Prions and Spongiform Encephalopathies

• Prions are proteinaceous infectious particles or prion proteins (PrP).
• Contain little to no nucleic acid.
• The term "prion" was coined by Prusiner in 1982.
• Prion protein is encoded by a cellular gene and naturally occurs.

Abnormal Protein (PrPSc) Characteristics

• Insoluble in all but the strongest solvents.
• Highly resistant to digestion by proteases.
• Survives in tissues post-mortem.
• Extremely resistant to heat, normal sterilization processes, sunlight, and most disinfectants.
• Has no detectable immune response.

Prion Associated Diseases - Spongiform Encephalopathies

• Disease is confined in the CNS.
• Characterized by the absence of inflammatory lesions.
• Has a long incubation period, ranging from 2 months to over 20 years before any clinical signs.
• The clinical course is progressive, frequently prolonged(weeks to years), and leads to death.
• Reactive astrocytosis and vacuolation of neurons are the changes in the brain.
• Manifestations of CNS degeneration include slow infection, sporadic disease, and genetic disorder.

Prion-Associated Diseases and Natural Hosts

• Scrapie affects sheep and goats.
• Transmissible mink encephalopathy affects mink.
• Chronic wasting disease affects mule deer and elk.
• Bovine spongiform encephalopathy (BSE) affects cattle.
• Feline spongiform encephalopathy affects domestic cats.
• Kuru, Creutzfeldt-Jakob Disease (classic and variant), and Gertsmann-Straussler syndrome affect humans.

Scrapie

• It is known as lumbar prurigo, enzootic ovine paraplegia, and is the first spongiform encephalopathy recognized.
• Sheep have a genetic susceptibility to it.
• Reproduces slowly in lymphoreticular tissue before invading the central nervous system.
• Agent is detectable in the intestinal tract first, indicating oral infection.
• Transmission occurs naturally during lambing or through contaminated pastures.
• No known human cases contracted from sheep and goats
• Disease in sheep, but may affect goats sharing the same pasture.
• Incubation period is 1-4 years.
• Affected individuals are more excitable and show a slight tremor in the head and neck (maladie tremblante).
• First symptom is prurigo, lumbar prurigo; intense itching leads to rubbing and gnawing.
• Loss of wool extends to other body areas.
• End-stage is emaciation with impaired motor control.
• Can last from weeks to months, ending in death.
• No macroscopic lesions except skin abrasions.
• Histopathology shows neuron degeneration, vacuolization, and spongiform encephalopathy.
• Astrocyte hypertrophy and accumulation of amyloid plaques.
• Lesions are most pronounced in the cerebellar cortex, medulla oblongata, pons cerebelli, mesencephalon, diencephalon, and corpus striatum.
• Disinfection requires soaking instruments in 2.5N NaOH or another disinfectant.
• Control involves prohibiting animal importation from countries with scrapie, sacrificing animals in affected farms, and prohibiting ruminant-to-ruminant protein feeding.

Bovine Spongiform Encephalopathy (BSE)

• Synonym: Mad Cow Disease. Diagnosed in England in 1986.
• Cases stemmed from a common source as early as April 1985 in the UK.
• The UK made reporting BSE cases compulsory starting June 1988.
• 95% of cases were identified in the United Kingdom.
• Four cases have been confirmed in the United States.
• First case: December 2003; the cow was originally from Canada.
• Second case: June 2005, a native-born cow.
• Third case: March 2006.
• Fourth case: April 2012.
• Finland, Greece, Israel, and Sweden have reported single cases.
• Source of infection is scrapie.
• Via meat and bone meal supplements from viscera of infected sheep; beef brain in cattle feed supplements.
• Offal tissues of particular risk (SRM) include brain, spinal cord, eyes, spleen, distal ileum, tonsils, and certain nervous tissues.
• Does not spread horizontally between cattle or other TSE-affected species.
• Neurological symptoms: changes in mental state, behavior, apprehension, excitability, nervousness, fixed gaze, and humpback.
• Postural abnormalities, locomotor dysfunction, ataxia, tremors, and falling (93% of cases).
• Also causes hyperesthesia to touch and sound.
• There is no prurigo.
• Decreased milk production, loss of body condition and weight despite normal appetite, recumbency, and death.
• Course ranges from less than two weeks to a full year, typically one to two months.
• Incubation period is two-and-a-half to eight years or more.
• Most cattle affected are between 3 and 6 years old; no breed or sex predisposition.
• Primarily affects dairy cattle.
• Diagnosis is based on signs and histopathology.
• Laboratory confirmation is based on histopathology of the brain, medulla, spinal cord, and brain stem.
• The obex is tested for prions.
• Important lesion is neuroparenchymatous vacuolization in the brain.
• Post-mortem diagnosis involves histopathology of brain tissue, spongiform changes in gray matter, and abnormal prion protein detection.
• Prevention involves scrapie-free countries not importing sheep/ruminant-derived protein feed and avoiding imports.
• No known cases of cattle-to-cattle transmission.

Transmissible Mink Encephalopathy

• A rare disease in mink-raising facilities that feed animals sheep organs/tissues.
• Onset is insidious, like scrapie.
• Initial behavioral changes are excitability, hyperesthesia, and aggression.
• Rear legs become unsteady after a few days/weeks.
• Causes unsteadiness in all legs.
• End-stage: compulsive self-mutilation.

Human Diseases

• Kuru.
• Creutzfeldt-Jacob Disease (CJD).
• Gerstmann-Straussler Scheinker Syndrome (GSS).

KURU

• The disease is geographically limited to Papua New Guinea.
• From 1957 to 1975, more than 2500 deaths occurred.
• Incidence is attributed to traditional rituals of honoring dead relatives by consuming their bodies.
• Characterized by cerebellar ataxia and tremors, progressing to complete motor incapacity and death within a year.
• Speech difficulty is very common and progressive.
• Has no fever or convulsions
• Incubation period: a minimum of 4 to a maximum of 30 years.
• Infected by consuming tissue from the corpse (especially CNS tissues) during mourning rituals.
• Higher incidence in women and children.
• Portal of entry probably:
  • Skin
  • Conjunctiva
  • Oral mucosa

CREUTZFELDT JACOB DISEASE (CJD)

• Synonym: Subacute spongiform encephalopathy.
• It is a rare disease of worldwide distribution (always fatal)
• More than 200 cases per year in the US.
• Usually occurs in persons between 50 and 75 years of age.
• IP is unknown in most cases.
• Has insidious onset without fever
• Signs: -Rapidly progressing dementia. -Myoclonic spasms appear early. -Extrapyramidal signs, cerebellar ataxia, visual problems, and behavioral disturbances.
• EEG appears abnormal.
• Duration is usually two to five months, but can last up to two years can be invariably fatal.
• Classic CJD occurs worldwide at a rate of about 1 to 2 cases/1 million people: - 5-15% is hereditary; 85% sporadic - Others are iatrogenic
• Transmission mode is not known.
• Iatrogenic transmission is possible.

Variant CJD

• A potential zoonosis, acquired from bovines infected with BSE.
• Reported in 1996.
• V-CJD primarily affects young adults (median age at death is 28 years).
• Prolonged course of disease of up to 2 years.
• EEG changes are absent.
• By ingestion of brain, beef from cattle with BSE.
• Tissues considered to be of greater risk (e.g., skull, brain, trigeminal ganglia, eyes, vertebral column, spinal cord and dorsal root ganglia of cattle over 30 months old).
• Post-mortem diagnosis is definitive: -Amyloid plaques surrounded by vacuoles. -Prion protein accumulation in cerebellum. -Spongiform appearance in gray matter.
• Public Health Significance: -From 1996-2009, 217 cases of vCJD worldwide. -11 countries, with 170 cases from the U.K. -No cases of indigenous vCJD in the U.S.
• There is unknown an incubation period and consumption rate.
• Prevention: -All downer cattle banned from human food. -Suspect cattle carcass held until BSE test results received. -Specified Risk Material (SRM) is prohibited from the human food chain: -Cattle >30 months of age: neurological tissues. -All cattle: distal ileum and tonsils.

Gerstmann-StrausslerScheinker- Syndrome (GSS)

• Causes either dementia or slowly evolving cerebellar ataxia.
• Age 35-55 years' old
• Lasts 3-5 years.
• Spongiform alterations, and astrocytosis.
• Very low incidence.