Slow Virus Infections & Prion Diseases

8/8/2019 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

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Slow Virus Infections & Prion Diseases