Skip to main content

Advertisement

SpringerLink
Log in

Alternative complement pathway is activated in the brains of scrapie-infected rodents

  • Original Investigation
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

Activation of complement system in central nervous system (CNS) of the patients suffering from prion diseases or animal models infected with prion agents experimentally is reported repeatedly, but which pathways are involved in the complement system during prion infection is not well documented. Here, we evaluated the level of complement factor B (CFB), which is the key factor that triggers alterative pathway (AP) of complement in the brain tissues of scrapie-infected mice with various methodologies. We found that the levels of mRNA and protein of CFB significantly increased in the brain tissues of scrapie-infected mice. Morphologically, the increased CFB-specific signal overlapped with the elevated C3 signal in brain sections of scrapie-infected mice, meanwhile overlapped with damaged neurons and activated microglia, but not with the proliferative astrocytes. Additionally, the level of complement factor P (CFP), the key positive regulator of AP, also increased remarkably in the brain tissues of infected mice. The transcriptional levels of CD55 and CD46, two negative regulators of AP, decreased without significance in brain tissues of scrapie-infected mice at the terminal stage. However, the mRNA and protein levels of CFH, another negative regulator of AP, increased. Through the dynamic analyses of the expressions of CFB, CFP, and CFH in brain sections of 139A-infected mice, which were collected at different time-points during incubation period, illustrated time-dependent increase levels of each factor during the incubation period of scrapie infection. Taken together, our data here demonstrate that the AP of complement cascade is activated in the CNS microenvironment during prion infection.

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

Access this article

Log in via an institution

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Prusiner SB (1998) Prions. Proc Natl Acad Sci U S A 95(23):13363–13383

    Article  CAS  PubMed  Google Scholar 

  2. Prusiner SB, Scott MR, DeArmond SJ, Cohen FE (1998) Prion protein biology. Cell 93(3):337–348

    Article  CAS  PubMed  Google Scholar 

  3. 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(9006):921–925

    Article  CAS  PubMed  Google Scholar 

  4. Yanamadala V, Friedlander RM (2010) Complement in neuroprotection and neurodegeneration. Trends Mol Med 16(2):69–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Veerhuis R, Nielsen HM, Tenner AJ (2011) Complement in the brain. Mol Immunol 48(14):1592–1603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bonifati DM, Kishore U (2007) Role of complement in neurodegeneration and neuroinflammation. Mol Immunol 44(5):999–1010

    Article  CAS  PubMed  Google Scholar 

  7. Ishii T, Haga S, Yagishita S, Tateishi J (1984) The presence of complements in amyloid plaques of Creutzfeldt-Jakob disease and Gerstmann–Straussler–Scheinker disease. Appl Pathol 2(6):370–379

    CAS  PubMed  Google Scholar 

  8. Klein MA, Kaeser PS, Schwarz P, Weyd H, Xenarios I, Zinkernagel RM, Carroll MC, Verbeek JS, Botto M, Walport MJ, Molina H, Kalinke U, Acha-Orbea H, Aguzzi A (2001) Complement facilitates early prion pathogenesis. Nat Med 7(4):488–492

    Article  CAS  PubMed  Google Scholar 

  9. Lv Y, Chen C, Zhang BY, Xiao K, Wang J, Chen LN, Sun J, Gao C, Shi Q, Dong XP (2014) Remarkable Activation of the Complement System and Aberrant Neuronal Localization of the Membrane Attack Complex in the Brain Tissues of Scrapie-Infected Rodents. Mol Neurobiol 52(3):1165–1179

    Article  PubMed  CAS  Google Scholar 

  10. Chen C, Lv Y, Shi Q, Zhou W, Xiao K, Sun J, Yang XD, Dong XP (2016) Low activity of complement in the cerebrospinal fluid of the patients with various prion diseases. Infectious diseases of poverty 5:35

    Article  PubMed  PubMed Central  Google Scholar 

  11. Chen C, Xiao D, Zhou W, Shi Q, Zhang HF, Zhang J, Tian C, Zhang JZ, Dong XP (2014) Global Protein Differential Expression Profiling of Cerebrospinal Fluid Samples Pooled from Chinese Sporadic CJD and non-CJD Patients. Mol Neurobiol 49(1):290–302

    Article  CAS  PubMed  Google Scholar 

  12. Shi Q, Zhang BY, Gao C, Zhang J, Jiang HY, Chen C, Han J, Dong XP (2012) Mouse-adapted scrapie strains 139A and ME7 overcome species barrier to induce experimental scrapie in hamsters and changed their pathogenic features. Virol J 9:63

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhang J, Chen L, Zhang BY, Han J, Xiao XL, Tian HY, Li BL, Gao C, Gao JM, Zhou XB, Ma GP, Liu Y, Xu CM, Dong XP (2004) Comparison study on clinical and neuropathological characteristics of hamsters inoculated with scrapie strain 263 K in different challenging pathways. Biomed Environ Sci 17(1):65–78

    PubMed  Google Scholar 

  14. Chen C, Lv Y, Zhang BY, Zhang J, Shi Q, Wang J, Tian C, Gao C, Xiao K, Ren K, Zhou W, Dong XP (2014) Apparent Reduction of ADAM10 in Scrapie-Infected Cultured Cells and in the Brains of Scrapie-Infected Rodents. Mol Neurobiol 50(3):875–887

    Article  CAS  PubMed  Google Scholar 

  15. Gao JM, Gao C, Han J, Zhou XB, Xiao XL, Zhang J, Chen L, Zhang BY, Hong T, Dong XP (2004) Dynamic analyses of PrP and PrP(Sc) in brain tissues of golden hamsters infected with scrapie strain 263 K revealed various PrP forms. Biomed Environ Sci 17(1):8–20

    PubMed  Google Scholar 

  16. Kovacs GG, Gasque P, Strobel T, Lindeck-Pozza E, Strohschneider M, Ironside JW, Budka H, Guentchev M (2004) Complement activation in human prion disease. Neurobiol Dis 15(1):21–28

    Article  CAS  PubMed  Google Scholar 

  17. Mabbott NA (2004) The complement system in prion diseases. Curr Opin Immunol 16(5):587–593

    Article  CAS  PubMed  Google Scholar 

  18. Narni-Mancinelli E, Gauthier L, Baratin M, Guia S, Fenis A, Deghmane AE, Rossi B, Fourquet P, Escaliere B, Kerdiles YM, Ugolini S, Taha MK, Vivier E (2017) Complement factor P is a ligand for the natural killer cell-activating receptor NKp46. Sci Immunol 2 (10): eaam9628

    Article  PubMed  PubMed Central  Google Scholar 

  19. Yamada T, McGeer PL, McGeer EG (1992) Lewy bodies in Parkinson’s disease are recognized by antibodies to complement proteins. Acta Neuropathol 84(1):100–104

    Article  CAS  PubMed  Google Scholar 

  20. Singhrao SK, Neal JW, Morgan BP, Gasque P (1999) Increased complement biosynthesis by microglia and complement activation on neurons in Huntington’s disease. Exp Neurol 159(2):362–376

    Article  CAS  PubMed  Google Scholar 

  21. Yasojima K, Schwab C, McGeer EG, McGeer PL (1999) Up-regulated production and activation of the complement system in Alzheimer’s disease brain. Am J Pathol 154(3):927–936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shi Q, Chen LN, Zhang BY, Xiao K, Zhou W, Chen C, Zhang XM, Tian C, Gao C, Wang J, Han J, Dong XP (2015) Proteomics analyses for the global proteins in the brain tissues of different human prion diseases. Mol Cell Proteomics 14(4):854–869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gasque P, Dean YD, McGreal EP, VanBeek J, Morgan BP (2000) Complement components of the innate immune system in health and disease in the CNS. Immunopharmacology 49(1–2):171–186

    Article  CAS  PubMed  Google Scholar 

  24. Brodbeck WG, Kuttner-Kondo L, Mold C, Medof ME (2000) Structure/function studies of human decay-accelerating factor. Immunology 101(1):104–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Liszewski MK, Farries TC, Lublin DM, Rooney IA, Atkinson JP (1996) Control of the complement system. Adv Immunol 61:201–283

    Article  CAS  PubMed  Google Scholar 

  26. Sjoberg A, Onnerfjord P, Morgelin M, Heinegard D, Blom AM (2005) The extracellular matrix and inflammation: fibromodulin activates the classical pathway of complement by directly binding C1q. J Biol Chem 280(37):32301–32308

    Article  PubMed  CAS  Google Scholar 

  27. Sjoberg AP, Trouw LA, Clark SJ, Sjolander J, Heinegard D, Sim RB, Day AJ, Blom AM (2007) The factor H variant associated with age-related macular degeneration (His-384) and the non-disease-associated form bind differentially to C-reactive protein, fibromodulin, DNA, and necrotic cells. J Biol Chem 282(15):10894–10900

    Article  PubMed  CAS  Google Scholar 

  28. Sjoberg AP, Manderson GA, Morgelin M, Day AJ, Heinegard D, Blom AM (2009) Short leucine-rich glycoproteins of the extracellular matrix display diverse patterns of complement interaction and activation. Mol Immunol 46(5):830–839

    Article  PubMed  CAS  Google Scholar 

  29. Perkins SJ, Nan R, Li K, Khan S, Miller A (2012) Complement factor H-ligand interactions: self-association, multivalency and dissociation constants. Immunobiology 217(2):281–297

    Article  CAS  PubMed  Google Scholar 

  30. Deban L, Jarva H, Lehtinen MJ, Bottazzi B, Bastone A, Doni A, Jokiranta TS, Mantovani A, Meri S (2008) Binding of the long pentraxin PTX3 to factor H: interacting domains and function in the regulation of complement activation. J Immunol 181(12):8433–8440

    Article  CAS  PubMed  Google Scholar 

  31. Okemefuna AI, Nan R, Miller A, Gor J, Perkins SJ (2010) Complement factor H binds at two independent sites to C-reactive protein in acute phase concentrations. J Biol Chem 285(2):1053–1065

    Article  CAS  PubMed  Google Scholar 

  32. Peake P, Shen Y (2010) Factor H binds to the N-terminus of adiponectin and modulates complement activation. Biochem Biophys Res Commun 397(2):361–366

    Article  CAS  PubMed  Google Scholar 

  33. Sjoberg AP, Nystrom S, Hammarstrom P, Blom AM (2008) Native, amyloid fibrils and beta-oligomers of the C-terminal domain of human prion protein display differential activation of complement and bind C1q, factor H and C4b-binding protein directly. Mol Immunol 45(11):3213–3221

    Article  PubMed  CAS  Google Scholar 

  34. Mitchell DA, Kirby L, Paulin SM, Villiers CL, Sim RB (2007) Prion protein activates and fixes complement directly via the classical pathway: implications for the mechanism of scrapie agent propagation in lymphoid tissue. Mol Immunol 44(11):2997–3004

    Article  CAS  PubMed  Google Scholar 

  35. Bradford BM, Mabbott NA (2012) Prion disease and the innate immune system. Viruses 4(12):3389–3419

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by National Natural Science Foundation of China (81772197, 81401670, and 81630062), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2018RC330004), National Key R&D Program of China (2018YFC1200305 and 2016YFC1202700), SKLID Development Grant (2015SKLID503 and 2016SKLID603), and the Young Scholar Scientific Research Foundation of China CDC (2016A101).

Author information

Author notes

  1. Cao Chen, Yan Lv, and Chao Hu have contributed equally to this study.

Authors and Affiliations

  1. State Key Laboratory for Infectious Disease Prevention and Control, NHC Key Laboratory of Medical Virology and Viral Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of China

    Cao Chen, Yan Lv, Chao Hu, Xiao-Feng Xu, Ren-Qing Zhang, Kang Xiao, Yue Ma, Li-Ping Gao, Jian-Le Li, Qiang Shi, Jing Wang, Qi Shi & Xiao-Ping Dong

  2. Center of Global Public Health, Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of China

    Xiao-Ping Dong

  3. Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, People’s Republic of China

    Cao Chen & Xiao-Ping Dong

  4. China Academy of Chinese Medical Sciences, Dongzhimeinei, South Rd 16, Beijing, 100700, China

    Xiao-Ping Dong

Authors
  1. Cao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yan Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chao Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiao-Feng Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ren-Qing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kang Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yue Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Li-Ping Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jian-Le Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Qiang Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Qi Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Xiao-Ping Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CC and YL designed the study and drafted the manuscript; CH and RQZ carried out the Western blot; XFX, YM, and LPG carried out the IHC; JLL and QS carried out the IFA; QS carried out the real-time PCR; KX and JW performed the statistical analysis. XPD conceived of the study, participated in its design and coordination, and helped to draft the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xiao-Ping Dong.

Ethics declarations

Conflict of interest

All the authors declare that they have no conflict of interest.

Additional information

Edited by Matthias J. Reddehase.

Publisher's Note

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

430_2019_641_MOESM1_ESM.jpg

Supplementary Fig. 1. Control experiments. (A) Immunofluorescent staining with 2nd-Ab only in brain slices of age-matched healthy control and 139A-infected mice at terminal stage of prion infection (63×). Various 2nd-Ab are indicated on the top. (B) IHC staining with 2nd-Ab only in brain slices of age-matched healthy control, 139A-infected mice and 263 K-infected hamsters at terminal stage of prion infection (40×). Various brain regions are indicated on the top. Brain slices from 3 mice/hamsters in each group (JPEG 2558 kb)

Supplementary material 2 (JPEG 5604 kb)

430_2019_641_MOESM3_ESM.jpg

Supplementary Fig. 2. Hierarchical scanning of the colocalization between CFB (green) and Iba1 (red) in the cortex of control and 139A-infected mice at end stage of prion infection (63×). (A) age-matched healthy control, (B) 139A-infected mice. The scale is shown at the bottom right of each image. Brain slices from 3 mice/hamsters in each group (JPEG 3502 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, C., Lv, Y., Hu, C. et al. Alternative complement pathway is activated in the brains of scrapie-infected rodents. Med Microbiol Immunol 209, 81–94 (2020). https://doi.org/10.1007/s00430-019-00641-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-019-00641-6

Keywords

Search

Navigation