Unit 10: Unconventional Slow Viruses and Prions

Slow Virus Diseases

• group of diseases caused by viruses or prions that have a prolonged incubation period and progress slowly

• often no acute illness

Slow Virus Disease characteristics

• asymptomatic primary infection

• long incubation period

• slow but progressive course

• patient tends to have genetic predisposition

• often re-emerge from latency in immunocompromised host 

Factors that lead to slow virus diseases

• infectious agents remain dormant 

• slow replication and gradual accumulation of agent

• agents suppress immune system 

• gradual cellular damage as agent accumulates 

Measles Virus 

• Subacute Sclerosing Panencephalitis 

  • progressive cognitive decline

Four Stages of Measles Virus

• Personality changes

• progressive motor function decline

• extrapyramidal symptoms 

• akinetic mutism or vegetative state 

Mechanism for measles virus

• mutated measles virus

  • matrix (M) gene 

Rubella Virus

• progressive rubella panencephalitis (PRP)

  • complication of congenital rubella syndrome 

Pathogenesis of Slow Virus Diseases

• rubella virus

• cancers caused by HTLV-1 and HPV

Prions Structure 

• misfolded proteins

• accumulate into amyloids

• proteinaceous infectious particles 

• 35 kDa

Prions Characteristics

• highly resistant to infection 

  • resistant to chemicals

  • decontaminate with NaOH or undiluted bleach for 1 hour and autoclave for 1 hour

Prion Protein (PrP)

• encoded by the PRNP gene 

• ‘needed for replication 

PrPC

• normal cellular isoform 

PrPsc

• infectous isoform 

  • scrapie prion protein 

two theories of prion replication

1. PrPsc binds to PrPc and converts it to PrPsc

2. unknown ligand protein binds a PrPsc and one PrPc and converts it to PrPsc

Different ways prions are transmitted

• Acquired

• Inherited

• Sporadic 

Acquired Transmission

• gastrointestinal tract or broken skin

• corneal or dura mater grafts 

• human growth hormone 

Inherited Transmission

• familial 

Sporadic Transmission

• spontaneous mutations/misfolding or unknown cause

Progressive and Relentless Degeneration of CNS via prions 

• as concentrations of PrPsc increase, amyloid plaque formation occurs 

• some forms of PrPsc cause death of neurons 

Features and symptoms of prions disease

1. transmibble

2. rapidly developing dementia

3. involuntary movements

4. difficulty walking/speaking

5. muscle stiffness

6. fatigue 

Scrapie

• sheep and goats

• highly contagious

• not transmittable to humans 

• mother to lamb transmission 

Bovine Spongiform Encephalopathy (BSE)

• known as “Mad Cow Disease”

• first seen in the UK

• transmission to cattle by sheep/cattle offal consumption 

Chronic Wasting Disease (CWD)

• deer, reindeer, elk,moose

• caused drastic weight loss, wasting, stumbling, drooling, lack of fear of people 

Kuru

• first seen in New Guinea

• cannibalism during funerals

• symptoms

  • unsteady stance/gait

  • loss of mobility

  • dysphasia,inability to speak, unresponsive

Forms of Transmissible Spongiform Encephalopathies in Animals 

• Scrapie

• Bovine Spongiform Encephalitis

• Chronic Wasting Disease

Forms of Transmissible Spongiform Encephalopathies in Humans 

• Kuru

• Creutzfely-Jacob Disease

• Varient Credtzfelt-Jacob Disease

Creutzfeld-Jakob Disease (Classic CJD)

• worldwide

• 85% sporadic cases; 5-15% inferited

• vague sensory disturbances, loss of memory, progressive dementia, jerky movements 

Variant Creutzfeldt-Jakob Disease (vCJD)

• infectious transmission 

  • caused by same prion as BSE (ingestion of prions)

• cases began following a rise in mad cow disease 

How does vCDJ differ from CDJ

• age of onset younger in vCJD

• more prolonged: death within 14 months

• heavy accumulation of amyloid plaques 

How is CJD diagnosed

• difficult while patient is alive

• symptoms: rapid mental degeneration 

• neurologic exam

• EEG/MRI

• elevated 14-3-3 protein levels in CSF

What is really helpful in diagnosing CJD?

• real time quaking induced conversion (RT-QuIC) assay

• definitive diagnosis requires a brain biopsy