CNS Infections: DNA Viruses and TSE Flashcards
What are two broad ways that virus can cross the BB to enter the CNS?
- Via trauma-induced breaches
2. By mimicking legal cargo
What are the three ways a virus can mimic legal cargo?
- Transcytosis across endothelial cell
- Infection of endothelial cell and subsequent transmission
- Inside infected lymphocytes / monocytes
How does a virus like Rabies enter the CNS?
Infects the PNS, then uses directional transport on microtubules to travel retrograde (+ end to - end) up the nerve axon to reach nuclei in the CNS.
How do most viral CNS infections begin?
Non-neuronal infections of epithelial cells, followed by infection of innervating peripheral neurons with synaptic transmission to CNS
What is neurotropic vs neuroinvasive vs neurovirulent?
Neurotropic = virus is able to infect a neuron or glial cell, regardless of outcome
Neuroinvasive = virus is able to enter the CNS after infecting a peripheral site
Neurovirulent = virus can cause disease by damaging nervous tissue
How do Mumps and Rabies differ in neuroinvasiveness vs neurovirulence?
Mumps and Rabies both commonly infect the CNS and are thus highly neuroinvasive
Mumps rarely causes severe disease while Rabies always does -> Rabies has high neurovirulence
What is the most common form of sporadic fatal encephalitis in adults? What lobe is most affected, and is it focal or diffuse?
HSV-1 encephalitis
Typically the temporal lobe
Focal lesion - with fever, altered consciousness / behavior, and disordered thinking
How is definitive diagnosis of HSV-1 encephalitis made?
Via MRI evidence of temporal lobe edema or hemorrhage, followed by PCR of CSF for HSV-1
What are the most common complications of varicella and zoster?
Encephalitis for both varicella and zoster
Zoster only -> post herpetic neuralgia (from reactivation in PNS dorsal root ganglia)
What does congenital varicella cause?
Mental retardation, cerebral atrophy, and non-CNS abnormalities
How is VZV encephalitis or meningitis diagnosed and treated and prevented?
Diagnosed via PCR of CSF
Treatment: Similar to herpes, Valacyclovir or famciclovir
Prevented via Zostavax! 20x normal Varivax dosage, for adults.
What is the most common cause of birth defects and childhood disabilities in the US?
Congenital cytomegalovirus - has transplacental transmission
What proportion of kids have clinical signs of CMV at birth if infected, and what are they?
10%: Intrauterine growth retardation, hepatosplenomegaly, microcephaly, other symptoms
Majority will develop longterm sequelae including mental retardation, seizures, blindness, deafness, and death
What do the other 90% end up with? This is another one of those “leading cause” things
10-15% of these will develop hearing / vision problems or intellectual impairment in their lives.
It is the leading cause of non-hereditary deafness in children
How is CMV treated?
Ganciclovir is the only treatment available -> remember bone marrow suppression
Who carries the Herpes B virus, where do they carry it, and what is the treatment?
Macaca old world monkeys, in saliva / other secretions.
Treatment is high doses of acyclovir and ganciclovir -> cause fatal encephalitis
What is the structure and relative size of the Polyomavirus family?
Circular dsDNA genomes, with relatively few genes -> highly dependent on cellular enzymes for DNA replication / gene expression
What are the two major viruses of the polyomavirus family?
- JC virus (JCV)
2. BK virus (BKV)
What does JCV cause in immunocompetent vs immunocompromised hosts?
Immunocompetent - mild respiratory disease
Immunocompromised - Progressive Multifocal Leukoencephalopathy (PML)
What causes pathology in PML?
Demyelination of deep cortical white matter via replication in oligodendrocytes, with minimal inflammatory processes going on
What are the normal clinical features of PML? How quick do these patients die?
Focal cerebral involvement: personality alterations, loss of motor skills or sensory loss, intellectual deficits.
It rarely involves cerebellar signs or brainstem
Patients die within 12 months without proper treating of immune system
When would a brain biopsy be needed?
When the pattern deviates from typical subcortical white matter, need to get differential from other possible pathogens: Toxoplasma gondii, Cryptococcus neoformans, Mycobacterium tuberculosis
What does BK virus cause in immunocompetent vs immunocompromised hosts?
Immunocompetent: Mild upper respiratory disease
Immunocompromised:
- Polyomavirus nephropathy, especially in renal transplant patients.
- Hemorrhagic cystitis, in bone marrow transplant patients.
What does PrP^sc mean vs PrP^c? What is their functional difference?
PrP^c = normal prion protein, sensitive to proteases, works in cell adhesion / signalling
PrP^sc = scrapie, referring to sheep transmissable spongiform encephalopathy. It is resistant to degradation by proteases, and infectious
PrP = PRNP = Prion Protein
What can be seen on histology for TSEs?
Cerebral atrophy: spongiform degeneration, amyloid plaques, and activated astrocytes and microglial cells
No inflammation
What is sCJD vs fCJD vs iCJD vs vCJD?
Creutzfeldt - Jakob Disease
sCJD = sporadic - no identified cause, affects 1 in a million per yr fCJD = familial - autosomal dominant mutation in chromosome 20 PrP gene iCJD = iatrogenic - transmission from neurosurgeon's instruments, doesn't occur vCJD = variant - transmission from Bovine SE to humans
How is proteinase resistance proven in the lab?
PRNP proteins are subjected to proteinase K, and a western blot is done. If the samples taken from brain or tonsils still show up on Western blot after enzymatic digestion -> resistance
What codon of the PRNP gene is variable, and what are the two amino acids held by the population? Which is most susceptible?
Codon 129
Methionine and Valine
2 methionine chromosomes is most susceptible to variant and sporadic CJD
When might it be selected for to have a “resistant” PRNP genotype? Which codon is this?
Codon 127 - Valine = resistance
Selected for in disease called “Kuru”, in which people got CJD from cannibalism, and the VV genotype made you way less likely to actually get spreading disease from a prion
What is meant by “breed true”?
Different isolates or strains of PrP cause the the same pathogenesis in each person.
What determines the properties of a prion protein?
The actual properties of the isolate is highly dependent on where it was taken from in the brain (cerebrum vs cerebellum), and its related time course and ability to infect other species. This is due to conformation of protein (lots of beta sheets, but some variance)
How is BSE thought to have originally spread to cattle?
Sheep and cattle offal (waste tissue) were used to make meat and bone meal which was added to feed as a protein source, contaminating the food supply with scrapie prions
