Transmissible spongiform encephalopathies

Transmissible spongiform encephalopathies

• Animals

• Bovine spongiform encephalopathy (BSE)
• Scrapie in sheep and goats
• Transmissible mink encephalopathy
• Chronic wasting disease of deer, elk

• Humans

• Kuru
• Creutzfeldt-Jacob disease (CJD)
• Fatal familial insomnia (FFI)
• Gerstmann-Straussler syndrome (GSS)

• TSEs are always fatal

Types of TSEs

• Infectious

• e.g., kuru, BSE (mad cow disease), scrapie
• Spread by
• consumption of infected material
• Iatrogenic spread (organ transplant, esp. cornea)
• transfusion

• Sporadic

• 1-2 million infected worldwide, late in life
• Evidence mounting that some sporadic TSE is really result of infection

• Familial

• Due to autosomal dominant mutation of PrP
• Inherited – at least 10-15% of total human TSE cases

• Each of these can be transmitted experimentally

Kuru

• Identified by epidemiology in New Guinea base on anthropological research by Robert and Louise Glasse in 1950’s

• 1% of the Fore tribe was afflicted; mostly women, some children, few adult males

• Symptoms: headache, joint pain, then 6-12 weeks later, difficulty walking, then death usually within 12 months, always within 2 years

• Disease was of recent origin: ~1910-1920

• Epidemiological evidence led the Glasses to suggest that endocannibalism was associated with disease

• This hypothesis was not well accepted among medical community

Kuru

• Australian government suppressed cannibalism among North Fore in early 1950’s

• South Fore were convinced to discontinue the practice in 1959

• Incidence of kuru among North Fore ceased ~ 5 years before South Fore; no child born since then has died of kuru

• Carlton Gadjusek, a medical research scientist with NIH, inoculated chimps with brain extracts of kuru victims; all chimps died after 50 months

• No unique antibodies were associated with disease, no virus particles or aberrant nucleic acids were identified

• Gadjusek got Nobel Prize; Glasses didn’t

Scrapie

• An animal model was needed to study TSEs

• Scrapie disease of sheep had many similarities to kuru in terms of symptomatology and etiology

• Could be transmitted to hamsters and mice, kuru could not

• Scrapie was used as first good animal model TSE

• 2 month incubation in rodents

• Infectious agent purified 5000 fold

• Nuclease resistant
• UV and heat resistant
• Sensitive to protease (only at high levels) & protein denaturants

Bovine spongiform encephalopathy (BSE) “mad cow disease”

Evidence that BSE gave rise to vCJD in humans

Cost of Mad Cow Disease

• 3 BSE-infected cows identified in Canada in May, 2003

• BSE identified in a cow, originally from Canada, in Washington state in Dec., 2003; another in Texas in 2005

• Embargoes against U.S. and Canadian beef brought immediately by most importers

• Loss to U.S. and Canadian beef industries so far due to embargoes: approximately $10 billion

• Canada and U.S. test only a small proportion (<1%) of cattle; Europe and Japan test 100%

• Practice of feeding cow remains, including blood meal, to cattle still done in U.S. and Canada

Different prions affect different parts of the brain

Species barrier

• Infectous dose between species is usually higher than between animals of the same species (possibly a million fold), but it is sometimes the same (e.g. between scrapie doses for mink)

• When a species has been infected with a TSE of a different species it can then go on to infect a range of animals that the original species could not, and with a different dose.

• When a species has been infected, it can infect additional animals of the same species with much lower doses of agent.

• The histopathology of the disease in an animal infected from another species is not the same as if it had been infected from one of the same species.

• The incubation period of an animal infected from another species is much longer than that of an animal from one of the same species.

Sequence of prion protein

Prions of yeast and fungi

• Yeast and filamentous fungi make great experimental tools because they are eukaryotes that normally grow as haploids with small genome sizes and powerful genetics

• Prions in yeast first identified by Wickner as non-Mendelian elements associated with nitrogen metabolism [URE3], then as a component of a suppressor tRNA activity [PSI].

• The first prion in filamentous fungi was identified in association with heterokaryon (vegetative) incompatibility in the ascomycete Podospora anserina

• This is the only prion identified to date that is not associated with a diseased state