Estimating relative CWD susceptibility and disease progression in farmed white-tailed deer with rare PRNP alleles

Autoři: Nicholas J. Haley aff001;  Kahla Merrett aff001;  Amy Buros Stein aff002;  Dennis Simpson aff003;  Andrew Carlson aff003;  Gordon Mitchell aff004;  Antanas Staskevicius aff004;  Tracy Nichols aff005;  Aaron D. Lehmkuhl aff006;  Bruce V. Thomsen aff006
Působiště autorů: Department of Microbiology and Immunology, College of Graduate Studies, Midwestern University, Glendale, Arizona aff001;  Office of Research and Sponsored Programs, Midwestern University, Glendale, Arizona aff002;  Simpson Whitetails Genetic Testing, Belleville, Michigan aff003;  National and OIE Reference Laboratory for Scrapie and CWD, Canadian Food Inspection Agency, Ottawa Laboratory-Fallowfield, Ottawa, Ontario, Canada aff004;  United States Department of Agriculture, APHIS, Veterinary Services, Cervid Health Program, Fort Collins, Colorado, United States of America aff005;  United States Department of Agriculture, APHIS, Veterinary Services, National Veterinary Services Laboratories, Ames, Iowa, United States of America aff006;  United States Department of Agriculture, APHIS, Veterinary Services, Center for Veterinary Biologics, Ames, Iowa, United States of America aff007
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224342


Chronic wasting disease is a prion disease affecting both free-ranging and farmed cervids in North America and Scandinavia. A range of cervid species have been found to be susceptible, each with variations in the gene for the normal prion protein, PRNP, reportedly influencing both disease susceptibility and progression in the respective hosts. Despite the finding of several different PRNP alleles in white-tailed deer, the majority of past research has focused on two of the more common alleles identified—the 96G and 96S alleles. In the present study, we evaluate both infection status and disease stage in nearly 2100 farmed deer depopulated in the United States and Canada, including 714 CWD-positive deer and correlate our findings with PRNP genotype, including the more rare 95H, 116G, and 226K alleles. We found significant differences in either likelihood of being found infected or disease stage (and in many cases both) at the time of depopulation in all genotypes present, relative to the most common 96GG genotype. Despite high prevalence in many of the herds examined, infection was not found in several of the reported genotypes. These findings suggest that additional research is necessary to more properly define the role that these genotypes may play in managing CWD in both farmed and free-ranging white-tailed deer, with consideration for factors including relative fitness levels, incubation periods, and the kinetics of shedding in animals with these rare genotypes.

Klíčová slova:

Alleles – Animal prion diseases – Canada – Deer – Chronic wasting disease – United States – Variant genotypes – Veterinary diseases


1. Williams ES, Young S (1980) Chronic wasting disease of captive mule deer: a spongiform encephalopathy. J Wildl Dis 16: 89–98. doi: 10.7589/0090-3558-16.1.89 7373730

2. Prusiner SB (1982) Novel proteinaceous infectious particles cause scrapie. Science 216: 136–144. doi: 10.1126/science.6801762 6801762

3. Benestad SL, Telling GC (2018) Chronic wasting disease: an evolving prion disease of cervids. Handb Clin Neurol 153: 135–151. doi: 10.1016/B978-0-444-63945-5.00008-8 29887133



6. Sohn HJ, Kim JH, Choi KS, Nah JJ, Joo YS, et al. (2002) A case of chronic wasting disease in an elk imported to Korea from Canada. J Vet Med Sci 64: 855–858. doi: 10.1292/jvms.64.855 12399615

7. Benestad SL, Mitchell G, Simmons M, Ytrehus B, Vikoren T (2016) First case of chronic wasting disease in Europe in a Norwegian free-ranging reindeer. Vet Res 47: 88. doi: 10.1186/s13567-016-0375-4 27641251

8. Haley NJ, Hoover EA (2015) Chronic Wasting Disease of Cervids: Current Knowledge and Future Perspectives. Annu Rev Anim Biosci.

9. Miller MW, Wild MA (2004) Epidemiology of chronic wasting disease in captive white-tailed and mule deer. J Wildl Dis 40: 320–327. doi: 10.7589/0090-3558-40.2.320 15362835

10. Mathiason CK, Hays SA, Powers J, Hayes-Klug J, Langenberg J, et al. (2009) Infectious Prions in Pre-Clinical Deer and Transmission of Chronic Wasting Disease Solely by Environmental Exposure. PLoS ONE 4: e5916. doi: 10.1371/journal.pone.0005916 19529769

11. Henderson DM, Manca M, Haley NJ, Denkers ND, Nalls AV, et al. (2013) Rapid Antemortem Detection of CWD Prions in Deer Saliva. PLoS One 8: e74377. doi: 10.1371/journal.pone.0074377 24040235

12. Haley NJ, Mathiason CK, Carver S, Zabel M, Telling GC, et al. (2011) Detection of chronic wasting disease prions in salivary, urinary, and intestinal tissues of deer: potential mechanisms of prion shedding and transmission. J Virol 85: 6309–6318. doi: 10.1128/JVI.00425-11 21525361

13. Angers RC, Seward TS, Napier D, Green M, Hoover E, et al. (2009) Chronic wasting disease prions in elk antler velvet. Emerg Infect Dis 15: 696–703. doi: 10.3201/eid1505.081458 19402954

14. Race B, Meade-White K, Race R, Chesebro B (2009) Prion infectivity in fat of deer with chronic wasting disease. J Virol 83: 9608–9610. doi: 10.1128/JVI.01127-09 19570855

15. Mathiason CK, Powers JG, Dahmes SJ, Osborn DA, Miller KV, et al. (2006) Infectious prions in the saliva and blood of deer with chronic wasting disease. Science 314: 133–136. doi: 10.1126/science.1132661 17023660

16. Haley NJ, Van de Motter A, Carver S, Henderson D, Davenport K, et al. (2013) Prion-seeding activity in cerebrospinal fluid of deer with chronic wasting disease. PLoS ONE 8: e81488. doi: 10.1371/journal.pone.0081488 24282599

17. Henderson DM, Tennant JM, Haley NJ, Denkers ND, Mathiason CK, et al. (2017) Detection of chronic wasting disease prion seeding activity in deer and elk feces by real-time quaking-induced conversion. J Gen Virol 98: 1953–1962. doi: 10.1099/jgv.0.000844 28703697

18. Angers RC, Browning SR, Seward TS, Sigurdson CJ, Miller MW, et al. (2006) Prions in skeletal muscles of deer with chronic wasting disease. Science 311: 1117. doi: 10.1126/science.1122864 16439622

19. Prusiner SB (1998) Prions. Proc Natl Acad Sci U S A 95: 13363–13383. doi: 10.1073/pnas.95.23.13363 9811807

20. DeArmond SJ (2004) Discovering the mechanisms of neurodegeneration in prion diseases. Neurochem Res 29: 1979–1998. doi: 10.1007/s11064-004-6872-2 15662833

21. Dormont D (2002) Prion diseases: pathogenesis and public health concerns. FEBS Lett 529: 17–21. doi: 10.1016/s0014-5793(02)03268-4 12354606

22. Lloyd SE, Mead S, Collinge J (2013) Genetics of prion diseases. Curr Opin Genet Dev 23: 345–351. doi: 10.1016/j.gde.2013.02.012 23518043

23. Murdoch BM, Murdoch GK (2015) Genetics of Prion Disease in Cattle. Bioinform Biol Insights 9: 1–10.

24. Niedermeyer S, Eiden M, Toumazos P, Papasavva-Stylianou P, Ioannou I, et al. (2016) Genetic, histochemical and biochemical studies on goat TSE cases from Cyprus. Vet Res 47: 99. doi: 10.1186/s13567-016-0379-0 27716411

25. Richt JA, Hall SM (2008) BSE case associated with prion protein gene mutation. PLoS Pathog 4: e1000156. doi: 10.1371/journal.ppat.1000156 18787697

26. Robinson SJ, Samuel MD, O'Rourke KI, Johnson CJ (2012) The role of genetics in chronic wasting disease of North American cervids. Prion 6: 153–162. doi: 10.4161/pri.19640 22460693

27. Watts JC, Westaway D (2007) The prion protein family: diversity, rivalry, and dysfunction. Biochim Biophys Acta 1772: 654–672. doi: 10.1016/j.bbadis.2007.05.001 17562432

28. Windl O, Dempster M, Estibeiro JP, Lathe R, de Silva R, et al. (1996) Genetic basis of Creutzfeldt-Jakob disease in the United Kingdom: a systematic analysis of predisposing mutations and allelic variation in the PRNP gene. Hum Genet 98: 259–264. doi: 10.1007/s004390050204 8707291

29. Pastore A, Zagari A (2007) A structural overview of the vertebrate prion proteins. Prion 1: 185–197. doi: 10.4161/pri.1.3.5281 19164911

30. Wopfner F, Weidenhofer G, Schneider R, von Brunn A, Gilch S, et al. (1999) Analysis of 27 mammalian and 9 avian PrPs reveals high conservation of flexible regions of the prion protein. J Mol Biol 289: 1163–1178. doi: 10.1006/jmbi.1999.2831 10373359

31. Laurent M (1998) Bistability and the species barrier in prion diseases: stepping across the threshold or not. Biophys Chem 72: 211–222. doi: 10.1016/s0301-4622(98)00135-5 17029708

32. Mawhinney S, Pape WJ, Forster JE, Anderson CA, Bosque P, et al. (2006) Human prion disease and relative risk associated with chronic wasting disease. Emerg Infect Dis 12: 1527–1535. doi: 10.3201/eid1210.060019 17176567

33. Raymond GJ, Bossers A, Raymond LD, O'Rourke KI, McHolland LE, et al. (2000) Evidence of a molecular barrier limiting susceptibility of humans, cattle and sheep to chronic wasting disease. EMBO J 19: 4425–4430. doi: 10.1093/emboj/19.17.4425 10970836

34. Surewicz WK, Jones EM, Apetri AC (2006) The emerging principles of mammalian prion propagation and transmissibility barriers: Insight from studies in vitro. Acc Chem Res 39: 654–662. doi: 10.1021/ar050226c 16981682

35. Belay ED, Maddox RA, Williams ES, Miller MW, Gambetti P, et al. (2004) Chronic wasting disease and potential transmission to humans. Emerg Infect Dis 10: 977–984. doi: 10.3201/eid1006.031082 15207045

36. Asante EA, Smidak M, Grimshaw A, Houghton R, Tomlinson A, et al. (2015) A naturally occurring variant of the human prion protein completely prevents prion disease. Nature 522: 478–481. doi: 10.1038/nature14510 26061765

37. Fast C, Goldmann W, Berthon P, Tauscher K, Andreoletti O, et al. (2017) Protecting effect of PrP codons M142 and K222 in goats orally challenged with bovine spongiform encephalopathy prions. Vet Res 48: 52. doi: 10.1186/s13567-017-0455-0 28927447

38. Vouraki S, Gelasakis AI, Alexandri P, Boukouvala E, Ekateriniadou LV, et al. (2018) Genetic profile of scrapie codons 146, 211 and 222 in the PRNP gene locus in three breeds of dairy goats. PLoS One 13: e0198819. doi: 10.1371/journal.pone.0198819 29879210

39. Jeffrey M, Martin S, Chianini F, Eaton S, Dagleish MP, et al. (2014) Incidence of infection in Prnp ARR/ARR sheep following experimental inoculation with or natural exposure to classical scrapie. PLoS One 9: e91026. doi: 10.1371/journal.pone.0091026 24614120

40. Lacroux C, Cassard H, Simmons H, Yves Douet J, Corbiere F, et al. (2017) Classical scrapie transmission in ARR/ARR genotype sheep. J Gen Virol 98: 2200–2204. doi: 10.1099/jgv.0.000861 28721847

41. Baylis M, Goldmann W (2004) The genetics of scrapie in sheep and goats. Curr Mol Med 4: 385–396. doi: 10.2174/1566524043360672 15354869

42. Sutton D. USDA-APHIS Scrapie Program Update and Scrapie Surveillance Projects. In: Richey B, Janicek K, editors; 2015; Providence, RI. pp. 342–344.

43. Arnold M, Ortiz-Pelaez A (2014) The evolution of the prevalence of classical scrapie in sheep in Great Britain using surveillance data between 2005 and 2012. Prev Vet Med 117: 242–250. doi: 10.1016/j.prevetmed.2014.07.015 25183633

44. Nodelijk G, van Roermund HJ, van Keulen LJ, Engel B, Vellema P, et al. (2011) Breeding with resistant rams leads to rapid control of classical scrapie in affected sheep flocks. Vet Res 42: 5. doi: 10.1186/1297-9716-42-5 21314971

45. Jewell JE, Conner MM, Wolfe LL, Miller MW, Williams ES (2005) Low frequency of PrP genotype 225SF among free-ranging mule deer (Odocoileus hemionus) with chronic wasting disease. J Gen Virol 86: 2127–2134. doi: 10.1099/vir.0.81077-0 16033959

46. O'Rourke KI, Spraker TR, Hamburg LK, Besser TE, Brayton KA, et al. (2004) Polymorphisms in the prion precursor functional gene but not the pseudogene are associated with susceptibility to chronic wasting disease in white-tailed deer. J Gen Virol 85: 1339–1346. doi: 10.1099/vir.0.79785-0 15105552

47. Mitchell GB, Sigurdson CJ, O'Rourke KI, Algire J, Harrington NP, et al. (2012) Experimental oral transmission of chronic wasting disease to reindeer (Rangifer tarandus tarandus). PLoS One 7: e39055. doi: 10.1371/journal.pone.0039055 22723928

48. O'Rourke KI, Besser TE, Miller MW, Cline TF, Spraker TR, et al. (1999) PrP genotypes of captive and free-ranging Rocky Mountain elk (Cervus elaphus nelsoni) with chronic wasting disease. J Gen Virol 80 (Pt 10): 2765–2769.

49. Hamir AN, Greenlee JJ, Nicholson EM, Kunkle RA, Richt JA, et al. (2011) Experimental transmission of chronic wasting disease (CWD) from elk and white-tailed deer to fallow deer by intracerebral route: final report. Can J Vet Res 75: 152–156. 21731188

50. Johnson C, Johnson J, Vanderloo JP, Keane D, Aiken JM, et al. (2006) Prion protein polymorphisms in white-tailed deer influence susceptibility to chronic wasting disease. J Gen Virol 87: 2109–2114. doi: 10.1099/vir.0.81615-0 16760415

51. Kelly AC, Mateus-Pinilla NE, Diffendorfer J, Jewell E, Ruiz MO, et al. (2008) Prion sequence polymorphisms and chronic wasting disease resistance in Illinois white-tailed deer (Odocoileus virginianus). Prion 2: 28–36. doi: 10.4161/pri.2.1.6321 19164895

52. Brandt AL, Green ML, Ishida Y, Roca AL, Novakofski J, et al. (2018) Influence of the geographic distribution of prion protein gene sequence variation on patterns of chronic wasting disease spread in white-tailed deer (Odocoileus virginianus). Prion 12: 204–215. doi: 10.1080/19336896.2018.1474671 30041562

53. Samuel MD, Storm DJ (2016) Chronic wasting disease in white-tailed deer: infection, mortality, and implications for heterogeneous transmission. Ecology 97: 3195–3205. doi: 10.1002/ecy.1538 27870037

54. Wolfe LL, Fox KA, Miller MW (2014) "Atypical" chronic wasting disease in PRNP genotype 225FF mule deer. J Wildl Dis 50: 660–665. doi: 10.7589/2013-10-274 24807352

55. Haley N, Henderson D, Donner R, Wyckoff S, Merrett K, et al. (Under Review) Management of Chronic Wasting Disease in Ranched Elk: Conclusions from a Longitudinal Three-Year Study.

56. Haley NJ, Siepker C, Walter WD, Thomsen BV, Greenlee JJ, et al. (2016) Antemortem Detection of Chronic Wasting Disease Prions in Nasal Brush Collections and Rectal Biopsy Specimens from White-Tailed Deer by Real-Time Quaking-Induced Conversion. J Clin Microbiol 54: 1108–1116. doi: 10.1128/JCM.02699-15 26865693

57. Thomsen BV, Schneider DA, O'Rourke KI, Gidlewski T, McLane J, et al. (2012) Diagnostic accuracy of rectal mucosa biopsy testing for chronic wasting disease within white-tailed deer (Odocoileus virginianus) herds in North America: effects of age, sex, polymorphism at PRNP codon 96, and disease progression. J Vet Diagn Invest 24: 878–887. doi: 10.1177/1040638712453582 22914819

58. Burkner P (2018) Advanced Bayesian Multilevel Modeling with the R Package brms. The R Journal 10: 395–411.

59. Pinheiro J, Bates D, DebRoy S, Sarkar D, Team RC (2019) nlme: Linear and Nonlinear Mixed Effects Models. R Package version 31–139.

60. Knowles JE, Frederick C merTools: Tools for Analyzing Mixed Effect Regression Models. R Package version 050.

61. Johnson CJ, Herbst A, Duque-Velasquez C, Vanderloo JP, Bochsler P, et al. (2011) Prion protein polymorphisms affect chronic wasting disease progression. PLoS One 6: e17450. doi: 10.1371/journal.pone.0017450 21445256

62. Robinson SJ, Samuel MD, Johnson CJ, Adams M, McKenzie DI (2012) Emerging prion disease drives host selection in a wildlife population. Ecol Appl 22: 1050–1059. doi: 10.1890/11-0907.1 22645831

63. Keane DP, Barr DJ, Bochsler PN, Hall SM, Gidlewski T, et al. (2008) Chronic wasting disease in a Wisconsin white-tailed deer farm. J Vet Diagn Invest 20: 698–703. doi: 10.1177/104063870802000534 18776116

64. Otero A, Duque Velasquez C, Johnson C, Herbst A, Bolea R, et al. (2019) Prion protein polymorphisms associated with reduced CWD susceptibility limit peripheral PrP(CWD) deposition in orally infected white-tailed deer. BMC Vet Res 15: 50. doi: 10.1186/s12917-019-1794-z 30717795

65. Haley NJ, Rielinger R, Davenport KA, O'Rourke K, Mitchell G, et al. (2017) Estimating chronic wasting disease susceptibility in cervids using real-time quaking-induced conversion. J Gen Virol 98: 2882–2892. doi: 10.1099/jgv.0.000952 29058651

66. Plummer IH, Wright SD, Johnson CJ, Pedersen JA, Samuel MD (2017) Temporal patterns of chronic wasting disease prion excretion in three cervid species. J Gen Virol 98: 1932–1942. doi: 10.1099/jgv.0.000845 28708047

67. Henderson DM, Denkers ND, Hoover CE, Garbino N, Mathiason CK, et al. (2015) Longitudinal Detection of Prion Shedding in Saliva and Urine by Chronic Wasting Disease-Infected Deer by Real-Time Quaking-Induced Conversion. J Virol 89: 9338–9347. doi: 10.1128/JVI.01118-15 26136567

68. Davenport KA, Mosher BA, Brost BM, Henderson DM, Denkers ND, et al. (2018) Assessment of Chronic Wasting Disease Prion Shedding in Deer Saliva with Occupancy Modeling. J Clin Microbiol 56.

69. Haley N, Mathiason C, Zabel MD, Telling GC, Hoover E (2009) Detection of sub-clinical CWD infection in conventional test-negative deer long after oral exposure to urine and feces from CWD+ deer. PLoS ONE 4: e7990. doi: 10.1371/journal.pone.0007990 19956732

70. Smith PG, Bradley R (2003) Bovine spongiform encephalopathy (BSE) and its epidemiology. Br Med Bull 66: 185–198. doi: 10.1093/bmb/66.1.185 14522859

71. Raymond GJ, Raymond LD, Meade-White KD, Hughson AG, Favara C, et al. (2007) Transmission and adaptation of chronic wasting disease to hamsters and transgenic mice: evidence for strains. J Virol 81: 4305–4314. doi: 10.1128/JVI.02474-06 17287284

72. 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

73. Mahal SP, Browning S, Li J, Suponitsky-Kroyter I, Weissmann C (2010) Transfer of a prion strain to different hosts leads to emergence of strain variants. Proc Natl Acad Sci U S A 107: 22653–22658. doi: 10.1073/pnas.1013014108 21156827

74. Weissmann C, Li J, Mahal SP, Browning S (2011) Prions on the move. EMBO Rep 12: 1109–1117. doi: 10.1038/embor.2011.192 21997298

Článek vyšel v časopise


2019 Číslo 12