Intraperitoneal Infection of Wild-Type Mice with Synthetically Generated Mammalian Prion
The transmissible spongiform encephalopathies (TSEs) are a group of infectious neurodegenerative diseases affecting both humans and animals. The prion hypothesis postulates that prions are protein conformation based infectious agents responsible for TSE infectivity. Prions have been synthetically generated in vitro, but it remains unclear whether the properties of synthetically generated prion are the same as those of TSE agents and whether the disease caused by synthetically generated prion is identical to naturally occurring TSEs. In this study, we demonstrated that similar to the classical TSE agents, the synthetically generated prion has a titratable infectivity and is able to cause prion disease in wild-type mice via routes other than direct intra-cerebral inoculation. More importantly, we showed that the synthetically generated prion induced pathological changes, including the dissemination of disease-specific prion protein accumulation and the route and mechanism of neuroinvasion, were all typical of classical TSEs. These results demonstrate the similarity of synthetically generated prion to the infectious agent in TSEs, providing strong evidence supporting the prion hypothesis.
Vyšlo v časopise:
Intraperitoneal Infection of Wild-Type Mice with Synthetically Generated Mammalian Prion. PLoS Pathog 11(7): e32767. doi:10.1371/journal.ppat.1004958
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1004958
Souhrn
The transmissible spongiform encephalopathies (TSEs) are a group of infectious neurodegenerative diseases affecting both humans and animals. The prion hypothesis postulates that prions are protein conformation based infectious agents responsible for TSE infectivity. Prions have been synthetically generated in vitro, but it remains unclear whether the properties of synthetically generated prion are the same as those of TSE agents and whether the disease caused by synthetically generated prion is identical to naturally occurring TSEs. In this study, we demonstrated that similar to the classical TSE agents, the synthetically generated prion has a titratable infectivity and is able to cause prion disease in wild-type mice via routes other than direct intra-cerebral inoculation. More importantly, we showed that the synthetically generated prion induced pathological changes, including the dissemination of disease-specific prion protein accumulation and the route and mechanism of neuroinvasion, were all typical of classical TSEs. These results demonstrate the similarity of synthetically generated prion to the infectious agent in TSEs, providing strong evidence supporting the prion hypothesis.
Zdroje
1. Prusiner SB (1998) Prions. Proc Natl Acad Sci U S A 95: 13363–13383. 9811807
2. Aguzzi A, Baumann F, Bremer J (2008) The prion's elusive reason for being. Annu Rev Neurosci 31: 439–477. doi: 10.1146/annurev.neuro.31.060407.125620 18558863
3. Prusiner SB (1982) Novel proteinaceous infectious particles cause scrapie. Science 216: 136–144. 6801762
4. Meyer RK, McKinley MP, Bowman KA, Braunfeld MB, Barry RA, et al. (1986) Separation and properties of cellular and scrapie prion proteins. Proc Natl Acad Sci U S A 83: 2310–2314. 3085093
5. Caughey B, Neary K, Buller R, Ernst D, Perry LL, et al. (1990) Normal and scrapie-associated forms of prion protein differ in their sensitivities to phospholipase and proteases in intact neuroblastoma cells. J Virol 64: 1093–1101. 1968104
6. Caughey BW, Dong A, Bhat KS, Ernst D, Hayes SF, et al. (1991) Secondary structure analysis of the scrapie-associated protein PrP 27–30 in water by infrared spectroscopy. Biochemistry 30: 7672–7680. 1678278
7. Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, et al. (1993) Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A 90: 10962–10966. 7902575
8. Smirnovas V, Baron GS, Offerdahl DK, Raymond GJ, Caughey B, et al. (2011) Structural organization of brain-derived mammalian prions examined by hydrogen-deuterium exchange. Nat Struct Mol Biol 18: 504–506. doi: 10.1038/nsmb.2035 21441913
9. Hope J, Morton LJ, Farquhar CF, Multhaup G, Beyreuther K, et al. (1986) The major polypeptide of scrapie-associated fibrils (SAF) has the same size, charge distribution and N-terminal protein sequence as predicted for the normal brain protein (PrP). EMBO J 5: 2591–2597. 3096712
10. Safar J, Wille H, Itri V, Groth D, Serban H, et al. (1998) Eight prion strains have PrP(Sc) molecules with different conformations. Nat Med 4: 1157–1165. 9771749
11. Korth C, Stierli B, Streit P, Moser M, Schaller O, et al. (1997) Prion (PrPSc)-specific epitope defined by a monoclonal antibody. Nature 390: 74–77. 9363892
12. Nazor KE, Kuhn F, Seward T, Green M, Zwald D, et al. (2005) Immunodetection of disease-associated mutant PrP, which accelerates disease in GSS transgenic mice. Embo J 24: 2472–2480. 15962001
13. Kim C, Haldiman T, Cohen Y, Chen W, Blevins J, et al. (2011) Protease-sensitive conformers in broad spectrum of distinct PrPSc structures in sporadic Creutzfeldt-Jakob disease are indicator of progression rate. PLoS Pathog 7: e1002242. doi: 10.1371/journal.ppat.1002242 21931554
14. Kim C, Haldiman T, Surewicz K, Cohen Y, Chen W, et al. (2012) Small protease sensitive oligomers of PrPSc in distinct human prions determine conversion rate of PrP(C). PLoS Pathog 8: e1002835. doi: 10.1371/journal.ppat.1002835 22876179
15. Sajnani G, Silva CJ, Ramos A, Pastrana MA, Onisko BC, et al. (2012) PK-sensitive PrP is infectious and shares basic structural features with PK-resistant PrP. PLoS Pathog 8: e1002547. doi: 10.1371/journal.ppat.1002547 22396643
16. Pastrana MA, Sajnani G, Onisko B, Castilla J, Morales R, et al. (2006) Isolation and characterization of a proteinase K-sensitive PrPSc fraction. Biochemistry 45: 15710–15717. 17176093
17. Collinge J, Clarke AR (2007) A general model of prion strains and their pathogenicity. Science 318: 930–936. 17991853
18. Weissmann C (2012) Mutation and selection of prions. PLoS Pathog 8: e1002582. doi: 10.1371/journal.ppat.1002582 22479179
19. Li J, Browning S, Mahal SP, Oelschlegel AM, Weissmann C (2010) Darwinian evolution of prions in cell culture. Science 327: 869–872. doi: 10.1126/science.1183218 20044542
20. Klohn PC, Stoltze L, Flechsig E, Enari M, Weissmann C (2003) A quantitative, highly sensitive cell-based infectivity assay for mouse scrapie prions. Proc Natl Acad Sci U S A 100: 11666–11671. 14504404
21. Barron RM, Campbell SL, King D, Bellon A, Chapman KE, et al. (2007) High titers of transmissible spongiform encephalopathy infectivity associated with extremely low levels of PrPSc in vivo. J Biol Chem 282: 35878–35886. 17923484
22. Lasmezas CI, Deslys JP, Robain O, Jaegly A, Beringue V, et al. (1997) Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science 275: 402–405. 8994041
23. Kocisko DA, Come JH, Priola SA, Chesebro B, Raymond GJ, et al. (1994) Cell-free formation of protease-resistant prion protein. Nature 370: 471–474. 7913989
24. Bessen RA, Kocisko DA, Raymond GJ, Nandan S, Lansbury PT, et al. (1995) Non-genetic propagation of strain-specific properties of scrapie prion protein. Nature 375: 698–700. 7791905
25. Saborio GP, Permanne B, Soto C (2001) Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 411: 810–813. 11459061
26. Castilla J, Saa P, Hetz C, Soto C (2005) In vitro generation of infectious scrapie prions. Cell 121: 195–206. 15851027
27. Castilla J, Saa P, Morales R, Abid K, Maundrell K, et al. (2006) Protein misfolding cyclic amplification for diagnosis and prion propagation studies. Methods Enzymol 412: 3–21. 17046648
28. Morales R, Duran-Aniotz C, Diaz-Espinoza R, Camacho MV, Soto C (2012) Protein misfolding cyclic amplification of infectious prions. Nat Protoc 7: 1397–1409. doi: 10.1038/nprot.2012.067 22743831
29. Deleault NR, Harris BT, Rees JR, Supattapone S (2007) Formation of native prions from minimal components in vitro. Proc Natl Acad Sci U S A 104: 9741–9746. 17535913
30. Barria MA, Mukherjee A, Gonzalez-Romero D, Morales R, Soto C (2009) De novo generation of infectious prions in vitro produces a new disease phenotype. PLoS Pathog 5: e1000421. doi: 10.1371/journal.ppat.1000421 19436715
31. Wang F, Wang X, Yuan CG, Ma J (2010) Generating a prion with bacterially expressed recombinant prion protein. Science 327: 1132–1135. doi: 10.1126/science.1183748 20110469
32. Makarava N, Kovacs GG, Bocharova O, Savtchenko R, Alexeeva I, et al. (2010) Recombinant prion protein induces a new transmissible prion disease in wild-type animals. Acta Neuropathol 119: 177–187. doi: 10.1007/s00401-009-0633-x 20052481
33. Kim JI, Cali I, Surewicz K, Kong Q, Raymond GJ, et al. (2010) Mammalian prions generated from bacterially expressed prion protein in the absence of any mammalian cofactors. J Biol Chem 285: 14083–14087. doi: 10.1074/jbc.C110.113464 20304915
34. Wang F, Zhang Z, Wang X, Li J, Zha L, et al. (2012) Genetic informational RNA is not required for recombinant prion infectivity. J Virol 86: 1874–1876. doi: 10.1128/JVI.06216-11 22090130
35. Deleault NR, Piro JR, Walsh DJ, Wang F, Ma J, et al. (2012) Isolation of phosphatidylethanolamine as a solitary cofactor for prion formation in the absence of nucleic acids. Proc Natl Acad Sci U S A 109: 8546–8551. doi: 10.1073/pnas.1204498109 22586108
36. Deleault NR, Walsh DJ, Piro JR, Wang F, Wang X, et al. (2012) Cofactor molecules maintain infectious conformation and restrict strain properties in purified prions. Proc Natl Acad Sci U S A 109: E1938–1946. doi: 10.1073/pnas.1206999109 22711839
37. Zhang Z, Zhang Y, Wang F, Wang X, Xu Y, et al. (2013) De novo generation of infectious prions with bacterially expressed recombinant prion protein. FASEB J 27: 4768–4775. doi: 10.1096/fj.13-233965 23970796
38. Hoinville LJ (1996) A review of the epidemiology of scrapie in sheep. Rev Sci Tech 15: 827–852. 9025137
39. Wilesmith JW, Ryan JB, Atkinson MJ (1991) Bovine spongiform encephalopathy: epidemiological studies on the origin. Vet Rec 128: 199–203. 1823120
40. Will RG (2003) Acquired prion disease: iatrogenic CJD, variant CJD, kuru. Br Med Bull 66: 255–265. 14522863
41. Tatzelt J, Groth DF, Torchia M, Prusiner SB, DeArmond SJ (1999) Kinetics of prion protein accumulation in the CNS of mice with experimental scrapie. J Neuropathol Exp Neurol 58: 1244–1249. 10604749
42. Crozet C, Lezmi S, Flamant F, Samarut J, Baron T, et al. (2007) Peripheral circulation of the prion infectious agent in transgenic mice expressing the ovine prion protein gene in neurons only. J Infect Dis 195: 997–1006. 17330790
43. Inoue Y, Yamakawa Y, Sakudo A, Kinumi T, Nakamura Y, et al. (2005) Infection route-independent accumulation of splenic abnormal prion protein. Jpn J Infect Dis 58: 78–82. 15858284
44. Shearin H, Bessen RA (2014) Axonal and transynaptic spread of prions. J Virol.
45. Jeffrey M, McGovern G, Siso S, Gonzalez L (2011) Cellular and sub-cellular pathology of animal prion diseases: relationship between morphological changes, accumulation of abnormal prion protein and clinical disease. Acta Neuropathol 121: 113–134. doi: 10.1007/s00401-010-0700-3 20532540
46. Jeffrey M, Gonzalez L (2007) Classical sheep transmissible spongiform encephalopathies: pathogenesis, pathological phenotypes and clinical disease. Neuropathol Appl Neurobiol 33: 373–394. 17617870
47. McBride PA, Schulz-Schaeffer WJ, Donaldson M, Bruce M, Diringer H, et al. (2001) Early spread of scrapie from the gastrointestinal tract to the central nervous system involves autonomic fibers of the splanchnic and vagus nerves. J Virol 75: 9320–9327. 11533195
48. van Keulen LJ, Schreuder BE, Vromans ME, Langeveld JP, Smits MA (2000) Pathogenesis of natural scrapie in sheep. Arch Virol Suppl: 57–71. 11214935
49. Jeffrey M, Ryder S, Martin S, Hawkins SA, Terry L, et al. (2001) Oral inoculation of sheep with the agent of bovine spongiform encephalopathy (BSE). 1. Onset and distribution of disease-specific PrP accumulation in brain and viscera. J Comp Pathol 124: 280–289. 11437504
50. Gonzalez L, Pitarch JL, Martin S, Thurston L, Moore J, et al. (2014) Identical pathogenesis and neuropathological phenotype of scrapie in valine, arginine, glutamine/valine, arginine, glutamine sheep infected experimentally by the oral and conjunctival routes. J Comp Pathol 150: 47–56. doi: 10.1016/j.jcpa.2013.06.006 24035191
51. Sigurdson CJ, Williams ES, Miller MW, Spraker TR, O'Rourke KI, et al. (1999) Oral transmission and early lymphoid tropism of chronic wasting disease PrPres in mule deer fawns (Odocoileus hemionus). J Gen Virol 80 (Pt 10): 2757–2764. 10573172
52. Jeffrey M, Gonzalez L, Espenes A, Press CM, Martin S, et al. (2006) Transportation of prion protein across the intestinal mucosa of scrapie-susceptible and scrapie-resistant sheep. J Pathol 209: 4–14. 16575799
53. Wang F, Wang X, Ma J (2011) Conversion of bacterially expressed recombinant prion protein. Methods 53: 208–213. doi: 10.1016/j.ymeth.2010.12.013 21176786
54. Casaccia P, Ladogana A, Xi YG, Pocchiari M (1989) Levels of infectivity in the blood throughout the incubation period of hamsters peripherally injected with scrapie. Arch Virol 108: 145–149. 2512893
55. Gonzalez L, Chianini F, Martin S, Siso S, Gibbard L, et al. (2007) Comparative titration of experimental ovine BSE infectivity in sheep and mice. J Gen Virol 88: 714–717. 17251591
56. Gonzalez L, Siso S, Monleon E, Casalone C, van Keulen LJ, et al. (2010) Variability in disease phenotypes within a single PRNP genotype suggests the existence of multiple natural sheep scrapie strains within Europe. J Gen Virol 91: 2630–2641. doi: 10.1099/vir.0.022574-0 20538906
57. Gonzalez L, Martin S, Begara-McGorum I, Hunter N, Houston F, et al. (2002) Effects of agent strain and host genotype on PrP accumulation in the brain of sheep naturally and experimentally affected with scrapie. J Comp Pathol 126: 17–29. 11814318
58. Bruce ME (1993) Scrapie strain variation and mutation. Br Med Bull 49: 822–838. 8137131
59. Bruce ME, McBride PA, Farquhar CF (1989) Precise targeting of the pathology of the sialoglycoprotein, PrP, and vacuolar degeneration in mouse scrapie. Neurosci Lett 102: 1–6. 2550852
60. Bruce ME, Fraser H (1991) Scrapie strain variations and its implications. Current Topics in Microbiology and Immunology 172: 125–138. 1810707
61. Makarava N, Kovacs GG, Savtchenko R, Alexeeva I, Ostapchenko VG, et al. (2012) A new mechanism for transmissible prion diseases. J Neurosci 32: 7345–7355. doi: 10.1523/JNEUROSCI.6351-11.2012 22623680
62. Jeffrey M, McGovern G, Makarava N, Gonzalez L, Kim YS, et al. (2014) Pathology of SSLOW, a transmissible and fatal synthetic prion protein disorder, and comparison with naturally occurring classical transmissible spongiform encephalopathies. Neuropathol Appl Neurobiol 40: 296–310. doi: 10.1111/nan.12053 23578208
63. Ma J (2012) The role of cofactors in prion propagation and infectivity. PLoS Pathog 8: e1002589. doi: 10.1371/journal.ppat.1002589 22511864
64. Wang F, Yang F, Hu Y, Wang X, Jin C, et al. (2007) Lipid interaction converts prion protein to a PrPSc-like proteinase K-resistant conformation under physiological conditions. Biochemistry 46: 7045–7053. 17503780
65. Wang F, Yin S, Wang X, Zha L, Sy MS, et al. (2010) Role of the highly conserved middle region of prion protein (PrP) in PrP-lipid interaction. Biochemistry 49: 8169–8176. doi: 10.1021/bi101146v 20718504
66. Gomes MP, Millen TA, Ferreira PS, e Silva NL, Vieira TC, et al. (2008) Prion protein complexed to N2a cellular RNAs through its N-terminal domain forms aggregates and is toxic to murine neuroblastoma cells. J Biol Chem 283: 19616–19625. doi: 10.1074/jbc.M802102200 18456654
67. Gomes MP, Vieira TC, Cordeiro Y, Silva JL (2012) The role of RNA in mammalian prion protein conversion. Wiley Interdiscip Rev RNA 3: 415–428. doi: 10.1002/wrna.118 22095764
68. Wang X, Bowers SL, Wang F, Pu XA, Nelson RJ, et al. (2009) Cytoplasmic prion protein induces forebrain neurotoxicity. Biochim Biophys Acta 1792: 555–563. doi: 10.1016/j.bbadis.2009.02.014 19281844
69. Fraser H, Dickinson AG (1968) The sequential development of the brain lesion of scrapie in three strains of mice. J Comp Pathol 78: 301–311. 4970192
70. Gonzalez L, Martin S, Houston FE, Hunter N, Reid HW, et al. (2005) Phenotype of disease-associated PrP accumulation in the brain of bovine spongiform encephalopathy experimentally infected sheep. J Gen Virol 86: 827–838. 15722546
71. McGovern G, Brown KL, Bruce ME, Jeffrey M (2004) Murine scrapie infection causes an abnormal germinal centre reaction in the spleen. J Comp Pathol 130: 181–194. 15003476
72. Polymenidou M, Moos R, Scott M, Sigurdson C, Shi YZ, et al. (2008) The POM monoclonals: a comprehensive set of antibodies to non-overlapping prion protein epitopes. PLoS One 3: e3872. doi: 10.1371/journal.pone.0003872 19060956
73. Choi JK, Park SJ, Jun YC, Oh JM, Jeong BH, et al. (2006) Generation of monoclonal antibody recognized by the GXXXG motif (glycine zipper) of prion protein. Hybridoma (Larchmt) 25: 271–277. 17044782
74. Farquhar CF, Somerville RA, Ritchie LA (1989) Post-mortem immunodiagnosis of scrapie and bovine spongiform encephalopathy. J Virol Methods 24: 215–221. 2569471
75. Liu WG, Brown DA, Fraser JR (2003) Immunohistochemical comparison of anti-prion protein (PrP) antibodies in the CNS of mice infected with scrapie. J Histochem Cytochem 51: 1065–1071. 12871988
76. Baral PK, Wieland B, Swayampakula M, Polymenidou M, Rahman MH, et al. (2012) Structural studies on the folded domain of the human prion protein bound to the Fab fragment of the antibody POM1. Acta Crystallogr D Biol Crystallogr 68: 1501–1512. doi: 10.1107/S0907444912037328 23090399
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2015 Číslo 7
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- Characterization of a Prefusion-Specific Antibody That Recognizes a Quaternary, Cleavage-Dependent Epitope on the RSV Fusion Glycoprotein
- N-acetylglucosamine Regulates Virulence Properties in Microbial Pathogens
- Activation of TLR2 and TLR6 by Dengue NS1 Protein and Its Implications in the Immunopathogenesis of Dengue Virus Infection
- RNA Virus Reassortment: An Evolutionary Mechanism for Host Jumps and Immune Evasion