PRIONS

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PRIONS

• PETER H. RUSSELL, BVSc, PhD, FRCPath, MRCVS
• Department of Pathology and Infectious Diseases,
  The Royal Veterinary College,
• Royal College Street,
• London NW1 OTU.
• E-mail Web site

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ObjectiveStudents should be able to

• define the characteristics of a prion including
  the proteinase- resistance, fibre formation and
  vacuolation in the brain.
• contrast how ruminant-derived protein transfers
  BSE between cows and how maternal leucocytes
  transfer Scrapie.
• describe how to suspect Scrapie and BSE and the
  means of diagnosis.
• outline the other transmissible spongiform
  encephalophies (TSEs) and the links between
  variant Creutzfeldt Jacob Disease of man and BSE.

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INTRODUCTION

• These are ALL notifiable diseases, including
  scrapie.
• The agent is found at highest titre in the brain.
• Scrapie and BSE are separate agents.

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Characteristics of Prions

• Proteinaceous infectious particles (Proins termed
  Prions) have not been visualised.
• Prions are assayed for infectivity by mouse
  inoculation by the intracerebral route, mice
  develop clinical symptoms several months later.
• Scrapie infectivity for mice can be co-purified
  with prion-protein, PrP of scrapie (PrPsc).
• Normal neuronal cells express cellular PrPc on
  their cell surface.

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Characteristics of Prions (cont.)

• Infectivity is not destroyed by ultraviolet light
  or nucleases which destroy nucleic acid as if any
  nucleic acid is highly protected or absent.
• The catalysis of PrPc into PrPsc, may depend on
  solely upon the interaction between the infective
  PrPsc and host PrPc without any nucleic acid
  replication..
• An antiserum and now a mAb to PrPsc cross-reacts
  to CJD PrP

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SCRAPIEPathogenesis and clinical signs

• Sheep
• Following experimental inoculation the agent is
  first recoverable from lymphoid tissues (tonsil
  mesenteric LN). PrP is seen by
  immuncytochemistry in dendritic cells and
  macrophages of 3rd eyelid germinal follicles and
  2-3 months later from the medullary region of the
  mid-brain. In the mid-brain the neurones become
  vacolated and then shrink. This is accompanied
  by the formation of amyloid plaques. These
  plaques contain fibrils of PrPsc. The
  vacuolation may be caused by the intracellular
  action of PrPsc. No antibody nor inflammation
  is produced in vivo.

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Genetic susceptibility to Scrapie

• The PrP gene determines incubation period which
  can be the difference between health at 70m and
  death at 25m. Amino acids at 3 positions, 136,
  154 and 171 are important. Resistance is
  dominant and 171 is the most important amino
  acid.

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Immunity and epidemiology, maternal transmission

• In 1990 a questionnaire to flock owners suggested
  that 33 of British flocks contained infected
  animals and at the rate of 1-10 with clinical
  symptoms. The national average was 0.5.

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Diagnosis

• Clinical symptoms hyperaesthesia to final ataxia.
• No test for animals incubating the disease.
• Post mortem pathology and histology (see above).
• The 27-30K protease-k-resistant band of PrPSc can
  be detected by Western blotting of solubilised
  medulla using a mAb to PrPSc. This is being
  developed as an automated diagnostic test for BSE
  (Prionic).

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BSE
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Pathology

• Cattle

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Pathology

• Sheep

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Epidemiology and immunity
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Epidemiology and immunity

• (cont.)

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Early-indoor lambers and creep-fed lambs are fed
RDP concentrate. However Scrapie /BSE did not
increase in sheep during the BSE outbreak in
cattle although MAFF now need to ensure that
sheep are free from BSE in case lambs can be
infected with BSE in the same manner as Scrapie
and represent a biohazard.
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Epidemiology and immunity

• (cont.)

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Epidemiology and immunity

• Other species

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Case against BSE in man

• No cases of human SE have been associated with
  handling or eating sheep or BSE-infected cattle
  or milkers eating cattle cake.
• Transgenic mice which contain the human PrPc gene
  in place of their own are no more susceptible to
  BSE than normal mice whereas they developed CJD
  faster then normal mice (213d instead of 420d).

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The effect on food consumption

• The consumption of beef dipped 30 after the
  start of BSE but then recovered although beef
  consumption is on a slow long-term downward
  trend. Certain food conglomerates once bought
  beef only from outside the UK.

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Diagnosis
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Control
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Other UK legislation
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MINK ENCEPHALOPATHY
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References

• BSE. Vet.Rec.,(1988) 123, 628-644, (1996), 139,
  126 (1996), 138,602-603
• BSE. J.Path., (1990) 160, 283-285
• Feline spongiform encephalopathy. Vet.Rec.,
  (1992), 131,307-310
• BSE in mice macaques preclin diag Nature
  (1995) 378, 761-762 (1996) 381, 734-735 (1996),
  381,563
• BSE/CJD epidemiologyNature, Aug 29th1996
• BSE, vert transmission,Vet Rec 1997, Aug 16th,
  239-243
• BSE, beef bones now safe, VetRec 1998, 143,
  Dec5th, pp622-623
• Variant CJD BSE?, Nature, 1997, 389, pp437-438,
  448-450, 498-501.
• PrP genotyping for selection of low scrapie
  rams, Vet Rec, (1998) 142 (23) pp623-625
• Prionics WB , Shaller et al., Acta Neuropath,
  (1999), 98, 437-44

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Summary

• Scrapie is maternally-transferred although
  selective breeding using resistant rams reduces
  disease.
• BSE is transferred by bovine brain being fed as
  ruminant-derived protein. This was discontinued
  in July 1988 but the feeding of some
  BSE-contaminated ruminant-derived protein
  continued until at least 1990.
• BSE also occurs in felidae which are fed RDP.
• BSE cannot be distinguished from variant CJD of
  man.
• BSE is a single pathotype and bovines lack genes
  for length of incubation period. Both sources of
  variation exist for Scrapie in sheep.

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Summary (cont.)

• BSE and Scrapie have incubation periods of
  several years. Animals do not make any immune
  response and die with a spongiform encephalopathy
  in which fibrils of PrPsc coat the neurones and
  appear as amyloid.
• Public health concern is high because of
  BSE-brain entering the human food chain and some
  florid cases of CJD since 1994.
• Whether BSE is in sheep is being researched