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Slow viral or prion diseases of the central nervous system
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Slow viral diseases of the central nervous system
• tempo of clinical disease
• protracted incubation period
• (may also be protracted course of disease)
• multiple neurological symptoms
3
SLOW INFECTIONS IN HUMANS
• VIRUSES– SV40-like viruses (PML)– measles virus (SSPE)– rubella virus (PRP)
• ATYPICAL AGENTS– Kuru, – Creutzfeld-Jakob disease (CJD)– (new) variant CJD disease (vCJD=nvCJD)
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Progressive multifocal leukoencephalopathy
• Polyoma virus family, SV40-like (JC virus etc)• progressive, usually fatal, associated with
immune suppression– HAART may prolong life in AIDS patients
• but little effect on PML incidence
• typically non inflammatory– but can get an inflammatory response in the brain
after HAART treatment (immune reconstitution inflammatory syndrome)
• demyelination (oligodendrocytes infected)
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SYMPTOMS
• weakness• speech problems• cognitive problems• headaches• gait problems• visual problems• sensory loss• seizures
http://library.med.utah.edu/WebPath/TUTORIAL/AIDS/AIDS076.html
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Progressive multifocal leukoencephalopathy
• reactivation of latent infection• 70-80% population are seropositive• associated with immunosuppression
– 1979: 1.5 per 10,000,000 population– 2004: 1 in 20 AIDS patients
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BK virus (polyoma)
• Associated with urinary tract infectionsin immunosuppression
• Possibly contributory factor in prostate cancer???
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MEASLES VIRUS
• paramyxovirus family (morbillivirus genus)• sub-acute sclerosing panencephalitis
– inflammatory disease– defective virus– ~1-10 yrs after initial infection
• early infection with measles is a risk factor• rare complication of measles (7-70 cases per
1,000,000 cases measles)• vaccine protects against SSPE
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RUBELLA VIRUS
• togavirus family (rubrivirus genus)
• progressive rubella panencephalitis– inflammatory disease
– years after initial infection
• congenital / very early infections
• very very rare
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transmissible subacute spongiform encephalopathies
prion diseases
transmissible cerebral amyloidoses
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http://www.cdc.gov/ncidod/dvrd/cjd/ (Ermias Belay)
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TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES (TSEs, TRANSMISSIBLE CEREBRAL AMYLOIDOSES, PRION
DISEASES)
• human– Kuru– Creutzfeldt-Jakob disease (CJD)– Gerstmann-Straussler-Scheinker syndrome (GSS)
– fatal familial insomnia (FFI)– variant CJD (‘human BSE’)
• animal– scrapie (sheep and goats)
– bovine spongiform encephalopathy (BSE)– transmissible mink encephalopathy– etc
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ATYPICAL AGENTS
• atypical viruses • atypical agents• prions
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ATYPICAL AGENTS
• SIMILAR TO VIRUSES– small– filterable– need host cells– no machinery for
energy generation or protein synthesis
• DIFFERENT FROM VIRUSES– no detectable virions
in infected tissues– no detectable virions
in purified infectious material
– if nucleic acid is present, very small
– very resistant to inactivation
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• RESISTANT TO OR ONLY PARTIALLY INACTIVATED BY:– formaldehyde – ethanol– glutaraldehyde– ultraviolet and ionizing irradiation– non-ionic detergents
• INACTIVATED BY:– autoclaving (121C for one hour) (> standard)– 5% sodium hypochlorite– sodium hydroxide– proteases, urea, other protein denaturants
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purified infectious material
• protein present (PrP)• proteases inactivate• nucleic acid controversial
• but little or none
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PRION DISEASE• CNS
• LONG INCUBATION
• SLOW COURSE OF DISEASE (FATAL)
• SPONGIFORM ENCEPHALOPATHY
• VACUOLATION OF NEURONS
• FIBRILLAR AGGREGATES, AMYLOID-TYPE MATERIAL (form plaques)
• RARE IN MAN
http://www.cdc.gov/ncidod/dvrd/cjd/ (Ermias Belay)
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PrP or PrPC
alpha-helicalprotease sensitive
PrPRES or PrPSC
beta-pleated sheetprotease resistant
PRION PROTEIN (PrP)(host cell gene)
Helical - Happy Beta-pleated sheet - Bad
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+
PrP
+
PrPSC
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acquired conversionACQUIRED
acquired PrPSC
somatic mutation, spontaneousconversion more likelySPORADIC
germline mutation, spontaneous conversion more likelyINHERITED
spontaneous conversionSPORADIC
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WHY ARE DIFFERENT PRION DISEASES
DIFFERENT?
SEEMS MORE THAN ONE CONFORMATION FOR THE
PrPSC FORM
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+
PrP
+
PrPSC
+
PrP
+
PrPSC disease caused by conformation 1 may differ from that caused by conformation 2
1
2
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WHY ARE PRION DISEASES SOMETIMES INHERITED?
MUTATIONS IN THE PrP GENE CAN INCREASE THE CHANCE
OF PrPSC FORMATION
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germline mutation 1INHERITED
germline mutation 2INHERITED
disease caused by germline mutation 1 may differ from that caused by germline mutation 2
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SCRAPIE
• sheep• loss of muscular control• wasting• glial proliferation• vacuolation of neurons• amyloid plaques• abnormal properties infectious material• does not seem to cross sheep/human species
barrier
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KURU
• human disease • tremors, ataxia, weakness• dementia, death• amyloid plaques• spongiform changes• transmission – contact with infectious
material
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CREUTZFELDT-JAKOB DISEASE
• spongiform appearance of brain at autopsy• dementia, myoclonus, ataxia• 16-80+, usually 50-70
• Median age at death in US=68 yrs
• 10% familial• also sporadic form• also acquired form (eg. iatrogenic CJD)• several hundred deaths in US per year
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CREUTZFELDT-JAKOB DISEASE
classical form
• no evidence for direct person to person transmission – blood– milk– other body fluids– intimate social contact
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CREUTZFELDT-JAKOB DISEASE
• iatrogenic CJD– human cadaver growth hormone– human cadaver gonadotropin– dural mater grafts– corneal transplantation– neurosurgical instruments– stereotactic EEG electrodes
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variant CJD (vCJD)
• patients younger at presentation, more protracted course of disease
• median age at death for UK vCJD patients=28 yrs• often patients present with psychiatric symptoms• BSE connection • seems bovine/human barrier is easier to cross than
sheep/human barrier• distinctive pathological appearance• distinctive properties of the PrPres
• agent is in some peripheral tissues– lymphoid tissues– 2 probable cases where transmitted by blood
• future?• two cases in US – both had spent time in UK
31
Belay et al (2005) Emerging Infectious Diseases • www.cdc.gov/eid • 11: 1351
32
CDC/ Teresa Hammett , Photo Credit: Sherif Zaki; MD; PhD; Wun-Ju Shieh; MD; PhD; MPH
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Amino acid 129 Met or Val?- both variants found in the human population
• Britain– 37% of the UK population is MM– 100% of clinical vCJD cases are MM
• Are MV, VV immune to vCJD, or will they develop vCJD later on?– 83% of sporadic CJD cases are MM
• Britain, France, Japan– excess of VV in growth hormone recipients with
iatrogenic CJD
• does heterozygosity (M/V) offer some protection?
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OTHER HUMAN PRION DISEASES
• Gerstmann-Sträussler-Scheinker syndrome (GSS) (familial)– motor– sometimes regarded as subclass of CJD
• fatal familial insomnia (FFI)– circadian rhythm problems– hypothalamus
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IMMUNE RESPONSE
• no inflammatory response• no interferon induction• no antibody response• no cell-mediated response
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TREATMENT
• invariably fatal
• attempts at drug therapy disappointing
• blood brain barrier
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DIAGNOSIS
• CLINICAL PICTURE, EEG, MRI (vCJD)• USUALLY CONFIRMED POST-
MORTEM• NOW HAVE ANTIBODIES RAISED IN
RECOMBINANT MICE – can use on biopsy of brain (or peripheral
lymphoid tissue in vCJD)
38
PLAQUES
• PrP
• NOT THE SAME AS IN ALZHEIMERS
39
40
http://www.cdc.gov/ncidod/dvrd/vcjd/
41
The Times (London)
42Belay, E. http://www.cdc.gov/ncidod/dvrd/vcjd/chart_percent_vcjd_cjd_deaths.htm