. J Virol 65 6292 5

29. KleinMAFriggRRaeberAJFlechsigEHegyiI 1998 PrP expression in B lymphocytes is not required for prion neuroinvasion. Nat Med 4 1429 33

30. ZabelMDHeikenwalderMPrinzMArrighiISchwarzP 2007 Stromal complement receptor CD21/35 facilitates lymphoid prion colonization and pathogenesis. J Immunol 179 6144 52

31. McBridePAEikelenboomPKraalGFraserHBruceME 1992 PrP protein is associated with follicular dendritic cells of spleens and lymph nodes in uninfected and scrapie-infected mice. J Pathol 168 413 8

32. BeekesMMcBridePA 2007 The spread of prions through the body in naturally acquired transmissible spongiform encephalopathies. FEBS Journal 274 588 605

33. MansonJCClarkeARHooperMLAitchisonLMcConnellI 1994 129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal. Mol Neurobiol 8 121 7

34. HaseKKawanoKNochiTPontesGSFukudaS 2009 Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response. Nature 462 226 30

35. VerbrugghePWaelputWDieriksBWaeytensAVandesompeleJ 2006 Murine M cells express annexin V specifically. J Pathol 209 240 249

36. BoltonDCSeligmanSJBablanianGWindsorDScalaLJ 1991 Molecular location of a species-specific epitope on the hamster scrapie agent protein. J Virol 65 3667 75

37. HumeDA 2006 The mononuclear phagocyte system. Curr Opin Immunol 18 49 53

38. BradfordBMSesteraDPHumeDAMabbottNA 2011 Defining the anatomical localisation of subsets of the murine mononuclear phagocyte system using integrin alpha X (Itgax, CD11c) and colony stimulating factor 1 receptor (Csf1r, CD115) expression fails to discriminate dendritic cells from macrophages. Immunobiology 216 1228 1237

39. PetersJPRademakersLHde BoerRJvan UnnikJA 1987 Cellular composition of follicles of follicle centre cell lymphomas in relation to germinal centres of reactive lymph nodes. A morphometrical electromicroscopical study. J Pathol 153 233 44

40. DenzerKvan EijkMKleijmeerMJJakobsonEde GrootC 2000 Follicular dendritic cells carry MHC class II-expressing microvesicles at their surface. J Immunol 165 1259 65

41. PastranaMASajnaniGOniskoBCastillaJMoralesR 2006 Isolation and Characterization of a Proteinase K-Sensitive PrP(Sc) Fraction. Biochemistry 45 15710 15717

42. GodsaveSFWilleHKujalaPLatawiecDDeArmondSJ 2008 Cryo-immunogold electron microscopy for prions: toward identification of a conversion site. J Neurosci 28 12489 99

43. PetersPJMironovAJrPeretzDvan DonselaarELeclercE 2003 Trafficking of prion proteins through a caveolae-mediated endosomal pathway. J Cell Biol 162 703 17

44. JohnstoneCNWhiteSJTebbuttNCClayFJErnstM 2002 Analysis of the regulation of the A33 antigen gene reveals intestine-specific mechanisms of gene expression. J Biol Chem 277 34531 9

45. LeeJWEpardaudMSunJBeckerJEChengAC 2007 Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat Immunol 8 181 90

46. PetersPJBorstJOorschotVFukudaMKrähenbühlO 1991 Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. J Exp Med 173 1099 109

47. AguzziARajendranL 2009 The transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron 64 783 90

48. FrostBDiamondMI 2010 Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci 11 155 9

49. MironovAJrLatawiecDWilleHBouzamondo-BernsteinELegnameG 2003 Cytosolic prion protein in neurons. J Neurosci 23 7183 93

50. KorthCStierliBStreitPMoserMSchallerO 1997 Prion (PrPSc)-specific epitope defined by a monoclonal antibody. Nature 390 74 7

51. WilliamsonRAPeretzDPinillaCBallHBastidasRB 1998 Mapping the prion protein using recombinant antibodies. J Virol 72 9413 8

52. SimonsMRaposoG 2009 Exosomes – vesicular carriers for intracellular communication. Current Opin in Cell Biol 21 575 581

53. PetersPJGeuzeHJvan der DonkHABorstJ 1990 A new model for lethal hit delivery by cytotoxic T lymphocytes. Immunol Today 11 28 32

54. van NielGMallegolJBevilacquaCCandalhCBrugiereS 2003 Intestinal epithelial exosomes carry MHC class II/peptides able to inform the immune system in mice. Gut 52 1690 7

55. FevrierBViletteDArcherFLoewDFaigleW 2004 Cells release prions in association with exosomes. Proc Natl Acad Sci U S A 101 9683 8

56. HoffmannCZieglerUBuschmannAWeberAKupferL 2007 Prions spread via the autonomic nervous system from the gut to the central nervous system in cattle incubating bovine spongiform encephalopathy. J Gen Virol 88 1048 55

57. BartzJCDejoiaCTuckerTKincaidAEBessenRA 2005 Extraneural prion neuroinvasion without lymphoreticular system infection. J Virol 79 11858 11863

58. SigurdsonCJ 2008 A prion disease of cervids: chronic wasting disease. Vet Res 39 41

59. BenestadSLArsacJNGoldmannWNöremarkM 2008 Atypical/Nor98 scrapie: properties of the agent, genetics, and epidemiology. Vet Res 39 19

60. SafarJGDeArmondSJKociubaKDeeringCDidorenkoS 2005 Prion clearance in bigenic mice. J Gen Virol 86 2913 2923

61. SafarJGGeschwindMDDeeringCDidorenkoSSattavatM 2005 Diagnosis of human prion disease. Proc Natl Acad Sci U S A 102 3501 3506

62. Pereira-FantiniPMJuddLMKalantzisAPetersonAErnstM 2009 A33 Antigen-deficient mice have defective colonic mucosal repair. Inflamm Bowel Dis 16 604 12

63. PetersPJBosEGriekspoorA 2006 Cryo-immunogold electron microscopy. Curr Protoc Cell Biol; Chapter 4: Unit 4.7

64. FarquharCFSomervilleRARitchieLA 1989 Post-mortem immunodiagnosis of scrapie and bovine spongiform encephalopathy. J Virol Methods 24 215 222