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Transmissible spongiform encephalopathies (What causes TSE disease…
Transmissible spongiform encephalopathies
TSEs in humans
Sporadic CJD: Occurs worldwide at incidence of ~1 per million
Familial disease; familial CJD, Gerstmann-Straussler-Scheinker syndrome (1 in 10 million), fatal familial insomnia, "Atypical" prion disease
Acquired disease: Kuru, Iatrogenic, Variant CJD
TSEs in animals
Chronic wasting disease
Bovine spongiform encephalopathy
Transmissable mink encephalopathy
Feline spongiform encephalopathy
Scrapie (sheep and goats)
Other spongiform encephalopathies
Characteristics of TSE diseases:
Progressive and invariably fatal
Holes in brain give spongiform texture
Long incubation period
No signs of fever, inflammation, antibody response, signs of a pathogen with a genome.
NO SIGN OF INFECTION
What causes TSE disease
Partial purification of brain tissue of scrapie-infected hamsters revealed a certain
protein
was essential for infectivity
Procedures that destroy nucleic acid (heat, radiation, enzymes) do not alter infectivity
If treated with proteases infectivity was altered
Prions - Proteinaceous infectious particles
Prion protein is a
host protein
encoded by PrP (protease-resistant protein) gene. Occurs in at least 2 forms. PrP^C is normal, PrP^Sc (Sc stands for scapie) is infectious and associated with disease
PrP (C) and PrP (Sc) have identical amino acid sequence, different tertiary structure
PrP(Sc) converted to PrP(C) (suggested)
PrP(Sc) partially resistant to digestion, in a normal cell PrP(C) is constantly made and digested. Hence (Sc) accumulates leading to disease
**Reaction catalyses itself (each one created another, both can then convert more, which converts more etc, cascade/exponential)
Uniqueness
Some prion diseases originate sporadically but can then be transmissable. Normally disease one or the other
Pathogenesis
Oral route infection of sheep
Entry to body through ileal Peyer's patch (lymphoid nodules). Dissemination through lymphatic/vascular system to tissues of lymphoreticular system (LRS), including tonsil, spleen, retropharyngeal and mesenteric lymph nodes
Presence of (Sc) is detectable in the LRS just weeks/months after infection
Infection spreads from LRS through autonomic nervous system to CNS
(Sc) accumulates primarily in glial cells (astrocytes) and neurons. Within the brain there is astrocytic gliosis
Diagnostics
Cannot use PCR as no nucleic acid or host immune response
Can use:
Clinical disease
Histopathological detection of vacuolation, gliosis etc
Bioassay (especially in mice or hamsters)
Molecular detection (Western blot or immunohisto-chemistry of PrP(Sc) after treatment with proteinase K (as (C) will be degraded so only (Sc) will remain)
Cyclic amplification of (Sc) from (C)
TSE strains
Why would be strains? Is your own protein?
But different strains exist, humans + cows + sheep can have different forms
Strains can have different incubation periods, severity and distribution of brain pathology
The same strain can be isolated from different hosts - Different host species have different PrP sequences so strain cannot be determined by the PrP amino acid sequence
The same host can be infected with different strains
Glycoforms
At least 8 prion strains have different 3D PrP(Sc) conformations, suggesting the biological properties of prions are enciphered in conformation
Different strains also have unique combinations of glycoforms that are maintained upon transmission to mice
TSE species barrier
Transmission of TSE agents limited by a "species-barrier", characterized by extended incubation times which notably decrease as the TSE agent is passed through individuals of the recipient species
A large species barrier means a large infectious dose is needed for inoculum
The cattle-human species barrier for BSE has saved many lives
Scrapie
Disease of sheep and goats, characterized by ataxia, tremors rubbing/scratching, loss of condition & death in 1-3 months
Endemic in UK
Incubation period of usually 2-5 years
Transmission by several routes, progression to disease is under strong genetic control
Occurs as different "strains"
Bovine spongiform encephalopathy
Disease of cattle, characterized by ataxia, nervous or aggressive behaviour, loss of condition & death in 1-6 months
Can be spread to many other animals: humans, sheep, goats, cats
Epidemic in UK from ~1985
Incubation period of 5 years or more
Transmission by oral route (MBM)
Little evidence of host genetic effect
Occurs as 2 different strains
Chronic wasting disease
First identified in captive deer in 1967 but then spread from captive deer to wild deer
Free-ranging mule deer, white tailed deer, rocky mountain elk
Originally centred on Wyoming/Colorado, but has spread widely in North America
Incubation period ~16 months
Only TSE of wild populations
Only naturally-spreading TSE
Limited genetic control of susceptibility
Zoonotic potential unknown
Creutzfeldt-Jakob disease
20/3/96 UK government announced that a variant of CJD has been detected in 10 people over previous 14 months
Clinical signs:
Psychiatric: Depression, anxiety, delusions, hallucinations
Neurological: Ataxia, chorea (dance-like motion of twisting & turning), myoclonus (involuntary muscle spasm), dementia
Pathology: Spongiform change and PrP-containing "florid plaques" throughout the brain. In human prion disease, plaques of this type are unique to vCJD
Mean duration of illness: 14 months
Young age of onset; Mean = 28 years [range 12-74]
Prevalence of infection ~1 in 3000 [spleens]
Genetic control: All non-surgical human cases so far MM, not MV or VV (while all Kuru cases were MM or MV)
Kuru
The Foré ate their dead. Women and children ate the internal organs and brains; men ate muscle. Cannibalism stopped in ~1957, encouraged by the governing Australian administration
The incidence of the disease declined from the 1960s, especially cases in young children