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 memory2. involvement with the immune system3. function in circadian rhythm and sleep regulation

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

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.

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)

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.

Different shapes of the prion protein accumulates in different regions of the brain

Thalamus Cortex

FFI

CJD

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.