Slow Virus Infections & Prion Diseases
Transcript of Slow Virus Infections & Prion Diseases
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"Slow virus infections" refers to the tempo of
the DISEASE, not to the growth rate of the virus
These diseases have a prolonged incubation
period (months or years), & a protracted,
progressive clinical course
Caused by conventional viruses or by the
unconventional agents or atypical
viruses/agents
Slow viral/prion diseases of the CNS tend to
have multiple neurological manifestations
Different patients may present with very
different symptoms
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Progressive multifocal leukoencephalopathy(PML)
A rare, progressive, fatal, demyelinating diseaseof the CNS that kills oligodendrocytes
Results in memory loss, loss of co-ordination,
mentation problems, vision problems, etc
Caused by certain members of thepolyomavirus family, usually JC virus
Abnormality of the immune system
PML develops in up to 5% of patients with AIDS
PML may be due to reactivation of a JC virus
latent infection, probably in the kidney
There is also abundant virus in brain
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HIV & AIDS
Rabies
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Visna & progressive pneumonia (maedi)viruses
Related viruses causing sheep disease
Retroviruses, genus Lentivirus
Visna infects all organs, but pathologic changesisolated to brain (demyelination), lungs & RE
system
Long I.P. of months to years
Disease progression rapid (wks)or slow (yrs) Virus can be recovered lifelong
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A group of unusual agents, whose true nature is
still controversialNo one has been able to prove that these agents
contain nucleic acid
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These agents:
o cause diseases that are
confined to the CNSo have a prolonged
incubation period
o show a slow, progressive,
fatal course of disease
o show a spongiformencephalopathy
o characteristically result in
vacuolation of neurons
o can cause formation offibrillar aggregates, whichcontain prion protein (PrP)
and have amyloid-like
characteristics
Microscopic "holes" are
characteristic in prion-
affected tissue sections,causing the tissue to
develop a "spongy"
architecture.
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Prion protein
immunostaining showing
amyloid plaques.
Immunocytochemistry for PrP
in the cerebellum showsstrong staining of a kuru-
type plaque (centre) withmultiple smaller plaques in
the granular layer andabundant pericellular
deposition in the molecularlayer
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Diseases (transmissible spongiformencephalopathies)are relatively rare in man
Speculation that they may be more common
than previously thought and they may haveimplications in the study of other CNS
degenerative diseases
They may be acquired, inherited, or occur
sporadically
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Scrapie
A disease of sheep
It results in behavioral changes, progresses to
tremor, ataxia (failure of muscle coordination),wasting and death
It is transmissible
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Bovine Spongioform Encephalopathy (BSE)
BSE causes a progressive neurological
deterioration in cattle similar to the course ofCJD in humans
Cattle with BSE are more temperamental, have
problems with their posture and coordination,
have progressively greater difficulty in rising offthe ground and walking, produce less milk, have
severe twitching of muscles, and loss weight
even though their appetite is undiminished
The I.P. ranges from 2-8 years After appearance of symptoms, deterioration is
rapid and the animal dies or is destroyed within
six months
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Creutzfeldt-Jakob disease (CJD)
Results in dementia & also often tremors andlack of motor co-ordination
1-3 cases per million population per annum
Can be transmitted to animals in the laboratory
Usually seen at 50 to 70 yrs (range 16-80+ yrs) Visually abnormal pinpoints (or plaques) in the
brain
The brain tissue, particularly in the cortex and
cerebellum, becomes filled with large openspaces (vacuoles) and becomes spongy in
texture
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Bovine Spongiform Encephalopathy (BSE)
Medulla of the BSE affected cow:
Vacuoles are seen in one neuronand in the neuropiles. Astrocytes
with small nucleus proliferate. Noinflammatory cells infiltrate in
the brain.
Spongiform change in CJD
consists of numerousrounded vacuoles within
the neuropile which occurboth singly and in
confluent groups,distorting the cortical
cytoarchitecture.
Creutzfeldt-Jakob disease (CJD)
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3 means of acquiring CJD have been identified:
First, the disease can be genetically inherited.(familial CJD, approx 10%)
Secondly, the disease can appear with no exact
origin being known (sporadic CJD)(about 85%)
Lastly, the disease can be acquired during surgery(iatrogenic CJD)
Can be transmitted by medical manipulations:
cornea/dura mater transplants, improperly
sterilized equipment in neurosurgery, human
cadaver growth hormone
No evidence for direct person-person
transmission
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New variant CJD disease (human BSE);nvCJD,vCJD
Reported, predominantly in the UK, in patientswho are usually younger(
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Gerstmann-Strussler-Scheinker syndrome
Has symptoms that are Kuru-like
Is a familial disease & is often regarded as a
genetically transmitted subclass of CJD cases
Can be transmitted to laboratory animals
Fatal Familial Insomnia
Results in progressive untreatable insomnia, loss
of circadian rhythm, endocrine disorders, motor
disorders, dementia Also a familial (inherited) disease that can be
transmitted to animals in the laboratory
Hypothalamus function may be the initial target
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"proteinaceous infectious particles
Discovered & their role in brain degeneration
was proposed by Stanley Pruisner (1997 Nobel
Laureate) The prion normally is a constituent of the
membrane that surrounds the cells (designated
PrP)
PrP is a small protein, being only some 250amino acids in length
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Arranged with regions
that have a helical
conformation andother regions that
adopt a flatter, zigzag
arrangement (beta
pleated) of the aminoacids
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What is the function of normal PrP?
The normal function of PrP is still not clear
Studies from mutant mice that are deficient in
prion manufacture indicate that the protein
may help protect the brain tissue fromdestruction that occurs with ageing
Normal prions may aid in the survival of brain
cells known as Purkinje cells, which
predominate in the cerebellum, a region of thebrain responsible for movement and
coordination
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How does the PrP become disease causing?
The so-called prion theory states that PrP isthe only cause of the prion-related diseases
Disease results when a normally stable PrP is
"flipped" into a different shape Regions that are helical and zigzag are still
present, but their locations in the protein
are altered
This confers a different three-dimensionalshape to the protein.
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The prion protein PrP (encoded by a cellular gene and
made in normal cells) can exist in two forms. In diseased
tissue the protease-resistant form (PrPsc) with a lot of
beta-pleated sheet accumulates as 'amyloid plaques'
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How does normal PrP become disease causing?
As of 2002, the mechanism by which normally
functioning protein is first triggered to become
infectious is not known
One hypothesis, known as the virinohypothesis, proposes that the infectious form ofa prion is formed when the PrP associates with
nucleic acid from some infectious organism
Efforts to find prions associated with nucleicacid have, as of 2001, been unsuccessful
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How does PrPSc cause disease? The altered protein is able to stimulate a similar
structural change in surrounding prions The change in shape may result from the direct
contact and binding of the altered and infectiousprion with the unaltered and still-normallyfunctioning prions
The altered proteins also become infective andencourage other proteins to undergo theconformational change
The cascade produces proteins that adversely effectneural cells and the cells lose their ability tofunction and die
The death of regions of the brain cells producesholes in the tissue
This appearance leads to the designation of thedisease as transmissible spongiformencephalopathy (TSE)
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Simplified model for prion diseasePrPsc, the protease-resistant form of the molecule, acts as a
'template'. It associates with the helical form allowing the latter
to be converted to the beta-pleated sheet resistant form(presumably by lowering the energy barriers that normally
prevent this happening). There are now two molecules of the
resistant form that can act as a template and so the process
accelerates
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Why are there differences in prion diseases? There may be subtle
differences in the protease-resistant form (PrPsc) of the prion proteinaccording to the source of the PrPsc or the mutation involved. As
indicated in the figure, the two related but subtly different formsof PrPsc convert the normal form to their own conformation. Thus, the
final PrPsc product that accumulates depends on the form that
initiated the process.
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The conversion from the alpha helical to the beta-sheet form may occur
spontaneously, though very rarely (sporadic). The conversion may be
catalyzed by PrPsc
that comes from some exogenous source (acquired).Germ line mutations may make spontaneous conversion more likely
(inherited). Somatic mutations may make spontaneous conversion more
likely (sporadic). In this case, the mutant form could start the processof conversion and the resulting PrPsc molecules would then convert the
normal form from surrounding cells
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TRANSMISSIBLE ENCEPHALOPATHIES AND OTHERDISEASES
Amyloid plaques are seen in other CNS diseases But the major components of amyloid plaques seen
in, e.g., Alzheimer's disease are NOT made of thesame material as those seen in Kuru, CJD, GSS
Amyloid refers to the staining properties, and many
glycosylated protein aggregates can have similarstaining properties
It is possible that the way in which prion diseasesinterfere with the function of cells in the CNS maypinpoint crucial processes in the CNS whose
disturbance leads to progressive degeneration ofnervous tissue
Understanding the nature of the pathogenesis ofprions may help understanding of other CNS diseases