CNS Infections: DNA Viruses and TSE

Question 1

What are two broad ways that virus can cross the BB to enter the CNS?

Answer 1

1. Via trauma-induced breaches

2. By mimicking legal cargo

Question 2

What are the three ways a virus can mimic legal cargo?

Answer 2

1. Transcytosis across endothelial cell
2. Infection of endothelial cell and subsequent transmission
3. Inside infected lymphocytes / monocytes

Question 3

How does a virus like Rabies enter the CNS?

Answer 3

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.

Question 4

How do most viral CNS infections begin?

Answer 4

Non-neuronal infections of epithelial cells, followed by infection of innervating peripheral neurons with synaptic transmission to CNS

Question 5

What is neurotropic vs neuroinvasive vs neurovirulent?

Answer 5

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

Question 6

How do Mumps and Rabies differ in neuroinvasiveness vs neurovirulence?

Answer 6

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

Question 7

What is the most common form of sporadic fatal encephalitis in adults? What lobe is most affected, and is it focal or diffuse?

Answer 7

HSV-1 encephalitis

Typically the temporal lobe

Focal lesion - with fever, altered consciousness / behavior, and disordered thinking

Question 8

How is definitive diagnosis of HSV-1 encephalitis made?

Answer 8

Via MRI evidence of temporal lobe edema or hemorrhage, followed by PCR of CSF for HSV-1

Question 9

What are the most common complications of varicella and zoster?

Answer 9

Encephalitis for both varicella and zoster

Zoster only -> post herpetic neuralgia (from reactivation in PNS dorsal root ganglia)

Question 10

What does congenital varicella cause?

Answer 10

Mental retardation, cerebral atrophy, and non-CNS abnormalities

Question 11

How is VZV encephalitis or meningitis diagnosed and treated and prevented?

Answer 11

Diagnosed via PCR of CSF

Treatment: Similar to herpes, Valacyclovir or famciclovir

Prevented via Zostavax! 20x normal Varivax dosage, for adults.

Question 12

What is the most common cause of birth defects and childhood disabilities in the US?

Answer 12

Congenital cytomegalovirus - has transplacental transmission

Question 13

What proportion of kids have clinical signs of CMV at birth if infected, and what are they?

Answer 13

10%: Intrauterine growth retardation, hepatosplenomegaly, microcephaly, other symptoms

Majority will develop longterm sequelae including mental retardation, seizures, blindness, deafness, and death

Question 14

What do the other 90% end up with? This is another one of those “leading cause” things

Answer 14

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

Question 15

How is CMV treated?

Answer 15

Ganciclovir is the only treatment available -> remember bone marrow suppression

Question 16

Who carries the Herpes B virus, where do they carry it, and what is the treatment?

Answer 16

Macaca old world monkeys, in saliva / other secretions.

Treatment is high doses of acyclovir and ganciclovir -> cause fatal encephalitis

Question 17

What is the structure and relative size of the Polyomavirus family?

Answer 17

Circular dsDNA genomes, with relatively few genes -> highly dependent on cellular enzymes for DNA replication / gene expression

Question 18

What are the two major viruses of the polyomavirus family?

Answer 18

1. JC virus (JCV)

2. BK virus (BKV)

Question 19

What does JCV cause in immunocompetent vs immunocompromised hosts?

Answer 19

Immunocompetent - mild respiratory disease

Immunocompromised - Progressive Multifocal Leukoencephalopathy (PML)

Question 20

What causes pathology in PML?

Answer 20

Demyelination of deep cortical white matter via replication in oligodendrocytes, with minimal inflammatory processes going on

Question 21

What are the normal clinical features of PML? How quick do these patients die?

Answer 21

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

Question 22

When would a brain biopsy be needed?

Answer 22

When the pattern deviates from typical subcortical white matter, need to get differential from other possible pathogens: Toxoplasma gondii, Cryptococcus neoformans, Mycobacterium tuberculosis

Question 23

What does BK virus cause in immunocompetent vs immunocompromised hosts?

Answer 23

Immunocompetent: Mild upper respiratory disease

Immunocompromised:

1. Polyomavirus nephropathy, especially in renal transplant patients.
2. Hemorrhagic cystitis, in bone marrow transplant patients.

Question 24

What does PrP^sc mean vs PrP^c? What is their functional difference?

Answer 24

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

Question 25

What can be seen on histology for TSEs?

Answer 25

Cerebral atrophy: spongiform degeneration, amyloid plaques, and activated astrocytes and microglial cells

No inflammation

Question 26

What is sCJD vs fCJD vs iCJD vs vCJD?

Answer 26

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

Question 27

How is proteinase resistance proven in the lab?

Answer 27

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

Question 28

What codon of the PRNP gene is variable, and what are the two amino acids held by the population? Which is most susceptible?

Answer 28

Codon 129
Methionine and Valine

2 methionine chromosomes is most susceptible to variant and sporadic CJD

Question 29

When might it be selected for to have a “resistant” PRNP genotype? Which codon is this?

Answer 29

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

Question 30

What is meant by “breed true”?

Answer 30

Different isolates or strains of PrP cause the the same pathogenesis in each person.

Question 31

What determines the properties of a prion protein?

Answer 31

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)

Question 32

How is BSE thought to have originally spread to cattle?

Answer 32

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