s3 l15 slow viral infection

8/8/2019 S3 L15 Slow Viral Infection

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S3 L15: Slow Viruses and Prions by Dr. Antonio Camacho November 26, 2010

SLOW VIRUS INFECTIONS

General Characteristics:

Prolonged incubation period (months or years)

Protracted, progressive clinical courseRefers to the TEMPO of the disease and NOT the growth rate of the virusConventional viruses

Unconventional viruses (AKA unconventional agents or atypicalviruses/agents)

Conventional Viruses

Progressive multifocal leukoencephalopathy (PML)

Subacute sclerosing panencephalitis (SSPE)Progressive rubella panencephalitis (PRP)

HIV

Rabies

Progressive Multifocal Leukoencepalopathy

Rare, progressive, fatal demyelinating disease of the CNS

Symptoms: memory loss, loss of coordination, mentation problems,vision problems

Caused by certain members of the polyomavirus family JC virus

Frequently have some abnormality in the immune system (developsin up to 5% of patients with AIDS)Probably due to a reactivation of a viral infection

Subacute Sclerosing Panencephalitis (SSPE)

Rare complication of measles infection

Develops ~ 1 – 10 years after initial infection

Progressive fatal diseaseSymptoms: mental and motor deterioration

Risk factor: acquiring primary measles at an early age Associated with defective forms of the virus in the brain

Difficult to isolate infectious virus from patients

Progressive Rubella Panencephalitis (PRP)

Very rare consequence of rubella virus infection

Symptoms: mental and motor deterioration

Initial infection is usually congenital or soon after birth

Onset of PRP 8-19 years old

Unconventional Viruses or Agents: Prions

Similar to viruseso Smallo Filterableo Needs host cellso No machinery for energy generation or protein synthesis

Different from viruseso No detectable virions in infected tissueso No detectable virions in purified preparations of infected

materialo No nucleic acid; if present, very smallo Very resistant

Resistant to or partially inactivated by:o Formaldehyde

o Ethanolo Glutaraldehydeo UV and ionizing radiationo Non-ionic detergents

Inactivated by:o

Autoclaving (121°C for 1 hour)o 5% sodium hypochloriteo Sodium hydroxideo Proteases, urea, other protein denaturants

Prions

Protein is present in purified preparations of infectious material

Treatments which destroy protein, destroy infectivity, but, treatmentswhich destroy nucleic acid do NOT destroy infectivityPrP (pr ion protein)

Causes diseases which are confined to the CNS

Have a prolonged incubation period

Show a slow, progressive, fatal course of disease

Show a spongiform encephalopathy (transmissible spongiform

encephalopathies)Characteristically results in vacuolation of neurons

Can cause formation of fibrillar aggregates, which contain PrP andhave amyloid-like characteristics

Prion Protein (PrP)

Stanley B. Prusiner – 1997 Nobel Prize in Physiology and MedicinePreparations of highly purified infectious material contain largeamounts of PrP

Encoded by a host cellular gene – short arm of chromosome 20

30-kD normal cellular protein in neurons

Normal form – α-helix

PrPres (resistant to protease)

PrPsc (first found in scrapie infections)o Diseased formo “amyloid plaques” o β-pleated sheet

Why is the protein infectious?

Hypothesis:

The resistant form can convert the normal form to the resistant formwhich will then beable to convert more normal to resistant itself, and thus, the rate oconversion will gradually amplify as the concentration of resistanform increases.

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Why are there differences in prion diseases?

Prion Protein (PrP)

Immune responseo Do not cause an inflammatory responseo Do not induce interferono No antibody response

Transmissible Spongiform Encephalopathies (TSEs)

AKA transmissible cerebral amyloidosis, prion diseasesRare

Acquired, inherited, or occur sporadically

Humano Kuruo Creutzfeldt-Jakob disease (CJD)o Gerstmann-Straussler-Scheinker (GSS) syndromeo Fatal familial insomnia (FFI)o New variant CJD (“human BSE”)

Animalo Scrapie (sheep and goats)o Transmissible mink encephalopathyo Bovine spongiform encephalopathy (BSE)

Diagnosiso Probable

Clinical picture EEG

o Final Postmortem examination of the brain vCJD PrPsc in peripheral lymphoid tissue (tons

biopsies) Western blot assay

Creutzfeldt-Jakob Disease (CJD)

1-3 cases per million population per annum

16 - 80+ years; usually, 50 - 70 years of age

Route of transmission – not known

No evidence for direct person-to-person transmission

Transmissible to animals

Sporadic – most cases

Familialo 10%o autosomal dominanto Libyan-born Jews in Israel and in a rural area in

CzechoslovakiaIatrogenic (medical manipulations)

o Cornea transplantso Dura mater transplantso Use of improperly sterilized equipment (e.g.

intracerebral electrodes) in neurosurgeryo Human cadaver growth hormone administration

Dementiao most common - rapidly progressive

Prodrome

o vague personality changes Alterations in higher cortical function, ataxic gait, visual disturbanceinvoluntary movement, dysphagia/dysarthria

Mental deterioration vegetative state

Entire clinical course typically lasts approx. 4 months before deathoccurs; others 2 years

Clinical triad (up to 75% of cases):o mental deteriorationo myoclonuso periodic sharp EEG complex

Pathologyo Limited to the CNSo Atrophy generally less severe than ADo Three major histologic changes:



spongiform changes – gray matter; diffuse or focal

gliosis neuronal loss

Gerstmann-Straussler-Scheinker (GSS) syndrome

Kuru-like symptoms

Familialo Most caseso Autosomal dominanto Genetically transmitted subclass of CJDo Almost exclusively in the northern hemisphere, including

western Europe, Japan, and the US; likely worldwideTransmissible to animal

Fatal Familial Insomnia (FFI)

Progressive untreatable insomnia

Loss of circadian rhythm

Endocrine disorders, motor disorders, dementia

Familial

Transmissible to animalsHypothalamus

New variant CJD (nvCJD, vCJD)

“Human BSE”? o Strong association with exposure to BSE-contaminated

beef

Younger – under 40 years of agePsychiatric problems more prominent

More protracted disease1996

128 in UK

6 in France

1 each in Ireland, Italy and in the US

Pathologyo

Distinctive neuropathological appearanceo More PrP amyloid plaque-type deposits than in typical

CJD caseso More infectious agents in the peripheral tissues, esp. in

the lymphoreticular tissues

Kuru

Confined to the Fore people in the Eastern Highlands of Papua NewGuineaTransmitted by rites for the dead – autopsy and ritual cannibalism

Prominent cerebellar signs (ataxia and tremors) and dementia witheventual deathNo evidence for transmission to fetus, via milk or intimate sexuacontact

Pathologyo Cerebral gray structures

spongiform changeso Cerebellum

amyloid plaques (“kuru plaques”) large single amyloid core surrounded by a

fine, fibrillar, rim-like halo

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Ang trans na ito ay inihahandog ng:

MICROBIOMAN (+ 1 )

From 1st row (L to R): Paulfie, Edo, Teacher

From 2nd row (L to R): Niña, Nickie, Turay

s3 l15 slow viral infection

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