Download HERPESVIRIDAE

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
Objective
Students 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 (TSE’s) and the links between
variant Creutzfeldt Jacob Disease of man and BSE.
INTRODUCTION
These are ALL notifiable
diseases, including scrapie.
The agent is found at highest
titre in the brain.
Scrapie and BSE are separate
agents.
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.
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 crossreacts to CJD PrP
SCRAPIE
Pathogenesis 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.
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.
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%.
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).
BSE
Pathology
Cattle:
Pathology
Sheep:
Epidemiology and immunity:
Epidemiology and immunity:
(cont.)
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.
Epidemiology and immunity:
(cont.)
Epidemiology and immunity:
Other species:
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).
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.
Diagnosis:
Control:
Other UK legislation
MINK ENCEPHALOPATHY
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, 498501.
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
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.
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