Prion Diseases L10 (virology) Flashcards
Unconventional infectious agents
What are prions?
= proteinaceous particles that don’t have ? acids and are encoded b the PRNP (pattern receptor nuclear? protein) gene
§ Normal cellular prion proteins (PrPC) are present on ? ? in humans and animals.
-> conversion to ?, abnormal, disease-causing PrPSC by post-translational modification -> cause ? and transmissible ? diseases
(transmissible spongiform encephalopathies = TSEs)
(PRNP = gene in our DNA which encodes for prion protein
prion protein or PrP is a protein on the surface of our cells
A prion is an infectious particle made up of misfolded prion proteins.)
What are prions?
= proteinaceous particles that don’t have nucleic acids and are encoded b the PRNP (pattern receptor nuclear? protein) gene
§ Normal cellular prion proteins (PrPC) are present on cellular surfaces in humans and animals.
-> conversion to misfolded, abnormal, disease-causing PrPSC by post-translational modification -> cause fatal and transmissible neurodegenerative diseases
(transmissible spongiform encephalopathies = TSEs)
use of prion proteins: have a role in kneeling formation and development of T cells, they are critical in the development of some progenitor cells for blood cells.
So they have a role in our body, their positive to start off with prion protein.
So normal cellular prion proteins are okay and have different roles, especially in relation to blood cell progenitors and immune cells.
Now when we have a conversion of that normal cellular protein to an abnormal form where we see beta sheets (and no longer the alpha helix,) that is a PrP”SC” and not PrP C.
C refers to scrapie bc scrapie has been the first prion disease that we’ve ever studied and this conversion to the misfolded form is a post-translational modification.
Once we have SC one in the body, that will cause these fatal degenerative diseases because we have then a protein particle that we can no longer remove.
So the PRNP gene, remember, that’s the gene that encodes the presence of your PRP C (normal) or PRP SC protein (infectious).
What are prions?
§ Misfolded proteins infect both animals and ? without inducing an ? response
§ Extreme resistance to physical and chemical methods of ? (“you can’t kill what isn’t alive”)
§ Misfolded proteins that can transmit their misfolded shape onto ? variants of the same protein!
What are prions?
§ Misfolded proteins infect both animals and ? without inducing an immune response
§ Extreme resistance to physical and chemical methods of inactivation (“you can’t kill what isn’t alive”)
§ Misfolded proteins that can transmit their misfolded shape onto normal variants of the same protein!
- So the misfolded proteins know they can infect both animals and humans and immune response is not induced as they’re very closely related to normal proteins on the cell surface.
- And on top of that, these misfolded proteins and that no longer have the alpha helix structure, but more beta sheets, they’ll have an extreme resistance to physical and chemical methods of inactivation.
- heating food infected with prion will not get rid of prions as they are very resistant.
Prions are a key example of something that’s considered infectious. But there’s only protein. There is no genes in there. You have the gene in our genome that encodes for the protein, but the protein by itself is the one that causes the disease.
3rd step: gradually you have more and more because the misfolded misstep post-translational modification will also occur in neighboring proteins.
So the first reason why this develops is just a spontaneous conversion.
What we have been able to show is that you can also get infected through ingestion or injection of the already misfolded protein. And this is what happens if you, for example, consume animals that are deceased with an transmissible spongiform encephalopathy.
So they hold on their different tissues, that abnormal protein with a beta sheet configuration, and that will be present in higher concentrations in neuronal and lymphoid tissue.
HOW DOES PrP SC cause fatal neurodegenerative disease: The prions that are misfolded, present on the cell surfaces, allow too much fluid to enter in the cell and that leads to spongiform looking like brain (literally holes in cells, rupturing of cells)
Mechanisms involved in the pathogenesis of TSEs
§ Conversion of cell membrane glycoprotein PrPc to an abnormal form PrPSc can be the result of
1. Interaction with ingested or injected PrPSc from an animal with ?
- ? conversion of ? to PrPSc
- Mutation of the ? gene, leading to production of PrPSc - v rare.
Mechanisms involved in the pathogenesis of TSEs
§ Conversion of cell membrane glycoprotein PrPc to an abnormal form PrPSc can be the result of
1. Interaction with ingested or injected PrPSc from an animal with transmissible spongiform encephalopathy
- spontaneous conversion of PrPC to PrPSc
- Mutation of the PRNP gene, leading to the production of PrPSc - v rare.
Transmissible Spongiform Encephalopathies (TSEs)
§ The accumulation of the protease-resistant PrPSc initiates a pathological process -> grey matter vacuolation
§ Group of ? diseases characterized by neuronal ?
§ Often fatal with long ? periods
Transmissible Spongiform Encephalopathies (TSEs)
§ The accumulation of the protease-resistant PrPSc initiates a pathological process -> grey matter vacuolation
§ Group of neurogenerative diseases characterized by neuronal degeneration
§ Often fatal with long incubation periods
They happen very gradually. And this is because of the gradual accumulation of these abnormal proteins.
Diseases of Transmissible Spongiform Encephalopathies (TSEs)
- ?
host: sheep, goat
info: worldwide (except from Australia and New Zealand) - bovine ? encephalopathy (BSE; Mad Cow Disease)
host: cattle
info: prevalence declined due to effective control measures - ? spongiform encephalopathy
host: cat
info: most cases in UK - Chronic ? disease
host: deer, elk
info: colorado
in humans:
Creutzfeldt-Jakob Disease (CJD)
Kuru (cannibalism or through meat)
Fatal familial insomnia
(CJD -> dementia and ataxia, blindness as well, some abnormalities in speech and it gradually develops)
Prion diseases in humans cannot be cured, so they cannot be cured. But there are certain medicines that have been developed to slow down the progression of such infections.
Diseases of Transmissible Spongiform Encephalopathies (TSEs)
- scrapies
host: sheep, goat
info: worldwide (except from Australia and New Zealand) - bovine spongiform encephalopathy (BSE; Mad Cow Disease)
host: cattle
info: prevalence declined due to effective control measures - feline spongiform encephalopathy
host: cat
info: most cases in UK - Chronic wasting disease
host: deer, elk
info: colorado
in pic:
for humans, entry of prions into us through oral consumption of proteins.
SCRAPIE
§ ? infectious ? disease of adult sheep, goats and moufflons
§ Incubation period: 2-7 ?
§ Horizontal and ? transmission
§ Symptoms: ?, fine tremors, itching, ? (loss of full control of body movements), hypersensitivity -> scrape against objects, emaciation, …
§ No ? available
§ Diagnosis: ? microscopic tissue examination
classic scrapie is when u have “brain stem” affected
atypical scrapie: cerebellum affected
Scrapie
§ Resistance occur at ? level in sheep (susceptible: Suffolk and Hampshire breeds)
-> selective breeding
§ ? & USA: notifiable disease
Countries free of disease impose ? ? procedures
§ Enforced ? policies
§ Strict ? policy
§ US: flock certification and movement restrictions
§There is no evidence that scrapie prions can infect people.
SCRAPIE
§ fatal infectious neurological disease of adult sheep, goats and moufflons
§ Incubation period: 2-7 years
§ Horizontal and vertical transmission
§ Symptoms: restlessness, fine tremors, itching, ataxia (loss of full control of body movements), hypersensitivity -> scrape against objects, emaciation, …
§ No diagnosis available
§ Diagnosis: postmortem microscopic tissue examination
(so The clinical signs and the histological examination are the key for determining whether or not you have a scrapie there)
Scrapie
§ Resistance occur at genetic level in sheep (susceptible: Suffolk and Hampshire breeds)
-> selective breeding
§ EU & USA: notifiable disease
Countries free of disease impose strict quarantine procedures
§ Enforced slaughter policies
§ Strict eradication policy
§ US: flock certification and movement restrictions
§There is no evidence that scrapie prions can infect people.
(scrapies spread through nasal secretions, saliva, milk and colostrum, feces, urine, contamination of environment with the placenta, and other gestational tissues or fluids)
PIC:
SCRAPIE: § Data from National Scrapie Eradication Program FY22 (USDA)
- If you’re aware of it. Scrapie, we do have an scrapie eradication program in the States and there’s a clear program here and as you can see, there is not that many cases of scrapie in the last couple of years.
- and the classical form of scraping sleep has been shown here in a couple of animals in these states.
- In that eradication program. We have different goals. It is not only the fact that it is a notifiable disease, there are different educational and preventative programs in place.
- Know there’s tracing the positive ones, tracing the exposed animals as well, the cleanup of the sources where we had scrapie.
- there’s also Scrapie Free Flock program,so that you buy new animals, that you are assured that this from a scrape free flock on.
BSE; Mad Cow Disease
Fatal infectious ? disease of cattle
§ Classical BSE: as a result of ? exposure to prions via contaminated animal-source proteins (meat, bone meal)
§ Atypical BSE: occurs spontaneously in ? animals
§ Incubation period: 2-8 ?
§ ** BSE is not transmitted ? **
§ Symptoms: progressive neurologic signs with ? and hyperesthesia with ? during milking, progressive ? (fearful something bad will happen) behavior and hind limb ?
§ No treatment available, only supportive care
§ Diagnosis: postmortem microscopic tissue examination -> spongiform ?, ? loss, no inflammation
BSE; Mad Cow Disease
Fatal infectious neurological disease of cattle
§ Classical BSE: as a result of foodborne exposure to prions via contaminated animal-source proteins (meat, bone meal)
§ Atypical BSE: occurs spontaneously in aged animals
§ Incubation period: 2-8 years
§ ** BSE is not transmitted horizontally **
§ Symptoms: progressive neurologic signs with ataxia and hyperesthesia with kicking during milking, progressive apprehensive behaviour (fearful something bad will happen) behavior and hind limb ataxia
§ No treatment available, only supportive care
§ Diagnosis: postmortem microscopic tissue examination -> spongiform leisions, neuronal loss, no inflammation
BSE; Mad Cow Disease
§ Prions found in the brain, ? tissues and ? organs <> muscle mostly free
§ Notifiable disease in EU with compulsory testing of fallen animals and cattle over 48 mo of age
§ BSE is transmitted through the ? route to humans
§ Prophylaxis:
§ ? slaughtered animals
§ Positive animals -> entire ? slaughtered and burned
(~ country-specific regulations)
§ No feeding or consumption of ? and ? tissues
BSE; Mad Cow Disease
§ Prions found in the brain, neural tissues and lymphatic organs <> muscle mostly free
§ Notifiable disease in EU with compulsory testing of fallen animals and cattle over 48 mo of age
§ BSE is transmitted through the alimentary route to humans
§ Prophylaxis:
§ testing slaughtered animals
§ Positive animals -> entire herd slaughtered and burned
(~ country-specific regulations)
§ No feeding or consumption of nervous and lymphatic tissues
CHRONIC WASTING DISEASE
§ Fatal, contagious progressive ? disorder of deer, elk, reindeer, sika deer and moose
§ Long incubation time, up to several ?
§ Transmission ?
§ Symptoms: significant ? loss, ?, ?, aspiration ?; affected animals separate from ?
§ ** CWD may be present in cervids that are not ? (abnormally thin or weak)!! **
§ No curative or ? treatment available
§ Reportable ? in most jurisdictions
CHRONIC WASTING DISEASE
§ Fatal, contagious progressive neurodegenerative disorder of deer, elk, reindeer, sika deer and moose
§ Long incubation time, up to several years
§ Transmission horizontally and vertically
§ Symptoms: significant weight loss, ataxia, hypersalivation, aspiration pneumonia; affected animals separate from herd
§ ** CWD may be present in cervids that are not emaciated (abnormally thin or weak)!! **
§ No curative or prophylactic treatment available
§ Reportable disease in most jurisdictions
One of the elements that we don’t know how to explain is why we have these misfolded proteins in these excreta secreted.
