Download Slow Virus Infection

Slow Virus Infection
• Diseases have a prolonged incubation period
and a protracted progressive clinical course.
• Slow virus diseases may be caused by
conventional viruses or unconventional
(atypical) agents.
• Diseases caused by conventional viruses
include; PML, SSPE, PRP, and AIDS dementia
complex.
Diseases caused by unconventional agents
(Prions)
In Animals
•
•
•
•
Scrapie
Transmissible Mink Encephalopathy (TME)
Chronic Wasting Disease of Mule deer (CWD)
Bovine Spongiform Encephalopathy (BSE)
In Humans
• Creutzfeldt -Jacob Disease (CJD)
• Gerstmann-Straussler-Scheinker Syndrome
(GSS)
• Fatal Familial Insomnia (FFI)
• kuru
Characteristics of prion disease
• They are confined to the CNS.
• They have a prolonged incubation period.
• They show a slow progressive fatal course.
• They show a spongiform encephalopathy.
• They result in vacuolation of neurons.
• Subacute Spongiform Encephalopathies are also
recognized as the transmissible cerebral amyloidoses
(TCA)
• their infectivity is associated with the modification of
the same host precursor protein into insoluble amyloid
fibrils.
• Prions are unconventional filterable agents with
unusual physical, chemical and biological properties.
• Lack detectable nucleic acids and consist of
aggregates of a protease-resistant, hydrophobic
glycoprotein with a molecular weight of 27-30 kd.
• It is given the abbreviation (PrPsc) to indicate
association with scrapie.
• Humans and animals encode a protein PrPc
(cellular prion protein).
• The gene for PrPc is present on the short arm
of chromosome 20.
• Normal PrPc differs form PrPsc in behavior
PrP Physiology?
• Function is still unknown - may be involved in
cell-to-cell communication?
• Researchers have found that PrPc on the
surface of nerve cells, can interact with other
molecules to relay signals arriving from outside
the cell ``signal transduction.''
• Some researchers speculate that prions are not
needed for “routine” functions but somehow
enable the nervous system to “fine-tune” itself
at the cellular level
PrP physiology
• Other researchers:
1. prion-like properties to a mechanism involved
in maintaining memory
2. involvement with the immune system
3. function in circadian rhythm and sleep regulation
Abnormal Prions –
sc
PrP
• Proteinacous Infectious Particle
• smaller than the smallest known virus
• self-replicating = prions multiply by converting normal
protein molecules into abnormal ones simply by
changing their shape into that of the infectious protein
molecules = abnormal PrP is “folded”
• no genetic material/nucleic acids present as in the
case of normal prions
• Resist normal degradation techniques e.g.
formaldehyde, ethylene oxide, temperature, UV light,
proteases & nucleases
• Stimulates no immune response in the host
Replicative Cycle of a Prion
• occurs when a normal PrPc protein is converted
to PrPsc protein in the endosomal compartment
of the cell, and is no longer recycled back to the
surface of the cell
• when the PrPsc protein begins to accumulate in
the endosomal compartments, amyloid deposits
form and cause the cell (neuron) to loose
viability, resulting in death
• Vacuolar change in grey matter = spongiform
Pathogenesis
• Vacuolation of neurons and formation of
amyloid- containing plaques and fibrils.
• Proliferation and hypertrophy of astrocytes and
fusion of neurons and adjacent glial cells.
• Prions reach high concentrations in the brain
and can be isolated from tissues other than the
brain but only the brain shows any pathology.
• No inflammation or immune response is
generated to the agent.
gliosis of cerebral cortex
spongiform degeneration in
the cerebral cortex from
patient with CJD (H and E)
PrP deposits in cerebellum
from patient with G-S-S
disease (immunostain)
Localization of Different Prion Diseases
In fatal familial insomnia
(FFI), mutated prions
accumulate in the thalamus,
with the result that the
patients are unable to sleep.
In Creutzfeldt-Jakob
disease, the prion protein
accumulates primarily in
the cerebral cortex.
In kuru and GSS, PrPSc
accumulates in cerebellum.
In BSE, PrPSc
accumulates in brain stem.
Thalamus
FFI
Different shapes of
the prion protein
accumulates in
different regions
of the brain
Cortex
C
J
D
Clinical Syndromes
• The incubation period for CJD and Kuru may be as
long as 30 years. Once symptoms become evident the
patient dies within a year.
• TCAs are a group of rare, usually sporadic, rapidly
fatal, presenile dementias found worldwide.
• They were first defined as Creutzfeldt-Jakob disease
named after the German neurologists, who each
described a few cases.
• Although Sporadic, about 5 to 10% of the cases occur
in a familial pattern of autosomal dominant inheritance
CJD
- Its incidence is 1-3/million /annum and it commonly
affects those between 50 and 70 years of age.
- It is characterized by a rapidly progressive dementia.
Other features are variable with a wide spectrum of
signs and symptoms.
- Disturbances in behavior and in higher cortical
functions eventually appear in most patients.
- Onset is usually insidious over weeks to months but
may be sudden with an episode of confusion, vertigo,
diplopia or blurred vision, or even as a sense of
clumsiness, cranial pressure or true headache.
• More often, onset is subacute with agitated or
depressed behavioral change. More rarely with
aggressive, but never violent, behavior.
• Commonly, there is an inability to find words,
perform simple arithmetic or write correctly.
• Two thirds of cases have ataxic gate at onset,
vertigo and nystagmus.
• Less commonly, there is trunk and limb ataxia,
tremors or dysarthria.
• Progression to global dementia leading to mutism,
cerebellar incoordination, myoclonus, and marked
progressive motor dysfunction follow.
• Epidemiologically, sporadic in 90-95% of cases and
familial in 5-10%.
• May be transmitted by corneal transplants, dura
matter transplants, infected neurological electrodes,
pituitary growth hormone administration and ingestion
of diseased nervous tissue.
• Jews of Libyan origin have a high incidence of CJD
which was linked to consumption of sheep eye balls.
New Variant CJD disease (vCJD)
• Reported in the UK in patients who are younger
(frequently under 40) than is the case for most CJD
patients. It also tends to present with psychiatric problems
• vCJD has a distinctive neuropathological appearance and
more PrPSC deposits than typical CJD.
• There has been considerable concern that this might be
associated with exposure to BSE-contaminated beef.
• Some believe it is more common than what was believed
(1/10.000 or more at death).
vCJD Surveillance
• Current data (January 2011)
- Cumulative number in the world is 222 cases
– 174 from the U.K (3 are secondary due to BT)
– 25 from France
– 5 from Spain, 4 from the Republic of Ireland, 3
from USA* and the Netherland, 2 from Italy, 2
from Portugal, 1 from Canada, 1 from KSA, 1
from Japan, and 1 from Taiwan.
– Only 7 are alive
variant CJD (vCJD)
sporadic CJD
variant CJD
age
55-70
19-39
presenting
features
dementia,
myoclonus
Behavioral, ataxia,
dysesthesia
course
rapidly progressive prolonged
PrP genotype codon 129
predominantly
val/val
100% met/met
PrP deposits
synaptic, rarely
plaques
florid plaques
PrP banding pattern
Type 1, Type 2
Type 4 (BSE like)
Age of Onset in Sporadic and Variant CJD
Comparison of BSE and vCJD cases per year
• Fatal Familial insomnia (FFI)
• FFI is a disease of man that results in
progressive untreatable insomnia, loss of
circadian rhythm, endocrine disorders, motor
disorders, and dementia.
• It seems that the hypothalamus function is the
target.
Kuru
• Characterized by cerebellar ataxia and a shivering-like
tremor.
• Progresses to complete motor incapacity with
dysarthria and total loss of speech and then to death
in less than 1 year from onset.
• The disease has three phases, ambulant, sedentary,
and terminal.
• Emotional liability leading to outbursts of pathologic
laughter is frequent; sometimes appearing in the first
stage of the disease
• Smiling and laughter are terminated slowly (laughing
death, a journalistic synonym). Nearly true euphoria
may be observed.
• Some, rarely develop pathologic belligerence to all
disturbances by family members.
• Terminally, patients develop incontinence, dysphagia
with thirst and starvation, flaccidity, inanition, mutism
and unresponsiveness.
Epidemiology
• Carlton Gajdusek solved the epidemiology of the
disease and demonstrated its infectious nature (1960).
He demonstrated its link with cannibalism.
• It was endemic among a Melanesian tribal people
called the Fore’ who inhabit a remote area in the
eastern highland province of Papua new Guinea.
(Kruu means shivering or trembling).
• Most common among females and children. Men
played a minor or no role in cannibalism. Women were
given viscera and brains.