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Slow viral or prion diseases of the central nervous system. 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. SLOW INFECTIONS IN HUMANS. VIRUSES

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slow viral diseases of the central nervous system
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
slow infections in humans
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)
progressive multifocal leukoencephalopathy
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)
symptoms
SYMPTOMS
  • weakness
  • speech problems
  • cognitive problems
  • headaches
  • gait problems
  • visual problems
  • sensory loss
  • seizures

http://library.med.utah.edu/WebPath/TUTORIAL/AIDS/AIDS076.html

progressive multifocal leukoencephalopathy6
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
bk virus polyoma
BK virus (polyoma)
  • Associated with urinary tract infections in immunosuppression
  • Possibly contributory factor in prostate cancer???
measles virus
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
rubella virus
RUBELLA VIRUS
  • togavirus family (rubrivirus genus)
  • progressive rubella panencephalitis
    • inflammatory disease
    • years after initial infection
  • congenital / very early infections
  • very very rare
transmissible subacute spongiform encephalopathies

transmissible subacute spongiform encephalopathies

transmissible cerebral amyloidoses

prion diseases

slide12

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
atypical agents
ATYPICAL AGENTS
  • atypical viruses
  • atypical agents
  • prions
atypical agents14
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

ATYPICAL AGENTS
slide15
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
purified infectious material
purified infectious material
  • protein present (PrP)
  • proteases inactivate
  • nucleic acid controversial
      • but little or none

PRION

prion disease
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)

prion protein prp host cell gene

Helical - Happy

Beta-pleated sheet - Bad

PRION PROTEIN (PrP)(host cell gene)

PrP or PrPC

alpha-helical

protease sensitive

PrPRES or PrPSC

beta-pleated sheet

protease resistant

slide19

PrP

+

+

PrPSC

slide20

spontaneous conversion

SPORADIC

acquired conversion

ACQUIRED

acquired PrPSC

germline mutation, spontaneous

conversion more likely

INHERITED

somatic mutation, spontaneous

conversion more likely

SPORADIC

why are different prion diseases different

WHY ARE DIFFERENT PRION DISEASES DIFFERENT?

SEEMS MORE THAN ONE CONFORMATION FOR THE PrPSC FORM

slide22

PrP

1

+

+

PrPSC

PrP

2

+

+

disease caused by conformation 1 may

differ from that caused by conformation 2

PrPSC

why are prion diseases sometimes inherited

WHY ARE PRION DISEASES SOMETIMES INHERITED?

MUTATIONS IN THE PrP GENE CAN INCREASE THE CHANCE OF PrPSC FORMATION

slide24

germline mutation 1

INHERITED

germline mutation 2

INHERITED

disease caused by germline mutation 1 may

differ from that caused by germline mutation 2

scrapie
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
slide26
KURU
  • human disease
  • tremors, ataxia, weakness
  • dementia, death
  • amyloid plaques
  • spongiform changes
  • transmission – contact with infectious material
creutzfeldt jakob disease
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
creutzfeldt jakob disease classical form
CREUTZFELDT-JAKOB DISEASEclassical form
  • no evidence for direct person to person transmission
    • blood
    • milk
    • other body fluids
    • intimate social contact
creutzfeldt jakob disease29
CREUTZFELDT-JAKOB DISEASE
  • iatrogenic CJD
    • human cadaver growth hormone
    • human cadaver gonadotropin
    • dural mater grafts
    • corneal transplantation
    • neurosurgical instruments
    • stereotactic EEG electrodes
variant cjd vcjd
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
amino acid 129 met or val both variants found in the human population
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?
other human prion diseases
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
immune response
IMMUNE RESPONSE
  • no inflammatory response
  • no interferon induction
  • no antibody response
  • no cell-mediated response
treatment
TREATMENT
  • invariably fatal
  • attempts at drug therapy disappointing
  • blood brain barrier
diagnosis
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)
plaques
PLAQUES
  • PrP
  • NOT THE SAME AS IN ALZHEIMERS
slide41

Belay, E. http://www.cdc.gov/ncidod/dvrd/vcjd/chart_percent_vcjd_cjd_deaths.htm