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Microbiology/Immunology > Prions > Flashcards

Prions Flashcards

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1
Q

History of Transmissible Spongiform Encephalopathy

A

-1730- Scrapie First Appears
-1950s- Kuru outbreak
-1960s- infectious agent
-1980s- 60 people die from CJD from contaminated from surgical instruments and growth hormone
-1982- PROteinaceous INfectious particle
-1985- our genes encode the protein
1986- outbreak of mad cow disease
-1996- Mad cow disease is found in humans

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2
Q

Prion diseases

A
  • Scrapie- sheep and goats
  • Cats- feline spongiform encephalopathy
  • Deer, elk- chronic wasting disease
  • Cattle- bovine spongiform encephalopathy (BSE), mad cow diase
  • Humans- Kuru, Fatal familial insomnia, Gerstmann-Staussler-Scheinker syndrome, vCJD, sCJD
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3
Q

Creutzfeldt- Jacob Disease

A

-the most frequent of human prion disease
-causes:
sporadic (cCDJ), no known cause (85-95%)
familial (fCJD), inherited genetic risk (7-10%)
iatrogenic (iCJD), exposure during medical procedures (<1%)
-sCJD can not be transmitted person to person by blood transfusion or meat contaminated with BSE- not related to mad cow disease

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4
Q

sCJD symptoms and signs

A
  • sCJD causes spongiform encephalopathy
  • loss of brain function resembles Alzheimer’s disease, but is very rapid progression
  • complete dementia usually occurs by the sixth month
  • death occurs within one year of symptom onset
  • mental deterioration and myoclonus (twitch, present at some point during illness)
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5
Q

What causes prion diseases

A
  • protein only hypothesis- no virus, bacteria, fungi, no nucleic acid is associated with infectivitiy- resistant to UV radiation and nucleases, no immune response
  • some evidence against- skeptics argue diseases like Alzheimers aren’t infectious; thus misfolded protein alone is not enough to transmit disease
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6
Q

PrPc Misfolding Causes Encephalopathy

A
  • prions are encoded by the host
  • Prnp gene encodes a 35kDa membrane glycoprotein in mammels
  • PrPc is involved in maintaining the brains white matter, regulatin innate immune cells, responses to oxidative stress, and neuron formation
  • protein misfolding converts PrPc into PrPsc leading to prion disease
  • PrPsc can arise by mutation or from exogenous sources (meat, blood)
  • PrPsc can be experimentally transmitted between animals
  • animals lacking PrPc do not contract prion disease
  • PrpSc mechanism of pathogenesis is unknown
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7
Q

PrPsc classification

A
  • several human PrPsc types have been identified in brains that are associated with different phenotypes of CJD
  • different fragment sizes are observed on Western blots following treatment with proteinase K
  • based on the ratio of the 3 PrP bands seen after protease digestion, 4 types of human PrPsc have been identified
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8
Q

Model for Prion Self Replication

A
  • prions are infectious, but contain no genetic material
  • once formed, the nucleus (seed) recruits other PrPc and converts them to PrPsc
  • the nucleus increases in size to become an amyloid fiber
  • fragmentation occurs- liberates new ends to allow for amplication, allows the dissemination of infectious material
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9
Q

sCJD diagnosis

A
  • brain biopsy- only definitive
  • sCJD characterized by spongiform change, neuronal loss without inflammation, accumlation of PrPsc

also

  • detection of 14-3-3- protein in CSF
  • abnormal MRI and EEG
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10
Q

sCJD treatment and prognosis

A
  • no effective treatment
  • median disease duration of 5-6 months
  • death usually occurs with 1 year
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11
Q

sCJD Epidemiology

A
  • from 1979 through 2006, 6917 deaths due to sCJD
  • 247 deaths occur annually
  • annual incidence has remained stable at 1 case per 100,000
  • higher in older population- median 68, most deaths 60-79
  • slight majority in women 52.6%
  • 94.6% deaths in whites
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12
Q

Varient Creutzfeld Jacob Disease

A
  • vCJD is a type 4 prion
  • vCJD represents bovine to human transmission of BSE
  • in cattle, BSE is transmitted via CNS, retina, the trigeminal and paraspinal ganglia, the distal ileum, and the bone marrow- muscle and milk no BSE
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13
Q

vCJD symptoms and signs

A
  • vCJD can have a similar clinical presentation as sCJD
  • loss of brain function associated with vCJD progresses slower than sCJD (still more rapid that Alzheimers)
  • mean duration is 14 months compared to vCJD versus 4-5 months for sCJD
  • vCJD has a peripheral pathogenesis distinct from classical forms of CJD, with prominent involvement of lymphoreticular tisues
  • vCJD is fatal
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14
Q

vCJD diagnosis

A
  • overall, vCJD is similar to sCJC
  • type 4 PrPsc found in patients with vCJD is not found in other human prion diseases
  • vCJD has tropism from lymphoid organs such as tonsils
  • detection of 14-3-3 protein in CSF is not a sensitive marker for vCJD
  • abnormal MRI signal is distinct from those obtained from sCJD patients- slow wave pattern
  • abnormal PrP deposition in sCJD presents as diffuse staining whereas vCJD florid PrP plaques consist of a round amyloid core (amyloids are insoluble fibrous protein aggregates) surrounded by a ring of spongiform vacuoles
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15
Q

vCJD onset of disease

A

-mean age at onset of vCJD is 29 years (range 11 to 74 years) compared with 65 years for sCJD

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16
Q

Time course of BSE in UK

A
  • the first case of BSE was diagnosed in 1986
  • ban on animal feed that contained animal ruminants was introduced in 1988
  • ban on specific bovine offal (SBO) introduced in 1991- brain, spinal cord, thymus, spleen and intestine
  • by 1992, these bans started to bring the BSE epidemic under control
17
Q

Incidence of BSE and vCJD in Great Britain

A
  • BSE epidemic peaked in 1992, 4 years after the introduction of the ban on ruminant feed
  • currently, BSE is trailing down to extinction
  • vCJD was not defined until 1996
  • predicted incubation period of 10-20 years
  • vCJD epidemic peaked between 1999-2000, ~8 years after BSE epidemic peaked
18
Q

vCJD vs sCJD

A
  • vCJD is distinguished from sCJD by the following features:
  • type 4 PrPsc is unique to vCJD
  • can be transmitted person to person by blood transfusion or ingestion of food contaminated with SE
  • a considerably younger age of onset (29 versus 65 years)
  • less rapid progression of illness (14 versus 5 months)
  • vCJD has a peripheral pathogenesis
  • differences in neuropathology
19
Q

vCJD problem in US?

A
  • CDC has received reports of 3 confirmed cases in US residents- born in UK or Saudi Arabia
  • a recent report indicated about 1 in 2000 people in UK carry the vCJD causing prion
  • incubation 20-30 years
  • uncertaintly exists about the possibility that human cases of vCJD that are silently incubating may be capable of producing secondary lateral
20
Q

New Targets for CJDs

A
  • PrP13, a peptide that can break a beta-sheet conformation, was shown to reduce the protease resistance of PrPsc and to delay he onet the symptoms in transmission experiments in mice
  • in murine scarpie model, anti-PrP monoclonal antibodies reduced PrPsc levels and prion infectivity
  • mice treated with adenovirus vector platforms that express PrPc single chain fragment antibodies, and subsequently infected with PrPsc had delayed pathogenesis
21
Q

TSE precautions for healthcare workers

A
  • employ universal precautions when handling blood and CSF
  • highest risk from brain, spinal cord, and eye tissues
  • scrupulously avoid contact with post-mortem tissues- don’t get it into cuts and scratches on your skin
  • all precautions should be followed during autopsy and embalming
22
Q

Sterilization Procedures for Prions

A
  • prions are highly resistant to conventional physical decontamination methods- resistant to disinfectants, heat, ultraviolet radiation, ionizing radiation, and formalin
  • immerse in NaOH
23
Q

Prions and Alzheimer’s Disease

A
  • Alzheimer’s disease is a form of progressive dementia
  • polymorphism is the Prnp gene is a risk factor for AD
  • PrPc binds to amyloid B peptides
  • PrPc interaction with amyloid B peptides has been confirmed in patients with AD
  • deletion of PrPc in mice prevented the development of AD
  • mice injected with brain tissue from AD patients will developed disease- is misfolded amyloid B a prion?

Microbiology/Immunology (46 decks)

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