Zoonotic pathogens of domestic and farm animals Flashcards
Give the 3 main veterinary transmissible spongiform encephalopathies? Give a little background for each.
- Scrapie in sheep and goats: neurological condition that affectsmotor control, usually in sheep at around 2-5 years
- Chronic wasting disease (CWD): affects the cervid (deer) family. Infected animals exhibit loss of co-ordination and abnormal behaviour. Estimated incubation period for chronic wasting disease is 2-4 years
3.Bovine spongiform encephalophathy (BSE): Neurological symptoms affect cows around the age 4-5 years. Altered behaviour and motor dysfunction.
What is Human TSEs?
Sporadic CJD
Average agee of onset: 65 yrs, 8/9 illness duration
Hereditary forms- example- fatal familial insomnia
Iatrogenic: relating to illness caused by medical examination or treatment.
Infectious- Kuru
What is vCJD?
Varient CJD average age onset 28 yrs
Infectious- vCJD similar to BSE
Zoonosis- Assumed to be due to eating BSE infected beef (one health
Where was Prions discovered?
Kuru-Endemic to south Fore Tribe (8000 people)
Isolated population
What are the symtoms of Kuru?
Behavioural changes including increased excitability, nervousness, aggression, altered sleep patterns, depression, and schizophrenia
Eventually become mute, immobile, and die
How do they discover that the causative agent is an infectious protein?
Proteases used as treatment on infected brain tissue, Reduced infectivity suggesting prions are the infectious agent
What is the ‘Prion’ or ‘protein only’ theory?
PrPc: Normal protein- Highly expressed on neurones, high % alpha helix, Produced continuously, Half life 24 hrs
PrPSc is the prion, Diseased associated isoform PrPSc
Different shape (Beta pleated sheet)
Only difference is in the seconday/tertiary structure.
The disease associated isoform is said to be misfolded.
Describe Prion replication?
PrPSc acts as a template that converts PrPc to PrPSc
PrPSc is said to be self replicating
PrPSc self aggrefates and forms plaques/fibrils
PrPSc is relatively protease resistant and consequently difficult to degrade
Aggregates of PrPSc are neurotoxic
Conc of PrPSc in the brain increases over time and eventually causes neurotoxicity(long incubation period)
What happens in PrP gene knock out?
PrP KO mice are normal
PrP KO mice do not get prion disease when infected with infected brain tissue
The initial does of PrPSc is not toxic but the conc of PrPSc increases over time to a point where it damages neurons
Describe the Biology of PrPc
Molecular weight-254 AA, variable Mwt due to differntial N-linked Glycosylation.
Attached to membrane via GPI Anchor
Highly expressed in neurones
Concentrated at the synapses
Recycle to and from the cell surface
Constantly being produced/degraded
Amounts of PrPc remain similar throughout infection
KO mice- no obvious neurological defects
What happens when you have PrPSc?
It accumulates at synapses
Activates cell signalling pathways in synapses
Damages synapses in vitro
Kills cultered neurones
Concentration of PrPSc in an animal increases exponentially
What is Neuroinflammation of Prion diseases?
Astrocytosis- proliferation and hypertrophy of astrocyyes and microglia (brain macrophages)
No infiltration of polymorphs
Rare to see brain swelling- BBB
PrPSc activates astroglial/microglial cells they produce cytokines
Cytokines can affect neurotransmission
PrPSc in vitro can cause all of the pathological changes seenduring infection
What is the Amyloid hypothesis in relation to alzheimers?
Normal APP protein expressed or neurones, function-unknown
Disease associated A beta 42
High Beta pleated content
Forms protease resistant- insoluble fibrils and plaques
Give as many similarities between Prions and Alzheimer’s disease.
Both diseases initiated by the abnormal folding of a host protein/peptide
Proteins generate contain a large % beta pleated sheet
Proteins generated self aggregate to form plaques
Proteins generated are relatively protease resistant
Both diseases have long incubation periods and the progression of disease is slow
Prions or A-Beta peptides alter synapse function and damage synapses, damage synapses by a similar mechanism, Kill neurons at high conc
What are the differences between Prions and Alzheimer’s disease?
Alzheimers disease is caused by a different peptides
Alzheimer’s disease does not cause vacuolation (spongiform)
A disease is not transmissible
Prion disease is associated with the whoe protein misfolding whereas alzheimers is due to peptide fragments
