DO NOT STUDY Transmissible Spongiform Encephalopathies, Clinical Flashcards
NOT ON EXAM
Features Transmissible spongiform encephalopathies
non febrile, slowly degenerative, transmissible, fatal diseases affects CNS; associated with aberrant prior protein expression, spongiform brain lesions, no immune response to infective agent; associated with aberrant prion protein expression, not viral
Histology of transmissible spongiform encephalopathies
clear vacuoles in neuron
Etiology TSE
prion protein gene encoded by host and its expression is not indicative of a specific disease; aberrant conformation denotes dx; protein synthesized in ER eventually inserted into PM
physiological function TSE
- cytoprotective (protect from oxidative stress)
- binds copper
- signaling molecule
infectious prion
aberrantly folded PrP = PrPsc is infectious prion resembles normal so can still insert into PM leads to aggregation and eventually neurodegenteratoin
normal prion formation
produced in ER -> Golgi -> PM
TSE classification requirements
- Prolonged incubation period
- slowly degenerative CNS signs
- Spongiform brain lesions
- transmissible to mice
- Presence of abnormal prion protein (PrPsc)
Human TSEs
- Kuru (specific nerve degeneration, found in papa New Guinea)
- creuzfeldtz-jacob disease (sporadic, familial, iatrogenic subtypes)
- New variant creuzfeldtz-jacob disease (human form BSE)
- Gerstmann-Straussler-Scheinker syndrome
- Fatal familial insomnia
- Multisystem atrophy
PrPc
host encoded, cellular membrane associated protein (this is normal one)
PrPsc
conformationally altered form of protein
PrPres
diagnostic technique with western blotting to detect PrPsc
Res= protease and hydrolysis resistant core of protein
PrPd
diagnostic approaches that don’t involve protein digestion such as immunohistochemistry (D= diseased prion protein)
Identifying pathogenic phenotype
western blot (reveal characteristics patterns of PrPres w/ variable molecular mass) or immunohistochemistry (detection PrPd in formalin fixed tissue)
Animal TSEs
- Scrapies (sheep and goat)
- Transmissible milk enceophalopathy
- Chronic wasting disease (Cervids)
- Bovine spongiform encephalopathy (BSE) (cows usually or cats, primates, captive non domestic ruminants, one goat)
TSE diagnostic tests
Histopathology Presence of PrPsc: -western blot - immunohistochemistry - ELISA
BSE
bovine spongiform encephalopathy -"Mad Cow Disease" don't call it that -Host species: cattle, exotic ruminants, felines, humans, primates -Animals get thin, splay legged NOT transmitted in milk
BSE clinical signs
- long incubation period 4-7yrs
- behavioral changes
- motor incoordination
- difficulty rising
- weight loss with appetite
- down or dead
- may be carrying it but not showing signs -> it entering food chain
BSE susceptibility
low contraction rate but if you have it it is fatal; carriers have LONG incubation period; breed and genetic suseptablity not established yet but possible role
BSE transmission
non-contagious but infectious
- oral transmission from ingestion of BSE-contaminated protein supplements; takes v little BSE brain material to contaminate
- BSE instances decreased once ruminant to ruminant feeding stopped
BSE UK Epidemic
recognized in 1986 ruminant to ruminant feed ban in 1988 takes a while to drop off bc long incubation, see more in active surveillance bc testing brains of everything but now see decline there too.. no new cases in last few years
Where did a lot of BSE infected protein come from
UK
Atypical BSE
These aren’t the ones from UK infected stuff, they are L type and H type; test for these with western blot; A typical has almost no spongiform changes while classical does in pons, obex, and midbrain
Products free of PrPsc
Milk, muscle tissue, and blood
Specified risk materials
BSE uptake in distal ileum by peyers patches; migrates to CNS where you get localization in the brain see in retinal neurons, retinal ganglia, and trigeminal ganglia; can affect spinal cord and DRG all these things are specialized risk materials which you keep out of the food chain
Response to BSE
downer cows not allowed for human consumption; hold rendered carcas until BSE testing done; ban high risk material from animal feed; prohibit materials from animals >30 months entering food chain; ban air injection stunning; ban high risk material in animal feed;
surveilance
-USDA implemented enhanced surveillance, test cattle of any age with CNS signs, BSE related clinical signs, or cow that died of unknown causes
CJD resistant mice
from mutation from Force people in papa New Guinea, display resistance to CJD bc express novel human prion protein
Scrapie
Sheep and goats; world wide except Australia and New Zeland; no known human health risk; first diagnosed in 1940s but was around wayyy before then; genetic / breed component
scrapie clincal signs
subtile behavioral and temperamental changes, scratching and rubbing against fixed objects may lead to excoriation, loss of coordination, weight loss despite good appetite, biting of limbs, lip smacking, blindness, death (1-6 month clinical duration; death rapid after development of severe weakness)
Scrapie transmission
Maternal through birth fluids, directly through blood, environmental transmission plays lesser role, 2-5 year incubation
Scrapie breed susceptibility
black face sheep more susceptible (no cases in 2018 thus far)
scrapie genetic susceptiblity
sheep prion protein 256 AA; diversity of genotype influences susceptibility to scrapie transmission; if you change certain AAs at certain positions can become more or less susceptable
sheep and goat BSE susceptability
can give it to them if inoculate cortex BUT this doesn’t reflect nature so it is not likely to be transmitted; once case in France of goat picking this up naturally so contingency plans in place
scrapie erradication
may be eradicated in our lifetime bc of scrapie eradication program; USDA monitoring closely surveillance and culling; encouraging submission goats and sheep over 18 months to diagnostic lab for necropsy and sample collection
scrapie testing
western blot with scrapie specific MoAb reacts with true scrapie; in live sheep get lymphoid tissue from third eye lid or rectum; in dead sheep test opex (cd pt brain stem) and lymph node (usually retorpharyngeal) (test lymph bc lymph carries prion throughout body); confirmatory tests IHC, Western-blot, ELISA
why test opex
highest number of nuclei so more likely to find something
Chronic wasting dx
v common in mountain west of US; deer, elk, reindeer and moose affected by this (cervids); known since 1967 as TSE in 1978; age 17 months to >15yrs (avg 3-5 yrs); no strict seasonality; clinical duration days - 1yr but usually months; incubation period min 17 months max unknown
Chronic wasting dx clinical signs
Ataxia and wide stance, subtle head tremors, periods of somnolence (head and ears down), ravenous appetite with weight loss, terminal polydipsia and polyuria, excessive salivation, found near water, may die of aspiration pneumonia
Chronic wasting dx histology
lesions focused in int grey, bilateral sym, spongiform change; neuronal vacuolization with astrocyte hyperplasia is common;
chronic wasting dx testing
detection PrPsc via IHC best way to visualize protein; nuclei of vagus usually most affected, protein can be found in CNS, PNS, lymphoid tissue; variety of ELISA and immunoblot tests
chronic wasting dx location
common in US in central rockies, some in N Canada, also in Norway and S Korea (S Korea bc Canadian imports), about 20 cases so far in Scandinavia they’re V panicked bc could effect tourist industry bc reindeer (found in Finland); unknown how it got there, may represent less transmissible atypical form
Chronic wasting dx transmission
more like scrapie than BSE; environmental contamination (spread in urine, feces, and saliva) agents persist in soil and other environmental areas, high prevalence in heavily contaminated areas (carcas decomposes near water easy spread and spreads to soil); agent spreads efficiently with in a herd, role of maternal transmission but appears to be of lesser importance
CWD origin
origin is unknown maybe derivative from scrapie that affects cervids but it is currently unknown
CWD transmission to rumminants
can be transmitted to cattle cerebrally but is atypicall of BSE but not all get it this way and no transmission from oral route or direct exposure;
CWD genetic susceptiblity
AAs at certain positions in endogenous prion protein strongly associated with susceptibility to infection
CWD public health significance
no evidence human transmission, most cases related to other human TSE conditions; appears there is considerable species barrier for TSE transmission to humans appears to be V specific to cervid populatoin
CWD vaccine
CSU working on this; potential for vaccine response indicated thus far
