Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Potential for transmission of sporadic Creutzfeldt–Jakob disease through peripheral routes



Five sporadic Creutzfeldt–Jakob disease (CJD) strains have been identified to date, based on differences in clinicopathological features of the patients, the biochemical properties of abnormal prion proteins, and transmission properties. Recent advances in our knowledge about iatrogenic transmission of sporadic CJD have raised the possibility that the infectivity of sporadic CJD strains through peripheral routes is different from that of intracranial infection. To test this possibility, here we assessed systematically the infectivity of sporadic CJD strains through the peripheral route for the first time using a mouse model expressing human prion protein. Although the infectivity of the V2 and M1 sporadic CJD strains is almost the same in intracerebral transmission studies, the V2 strain infected more efficiently than the M1 strain through the peripheral route. The other sporadic CJD strains examined lacked infectivity. Of note, both the V2 and M1 strains showed preference for mice with the valine homozygosity at the PRNP polymorphic codon. These results indicate that the V2 strain is the most infectious sporadic CJD strain for infection through peripheral routes. In addition, these findings raise the possibility that individuals with the valine homozygosity at the PRNP polymorphic codon might have higher risks of infection through peripheral routes compared with the methionine homozygotes. Thus, preventive measures against the transmission of the V2 sporadic CJD strain will be important for the eradication of iatrogenic CJD transmission through peripheral routes.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Western blot analysis of protease-resistant PrPSc in the spleens of Ki-Hu129M/M or Ki-Hu129V/V mice intraperitoneally inoculated with sCJD isolates.

Data availability

The data that support the findings are available from the corresponding author upon request.


  1. 1.

    Prusiner SB, Scott MR, DeArmond SJ, Cohen FE. Prion protein biology. Cell. 1998;93:337–48.

    CAS  Article  Google Scholar 

  2. 2.

    Colby DW, Prusiner SB. Prions. Cold Spring Harb Perspect Biol. 2011;3:a006833.

    Article  Google Scholar 

  3. 3.

    Brown P, Brandel JP, Sato T, Nakamura Y, MacKenzie J, Will RG, et al. Iatrogenic Creutzfeldt-Jakob disease, final assessment. Emerg Infect Dis. 2012;18:901–7.

    Article  Google Scholar 

  4. 4.

    Kobayashi A, Kitamoto T, Mizusawa H. Iatrogenic Creutzfeldt-Jakob disease. Handb Clin Neurol. 2018;153:207–18.

    Article  Google Scholar 

  5. 5.

    Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, et al. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol. 1999;46:224–33.

    CAS  Article  Google Scholar 

  6. 6.

    Bishop MT, Will RG, Manson JC. Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties. Proc Natl Acad Sci USA. 2010;107:12005–10.

    CAS  Article  Google Scholar 

  7. 7.

    Moda F, Suardi S, Di Fede G, Indaco A, Limido L, Vimercati C, et al. MM2-thalamic Creutzfeldt-Jakob disease: neuropathological, biochemical and transmission studies identify a distinctive prion strain. Brain Pathol. 2012;22:662–9.

    CAS  Article  Google Scholar 

  8. 8.

    Parchi P, Strammiello R, Giese A, Kretzschmar H. Phenotypic variability of sporadic human prion disease and its molecular basis: past, present, and future. Acta Neuropathol. 2011;121:91–112.

    CAS  Article  Google Scholar 

  9. 9.

    Kobayashi A, Matsuura Y, Mohri S, Kitamoto T. Distinct origins of dura mater graft-associated Creutzfeldt-Jakob disease: past and future problems. Acta Neuropathol Commun. 2014;2:32.

    Article  Google Scholar 

  10. 10.

    Kobayashi A, Matsuura Y, Iwaki T, Iwasaki Y, Yoshida M, Takahashi H, et al. Sporadic Creutzfeldt-Jakob disease MM1+2C and MM1 are identical in transmission properties. Brain Pathol. 2016;26:95–101.

    CAS  Article  Google Scholar 

  11. 11.

    Rudge P, Jaunmuktane Z, Adlard P, Bjurstrom N, Caine D, Lowe J, et al. Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years. Brain. 2015;138:3386–99.

    Article  Google Scholar 

  12. 12.

    Ritchie DL, Barria MA, Peden AH, Yull HM, Kirkpatrick J, Adlard P, et al. UK iatrogenic Creutzfeldt-Jakob disease: investigating human prion transmission across genotypic barriers using human tissue-based and molecular approaches. Acta Neuropathol. 2017;133:579–95.

    CAS  Article  Google Scholar 

  13. 13.

    McLean CA, Ironside JW, Alpers MP, Brown PW, Cervenakova L, Anderson RM, et al. Comparative neuropathology of kuru with the new variant of Creutzfeldt-Jakob disease: evidence for strain of agent predominating over genotype of host. Brain Pathol. 1998;8:429–37.

    CAS  Article  Google Scholar 

  14. 14.

    Parchi P, Cescatti M, Notari S, Schulz-Schaeffer WJ, Capellari S, Giese A, et al. Agent strain variation in human prion disease: insights from a molecular and pathological review of the National Institutes of Health series of experimentally transmitted disease. Brain. 2010;133:3030–42.

    Article  Google Scholar 

  15. 15.

    Munesue Y, Shimazaki T, Qi Z, Isoda N, Sawa H, Aoshima K, et al. Development of a quick bioassay for the evaluation of transmission properties of acquired prion diseases. Neurosci Lett. 2018;668:43–47.

    CAS  Article  Google Scholar 

  16. 16.

    Takeuchi A, Mohri S, Kai H, Tamaoka A, Kobayashi A, Mizusawa H, et al. Two distinct prions in fatal familial insomnia and its sporadic form. Brain Commun. 2019;1:fcz054.

    Article  Google Scholar 

  17. 17.

    Asano M, Mohri S, Ironside JW, Ito M, Tamaoki N, Kitamoto T. vCJD prion acquires altered virulence through trans-species infection. Biochem Biophys Res Commun. 2006;342:293–9.

    CAS  Article  Google Scholar 

  18. 18.

    Kitamoto T, Mohri S, Ironside JW, Miyoshi I, Tanaka T, Kitamoto N, et al. Follicular dendritic cell of the knock-in mouse provides a new bioassay for human prions. Biochem Biophys Res Commun. 2002;294:280–6.

    CAS  Article  Google Scholar 

  19. 19.

    Kobayashi A, Sakuma N, Matsuura Y, Mohri S, Aguzzi A, Kitamoto T. Experimental verification of a traceback phenomenon in prion infection. J Virol. 2010;84:3230–8.

    CAS  Article  Google Scholar 

  20. 20.

    Kobayashi A, Asano M, Mohri S, Kitamoto T. Cross-sequence transmission of sporadic Creutzfeldt-Jakob disease creates a new prion strain. J Biol Chem. 2007;282:30022–8.

    CAS  Article  Google Scholar 

  21. 21.

    Raymond CR, Aucouturier P, Mabbott NA. In vivo depletion of CD11c+ cells impairs scrapie agent neuroinvasion from the intestine. J Immunol. 2007;179:7758–66.

    CAS  Article  Google Scholar 

  22. 22.

    Cordier-Dirikoc S, Chabry J. Temporary depletion of CD11c+ dendritic cells delays lymphoinvasion after intraperitonal scrapie infection. J Virol. 2008;82:8933–6.

    CAS  Article  Google Scholar 

  23. 23.

    Kitamoto T, Muramoto T, Mohri S, Doh-Ura K, Tateishi J. Abnormal isoform of prion protein accumulates in follicular dendritic cells in mice with Creutzfeldt-Jakob disease. J Virol. 1991;65:6292–5.

    CAS  Article  Google Scholar 

  24. 24.

    Mabbott NA, Mackay F, Minns F, Bruce ME. Temporary inactivation of follicular dendritic cells delays neuroinvasion of scrapie. Nat Med. 2000;6:719–20.

    CAS  Article  Google Scholar 

  25. 25.

    McCulloch L, Brown KL, Bradford BM, Hopkins J, Bailey M, Rajewsky K, et al. Follicular dendritic cell-specific prion protein (PrP) expression alone is sufficient to sustain prion infection in the spleen. PLoS Pathog. 2011;7:e1002402.

    CAS  Article  Google Scholar 

  26. 26.

    Srivastava S, Makarava N, Katorcha E, Savtchenko R, Brossmer R, Baskakov IV. Post-conversion sialylation of prions in lymphoid tissues. Proc Natl Acad Sci USA. 2015;112:E6654–62.

    CAS  Article  Google Scholar 

  27. 27.

    Katorcha E, Makarava N, Savtchenko R, Baskakov IV. Sialylation of the prion protein glycans controls prion replication rate and glycoform ratio. Sci Rep. 2015;5:16912.

    CAS  Article  Google Scholar 

  28. 28.

    Kobayashi A, Parchi P, Yamada M, Brown P, Saverioni D, Matsuura Y, et al. Transmission properties of atypical Creutzfeldt-Jakob disease: a clue to disease etiology? J Virol. 2015;89:3939–46.

    CAS  Article  Google Scholar 

  29. 29.

    Douet JY, Huor A, Cassard H, Lugan S, Aron N, Arnold M, et al. Wide distribution of prion infectivity in the peripheral tissues of vCJD and sCJD patients. Acta Neuropathol. 2021;141:383–97.

    CAS  Article  Google Scholar 

  30. 30.

    Béringue V, Herzog L, Jaumain E, Reine F, Sibille P, Le Dur A, et al. Facilitated cross-species transmission of prions in extraneural tissue. Science. 2012;335:472–5.

    Article  Google Scholar 

Download references


We thank members of the Creutzfeldt–Jakob Disease Surveillance Committee in Japan, Creutzfeldt–Jakob disease specialists in the prefectures, and Creutzfeldt–Jakob disease patients and families for providing important clinical information. We thank Hiroko Kudo, Miyuki Yamamoto, and Ayumi Yamazaki for their excellent technical assistance.


This study was supported by JSPS KAKENHI Grant Number 18K05963 (AK), a grant from The Kato Memorial Trust for Nambyo Research (AK), The Kurata Grants from The Hitachi Global Foundation (AK), and a grant from Takeda Science Foundation (AK).

Author information




Conceptualization: AK and T Kitamoto; Methodology: SM and T Kitamoto; Formal analysis and investigation: AK, YM, and TS; Writing—original draft preparation: AK; Writing—review and editing: KA, T Kimura, SM, T Kitamoto; Funding acquisition: AK; Resources: T Kitamoto, SM; Supervision: T Kimura, SM, and T Kitamoto.

Corresponding author

Correspondence to Atsushi Kobayashi.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

This study was approved by the Institutional Ethics Committee of Hokkaido University Faculty of Veterinary Medicine (approval number: VET1-5) and the Institutional Animal Care and Use Committees of Hokkaido University (approval number: 19-0025). All experiments using human materials are in compliance with the Helsinki Declaration. Animal experiments were performed in strict accordance with the Regulations for Animal Experiments and Related Activities at Hokkaido University.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kobayashi, A., Munesue, Y., Shimazaki, T. et al. Potential for transmission of sporadic Creutzfeldt–Jakob disease through peripheral routes. Lab Invest (2021).

Download citation


Quick links