1

Slow viral or prion diseases of the central nervous system

2

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)

4

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)

5

SYMPTOMS

• weakness• speech problems• cognitive problems• headaches• gait problems• visual problems• sensory loss• seizures

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

6

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

7

BK virus (polyoma)

• Associated with urinary tract infectionsin immunosuppression

• Possibly contributory factor in prostate cancer???

8

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

9

RUBELLA VIRUS

• togavirus family (rubrivirus genus)

• progressive rubella panencephalitis– inflammatory disease

– years after initial infection

• congenital / very early infections

• very very rare

10

transmissible subacute spongiform encephalopathies

prion diseases

transmissible cerebral amyloidoses

11

http://www.cdc.gov/ncidod/dvrd/cjd/ (Ermias Belay)

12

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

13

ATYPICAL AGENTS

• atypical viruses • atypical agents• prions

14

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

15

• 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

16

purified infectious material

• protein present (PrP)• proteases inactivate• nucleic acid controversial

• but little or none

17

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)

18

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

19

+

PrP

+

PrPSC

20

acquired conversionACQUIRED

acquired PrPSC

somatic mutation, spontaneousconversion more likelySPORADIC

germline mutation, spontaneous conversion more likelyINHERITED

spontaneous conversionSPORADIC

21

WHY ARE DIFFERENT PRION DISEASES

DIFFERENT?

SEEMS MORE THAN ONE CONFORMATION FOR THE

PrPSC FORM

22

+

PrP

+

PrPSC

+

PrP

+

PrPSC disease caused by conformation 1 may differ from that caused by conformation 2

1

2

23

WHY ARE PRION DISEASES SOMETIMES INHERITED?

MUTATIONS IN THE PrP GENE CAN INCREASE THE CHANCE

OF PrPSC FORMATION

24

germline mutation 1INHERITED

germline mutation 2INHERITED

disease caused by germline mutation 1 may differ from that caused by germline mutation 2

25

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

26

KURU

• human disease • tremors, ataxia, weakness• dementia, death• amyloid plaques• spongiform changes• transmission – contact with infectious

material

27

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

28

CREUTZFELDT-JAKOB DISEASE

classical form

• no evidence for direct person to person transmission – blood– milk– other body fluids– intimate social contact

29

CREUTZFELDT-JAKOB DISEASE

• iatrogenic CJD– human cadaver growth hormone– human cadaver gonadotropin– dural mater grafts– corneal transplantation– neurosurgical instruments– stereotactic EEG electrodes

30

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

33

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?

34

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

35

IMMUNE RESPONSE

• no inflammatory response• no interferon induction• no antibody response• no cell-mediated response

36

TREATMENT

• invariably fatal

• attempts at drug therapy disappointing

• blood brain barrier

37

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