Slow Virus Infection
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Transcript of Slow Virus Infection
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Slow Virus Infection
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• 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.
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Diseases caused by unconventional agents (Prions)
In Animals
• Scrapie • Transmissible Mink Encephalopathy (TME) • Chronic Wasting Disease of Mule deer (CWD) • Bovine Spongiform Encephalopathy (BSE)
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In Humans
• Creutzfeldt -Jacob Disease (CJD)• Gerstmann-Straussler-Scheinker Syndrome
(GSS)• Fatal Familial Insomnia (FFI) • kuru
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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.
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• 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.
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• 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
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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
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PrP physiology
• Other researchers:1. prion-like properties to a mechanism involved
in maintaining memory2. involvement with the immune system3. function in circadian rhythm and sleep regulation
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Abnormal Prions – PrPsc
• 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
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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
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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.
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spongiform degeneration in the cerebral cortex from patient with CJD (H and E)
gliosis of cerebral cortex
PrP deposits in cerebellum from patient with G-S-S disease (immunostain)
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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.
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Different shapes of the prion protein accumulates in different regions of the brain
Thalamus Cortex
FFI
CJD
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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
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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.
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• 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.
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• 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.
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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).
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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
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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)
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Age of Onset in Sporadic and Variant CJD
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Comparison of BSE and vCJD cases per year
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• 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.
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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
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• 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.
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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.