Skip to main content
Log in

Immunohistochemical characterization of cell types expressing the cellular prion protein in the small intestine of cattle and mice

  • Original Paper
  • Published:
Histochemistry and Cell Biology Aims and scope Submit manuscript

Abstract

The gastrointestinal tract is thought to be the main site of entry for the pathological isoform of the prion protein (PrPSc). Prion diseases are believed to result from a conformational change of the cellular prion protein (PrPc) to PrPSc. Therefore, PrPc expression is a prerequisite for the infection and spread of the disease to the central nervous system. However, the distribution of PrPc in the gut is still a matter of controversy. We therefore investigated the localization of PrPc in the bovine and murine small intestine. In cattle, most PrPc positive epithelial cells were detected in the duodenum, while a few positive cells were found in the jejunum. PrPc was expressed in serotonin producing cells. In bovine Peyer’s patches, PrPc was distributed in extrafollicular areas, but not in the germinal centre of the jejunum and ileum. PrPc was expressed in myeloid lineage cells such as myeloid dendritic cells and macrophages. In mice, PrPc was expressed in some epithelial cells throughout the small intestine as well as in cells such as follicular dendritic cell in the germinal centre of Peyer’s patches. In this study, we demonstrate that there are a number of differences in the localization of PrPc between the murine and bovine small intestines.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Andreoletti O, Berthon P, Marc D, Sarradin P, Grosclaude J, van Keulen L, Schelcher F, Elsen JM, Lantier F (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 81:3115–3126

    PubMed  CAS  Google Scholar 

  • Asano M, Mohri S, Ironside JW, Ito M, Tamaoki N, Kitamoto T (2006) vCJD prion acquires altered virulence through trans-species infection. Biochem Biophys Res Commun 342:293–299

    Article  PubMed  CAS  Google Scholar 

  • Beekes M, McBride PA (2000) Early accumulation of pathological PrP in the enteric nervous system and gut-associated lymphoid tissue of hamsters orally infected with scrapie. Neurosci Lett 278:181–184

    Article  PubMed  CAS  Google Scholar 

  • Bencsik A, Lezmi S, Hunsmann G, Baron T (2001) Close vicinity of PrP expressing cells (FDC) with noradrenergic fibers in healthy sheep spleen. Dev Immunol 8:235–241

    PubMed  CAS  Google Scholar 

  • Bergstrőm AL, Jensen TK, Heegaard PM, Cordes H, Hansen VB, Laursen H, Lind P (2006) Short-term study of the uptake of PrP(Sc) by the Peyer’s patches in Hamsters after oral exposure to Scrapie. J Comp Pathol. [Epub ahead of print]

  • Bons N, Mestre-Frances N, Belli P, Cathala F, Gajdusek DC, Brown P (1999) Natural and experimental oral infection of nonhuman primates by bovine spongiform encephalopathy agents. Proc Natl Acad Sci USA 96:4046–4051

    Article  PubMed  CAS  Google Scholar 

  • Brown HR, Goller NL, Rudelli RD, Merz GS, Wolfe GC, Wisniewski HM, Robakis NK (1990) The mRNA encoding the scrapie agent protein is present in a variety of non-neuronal cells. Acta Neuropathol (Berl) 80:1–6

    Article  CAS  Google Scholar 

  • Brown KL, Stewart K, Ritchie DL, Mabbott NA, Williams A, Fraser H, Morrison WI, Bruce ME (1999) Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells. Nat Med 5:1308–1312

    Article  PubMed  CAS  Google Scholar 

  • Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, McCardle L, Chree A, Hope J, Birkett C, Cousens S, Fraser H, Bostock CJ (1997) Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature 389:498–501

    Article  PubMed  CAS  Google Scholar 

  • Bűeler H, Aguzzi A, Sailer A, Greiner RA, Autenried P, Aguet M, Weissmann C (1993) Mice devoid of PrP are resistant to scrapie. Cell 73:1339–1347

    Article  PubMed  Google Scholar 

  • Burthem J, Urban B, Pain A, Roberts DJ (2001) The normal cellular prion protein is strongly expressed by myeloid dendritic cells. Blood 98:3733–3738

    Article  PubMed  CAS  Google Scholar 

  • Buschmann A, Groschup MH (2005) Highly bovine spongiform encephalopathy-sensitive transgenic mice confirm the essential restriction of infectivity to the nervous system in clinically diseased cattle. J Infect Dis 192:934–942

    Article  PubMed  Google Scholar 

  • Caughey B, Race RE, Chesebro B (1988) Detection of prion protein mRNA in normal and scrapie-infected tissues and cell lines. J Gen Virol 69:711–716

    PubMed  CAS  Google Scholar 

  • Ford MJ, Burton LJ, Morris RJ, Hall SM (2002) Selective expression of prion protein in peripheral tissues of the adult mouse. Neuroscience 113:177–192

    Article  PubMed  CAS  Google Scholar 

  • Foster JD, Hope J, Fraser H (1993) Transmission of bovine spongiform encephalopathy to sheep and goats. Vet Rec 133:339–341

    PubMed  CAS  Google Scholar 

  • Foster JD, Parnham DW, Hunter N, Bruce M (2001) Distribution of the prion protein in sheep terminally affected with BSE following experimental oral transmission. J Gen Virol 82:2319–2326

    PubMed  CAS  Google Scholar 

  • Fournier JG, Escaig-Haye F, Billette de Villemeur T, Robain O, Lasmezas CI, Deslys JP, Dormont D, Brown P (1998) Distribution and submicroscopic immunogold localization of cellular prion protein (PrPc) in extracerebral tissues. Cell Tissue Res 292:77–84

    Article  PubMed  CAS  Google Scholar 

  • Fournier JG, Escaig-Haye F, Grigoriev V (2000) Ultrastructural localization of prion proteins: physiological and pathological implications. Microsc Res Tech 50:76–88

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez L, Terry L, Jeffrey M (2005) Expression of prion protein in the gut of mice infected orally with the 301V murine strain of the bovine spongiform encephalopathy agent. J Comp Pathol 132:273–282

    Article  PubMed  CAS  Google Scholar 

  • Heggebø R, Press CM, Gunnes G, Lie KI, Tranulis MA, Ulvund M, Groschup MH, Landsverk T (2000) Distribution of prion protein in the ileal Peyer’s patch of scrapie-free lambs and lambs naturally and experimentally exposed to the scrapie agent. J Gen Virol 81:2327–2337

    PubMed  Google Scholar 

  • Heppner FL, Christ AD, Klein MA, Prinz M, Fried M, Kraehenbuhl JP, Aguzzi A (2001) Transepithelial prion transport by M cells. Nat Med 7:976–977

    Article  PubMed  CAS  Google Scholar 

  • Herrmann LM, Cheevers WP, Davis WC, Knowles DP, O’Rourke KI (2003) CD21-positive follicular dendritic cells: A possible source of PrPSc in lymph node macrophages of scrapie-infected sheep. Am J Pathol 162:1075–1081

    PubMed  CAS  Google Scholar 

  • Herzog C, Sales N, Etchegaray N, Charbonnier A, Freire S, Dormont D, Deslys JP, Lasmezas CI (2004) Tissue distribution of bovine spongiform encephalopathy agent in primates after intravenous or oral infection. Lancet 363:422–428

    Article  PubMed  CAS  Google Scholar 

  • Hill AF, Butterworth RJ, Joiner S, Jackson G, Rossor MN, Thomas DJ, Frosh A, Tolley N, Bell JE, Spencer M, King A, Al-Sarraj S, Ironside JW, Lantos PL, Collinge J (1997) Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy. Lancet 349:99–100

    Article  PubMed  CAS  Google Scholar 

  • Hill AF, Butterworth RJ, Joiner S, Jackson G, Rossor MN, Thomas DJ, Frosh A, Tolley N, Bell JE, Spencer M, King A, Al-Sarraj S, Ironside JW, Lantos PL, Collinge J (1999) Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 353:183–189

    Article  PubMed  CAS  Google Scholar 

  • Horiuchi M, Yamazaki N, Ikeda T, Ishiguro N, Shinagawa M (1995) A cellular form of prion protein (PrPC) exists in many non-neuronal tissues of sheep. J Gen Virol 76:2583–2587

    PubMed  CAS  Google Scholar 

  • Huang FP, Farquhar CF, Mabbott NA, Bruce ME, MacPherson GG (2002) Migrating intestinal dendritic cells transport PrP(Sc) from the gut. J Gen Virol 83:267–271

    PubMed  CAS  Google Scholar 

  • Iwanaga T, Han H, Hoshi O, Kanazawa H, Adachi I, Fujita T (1994) Topographical relation between serotonin-containing paraneurons and peptidergic neurons in the intestine and urethra. Biol Signals 3(5):259–270

    PubMed  CAS  Google Scholar 

  • Jenny M, Uhl C, Roche C, Duluc I, Guillermin V, Guillemot F, Jensen J, Kedinger M, Gradwohl G (2002) Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium. EMBO J 21:6338–6347

    Article  PubMed  CAS  Google Scholar 

  • Kitamoto T, Muramoto T, Mohri S, Doh-Ura K, Tateishi J (1991) Abnormal isoform of prion protein accumulates in follicular dendritic cells in mice with Creutzfeldt-Jakob disease. J Virol 65:6292–6295

    PubMed  CAS  Google Scholar 

  • Mabbott NA, Williams A, Farquhar CF, Pasparakis M, Kollias G, Bruce ME (2000) Tumor necrosis factor alpha-deficient, but not interleukin-6-deficient, mice resist peripheral infection with scrapie. J Virol 74:3338–3344

    Article  PubMed  CAS  Google Scholar 

  • Mabbott NA, Young J, McConnell I, Bruce ME (2003) Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphotoxin pathway dramatically reduces scrapie susceptibility. J Virol 77:6845–6854

    Article  PubMed  CAS  Google Scholar 

  • Manson JC, Clarke AR, McBride PA, McConnell I, Hope J (1994) PrP gene dosage determines the timing but not the final intensity or distribution of lesions in scrapie pathology. Neurodegeneration 3:331–340

    PubMed  CAS  Google Scholar 

  • Marcos Z, Pffeifer K, Bodegas ME, Sesma MP, Guembe L (2004) Cellular prion protein is expressed in a subset of neuroendocrine cells of the rat gastrointestinal tract. J Histochem Cytochem 52:1357–1365

    Article  PubMed  CAS  Google Scholar 

  • Marcos Z, Bodegas ME, Sesma MP, Guembe L (2005a) Characterization of PrPc-immunoreactive cells in monkey (Macaca fascicularis) gastrointestinal tract. Ann N Y Acad Sci 1040:387–390

    Article  CAS  Google Scholar 

  • Marcos Z, Bodegas ME, Sesma MP, Guembe L (2005b) Comparative Study of PrPc Expression in Rat, Monkey, and Cow Gastrointestinal Tract. Ann N Y Acad Sci 1040:391–394

    Article  CAS  Google Scholar 

  • Marsh RF, Bessen RA, Lehmann S, Hartsough GR (1991) Epidemiological and experimental studies on a new incident of transmissible mink encephalopathy. J Gen Virol 72:589–594

    Article  PubMed  Google Scholar 

  • McBride PA, Eikelenboom P, Kraal G, Fraser H, Bruce ME (2002) PrP protein is associated with follicular dendritic cells of spleens and lymph nodes in uninfected and scrapie-infected mice. J Pathol 168:413–418

    Article  Google Scholar 

  • Miyazawa K, Aso H, Kanaya T, Kido T, Minashima T, Watanabe K, Ohwada S, Kitazawa H, Rose MT, Tahara K, Yamasaki T, Yamaguchi T (2006a) Apoptotic process of porcine intestinal M cells. Cell Tissue Res 323:425–432

    Article  Google Scholar 

  • Miyazawa K, Aso H, Honda M, Kido T, Minashima T, Kanaya T, Watanabe K, Ohwada S, Rose MT, Yamaguchi T (2006b) Identification of bovine dendritic cell phenotype from bovine peripheral blood. Res Vet Sci 81:40–45

    Article  CAS  Google Scholar 

  • Montrasio F, Frigg R, Glatzel M, Klein MA, Mackay F, Aguzzi A, Weissmann C (2000) Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science 288:1257–1259

    Article  PubMed  CAS  Google Scholar 

  • Nakamura F, Seki I, Kobayashi K, Tanaka M, Fukunaga S (2002) Immunohistochemical detection of cellular prion protein (PrPc) in the rat central nervous system. Animal Sci J 73:553–556

    Article  CAS  Google Scholar 

  • Prinz M, Huber G, Macpherson AJ, Heppner FL, Glatzel M, Eugster HP, Wagner N, Aguzzi A (2003) Oral prion infection requires normal numbers of Peyer’s patches but not of enteric lymphocytes. Am J Pathol 162:1103–1111

    PubMed  CAS  Google Scholar 

  • Prusiner SB(1982) Novel proteinaceous infectious particles cause scrapie. Science 216:136–144

    Article  PubMed  CAS  Google Scholar 

  • Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95:13363–13383

    Article  PubMed  CAS  Google Scholar 

  • Race R, Oldstone M, Chesebro B (2000) Entry versus blockade of brain infection following oral or intraperitoneal scrapie administration: role of prion protein expression in peripheral nerves and spleen. J Virol 74:828–833

    Article  PubMed  CAS  Google Scholar 

  • Rescigno M, Urbano M, Valzasina B, Francolini M, Rotta G, Bonasio R, Granucci F, Kraehenbuhl JP, Ricciardi-Castagnoli P (2001) Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol 2:361–367

    Article  PubMed  CAS  Google Scholar 

  • Sakaguchi S, Katamine S, Nishida N, Moriuchi R, Shigematsu K, Sugimoto T, Nakatani A, Kataoka Y, Houtani T, Shirabe S, Okada H, Hasegawa S, Miyamoto T, Noda T (1996) Loss of cerebellar Purkinje cells in aged mice homozygous for a disrupted PrP gene. Nature 380:528–531

    Article  PubMed  CAS  Google Scholar 

  • Schreuder BE, van Keulen LJ, Vromans ME, Langeveld JP, Smits MA (1998) Tonsillar biopsy and PrPSc detection in the preclinical diagnosis of scrapie. Vet Rec 142:564–568

    PubMed  CAS  Google Scholar 

  • Shlomchik MJ, Radebold K, Duclos N, Manuelidis L (2001) Neuroinvasion by a Creutzfeldt-Jakob disease agent in the absence of B cells and follicular dendritic cells. Proc Natl Acad Sci USA 98:9289–9294

    Article  PubMed  CAS  Google Scholar 

  • Sigurdson CJ, Barillas-Mury C, Miller MW, Oesch B, van Keulen LJ, Langeveld JP, Hoover EA (2002) PrP(CWD) lymphoid cell targets in early and advanced chronic wasting disease of mule deer. J Gen Virol 83:2617–2628

    PubMed  CAS  Google Scholar 

  • Somerville RA, Birkett CR, Farquhar CF, Hunter N, Goldmann W, Dornan J, Grover D, Hennion RM, Percy C, Foster J, Jeffrey M (1997) Immunodetection of PrPSc in spleens of some scrapie-infected sheep but not BSE-infected cows. J Gen Virol 78:2389–2396

    PubMed  CAS  Google Scholar 

  • Sugaya M, Nakamura K, Watanabe T, Asahina A, Yasaka N, Koyama Y, Kusubata M, Ushiki Y, Kimura K, Morooka A, Irie S, Yokoyama T, Inoue K, Itohara S, Tamaki K (2002) Expression of cellular prion-related protein by murine Langerhans cells and keratinocytes. J Dermatol Sci 28:126–134

    Article  PubMed  CAS  Google Scholar 

  • Terry LA, Marsh S, Ryder SJ, Hawkins SA, Wells GA, Spencer YI (2003) Detection of disease-specific PrP in the distal ileum of cattle exposed orally to the agent of bovine spongiform encephalopathy. Vet Rec 152:387–392

    PubMed  CAS  Google Scholar 

  • Thielen C, Melot F, Jolois O, Leclercq F, Tsunoda R, Frobert Y, Heinen E, Antoine N (2001a) Isolation of bovine follicular dendritic cells allows the demonstration of a particular cellular prion protein. Cell Tissue Res 306:49–55

    Article  CAS  Google Scholar 

  • Thielen C, Antoine N, Melot F, Cesbron JY, Heinen E, Tsunoda R (2001b) Human FDC express PrPc in vivo and in vitro. Dev Immunol 8:259–266

    CAS  Google Scholar 

  • van Keulen LJ, Schreuder BE, Meloen RH, Mooij-Harkes G, Vromans ME, Langeveld JP (1996) Immunohistochemical detection of prion protein in lymphoid tissues of sheep with natural scrapie. J Clin Microbiol 34:1228–1231

    PubMed  Google Scholar 

  • Wadsworth JD, Joiner S, Hill AF, Campbell TA, Desbruslais M, Luthert PJ, Collinge J (2001) Tissue distribution of protease resistant prion protein in variant Creutzfeldt-Jakob disease using a highly sensitive immunoblotting assay. Lancet 358:171–80

    Article  PubMed  CAS  Google Scholar 

  • Wells GA, Dawson M, Hawkins SA, Green RB, Dexter I, Francis ME, Simmons MM, Austin AR, Horigan MW (1994) Infectivity in the ileum of cattle challenged orally with bovine spongiform encephalopathy. Vet Rec 135:40–41

    PubMed  CAS  Google Scholar 

  • Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, Poser S, Pocchiari M, Hofman A, Smith PG (1996) A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 347:921–925

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by a Grant-in-Aid for Scientific Research (18658104) from the Ministry of Education, Culture, Sports, Science and Technology, and by two grant (Prion Project and Secure and Healthy Livestock Farming Project) from the Ministry of Agriculture, Forestry and Fisheries.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hisashi Aso.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Miyazawa, K., Kanaya, T., Tanaka, S. et al. Immunohistochemical characterization of cell types expressing the cellular prion protein in the small intestine of cattle and mice. Histochem Cell Biol 127, 291–301 (2007). https://doi.org/10.1007/s00418-006-0250-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00418-006-0250-x

Keywords

Navigation