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Virology > Lecture 14 - Pathogenesis of Viral Infections III > Flashcards

Lecture 14 - Pathogenesis of Viral Infections III Flashcards

1
Q

What is virulence?

A

The capacity of a virus to cause disease in a host

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2
Q

How can virulence be quantified?
1)
2)
3)

A

1) Mean time to death
2) Mean time to appearance of symptoms
3) Measurement of symptoms: fever, weight loss, pathological lesions (polio), CD4+ count (HIV), etc.

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3
Q

Example of a measurement of viral virulence
1)
2)

A

1) Monkeys inoculated intracerebrally with different viruses (Japanese encephalitis, yellow fever, West Nile, Langat, Dengue)
2) Lesions in the CNS scored (cerebrum, brain stem, spinal cord)

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4
Q

Why can’t virulence be compared between different viruses?

A

Because different viruses enter the body through different routes, are transmitted differently, infect different cells, etc

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5
Q

How can virulence genes be found?

A

Compare viruses that differ only in their virulence

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6
Q

Four general classes of viral virulence genes

A

1) Gene products that alter the ability of the virus to replicate
2) Gene products that modify host defence mechanisms
3) Genes that enable virus to spread in the host
4) Toxic viral proteins

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7
Q

Are toxic viral proteins common?

A

No. Very uncommon

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8
Q

Two types of gene products that alter the ability of a virus to replicate

A

1) Those necessary for the production of a large number of viral particles. When these are removed, virus can’t replicate properly in animal host or in cell culture.
2) Those that are essential for disease. When these are removed, virus can replicate in cell culture, but have impaired virulence in animal host

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9
Q

Example of non-coding genome effects on virulence

A

Sabin polio strain has a single nucleotide change (C to U) in the 5’ non-coding region.
This region normally folds into IRES domain 5. It is disrupted with this mutation, and results in reduced neurovirulence. LD50 is dramatically increased

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10
Q

Examples of gene products that modify host defence mechanisms

A

1) Virokines. Defective cytokines that act as cytokine receptor antagonists.
2) Viroceptors. Decoy receptors for cytokines.

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11
Q

Where are virokines and viroceptors normally found?

A

In the genomes of large DNA viruses

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12
Q

Examples of genes that enable spread in the host
1)
2)
3)

A

1) Reovirus type 1 in mice spreads to CNS via the blood.
2) Reovirus type 3 spreads to CNS via neural route.
3) Outer capsid protein σ1 is different between type 1 and type 3. Outer capsid protein σ1 determines which receptor the virus binds to.

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13
Q

How is the toxicity of a viral protein tested?

A

Adding pure sample of protein into a cell culture

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14
Q 
Example of a viral toxin 
1)
2)
3)
4)
A

1) Rotavirus NSP4.
2) A non-structural glycoprotein that participates in formation of transient rotavirus envelope when particles bud into ER.
3) Causes influx of Ca2+ into insect cells, leading to Er stress, mitochondrial defects.
4) When fed to young mice, leads to Cl- secretion potentiation, leading to diarrhoea.

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15
Q

What does NSP4 act as?

A

A viral enterotoxin by triggering a signal transduction pathway in the mucosa.

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16
Q

How does NSP4 lead to increased intracellular [Ca2+]?

A

By activating phospholipase C

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17
Q

Average error frequency of RDRP

A

1 in 10^4 - 10^5 nucleotides polymerised

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18
Q

Genome recombination
1)
2)

A

1) Occurs when RDRP is able to switch viral templates if two viruses have infected a cell
2) Generally occurs when sub-genomic mRNAs are produced, as RDRP can jump between subgenomic promotors of different viral genomes

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19
Q

How does genome recombination occur?
1)
2)
3)

A

1) RDRP replicates subgenomic RNA from template ((+) sense)
2) Subgenomic mRNA ((-) sense)from another virus binds to subgenomic mRNA.
3) RDRP makes genomic RNA with subgenomic RNA from other virus instead of original subgenomic mRNA

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20
Q

How do genome reassortment and genome recombination differ?

A

Genome reassortment is the reassortment of genome segments from different segmented-genome viruses.

Genome recombination is the recombination of genomes of viruses that make subgenomic mRNA making a chimaeric viral genome

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21
Q

Example of gene recombination

A

Sydney 2212 norovirus.
Open reading frame 1 very similar to Lordsdale strain.
Open reading frame 2 very similar to New Orleans strain.
Subgenomic breakpoint at subgenomic promotor between open reading frames 1 and 2

22
Q

Two important proteins in establishing poliovirus replication

A

3A, 2BC

23
Q

3AB role in poliovirus

A

3AB aids in genome replication.
Cleaved into 3A and 3B (VpG)

3A impairs function of GTPases that mediate COP transfer

24
Q

2BC role in poliovirus

A

2B and 2C are essential for viral RNA synthesis.
2C is a nucleotidyl phosphatase

2BC also recruits COPII to form replication complex rosette

25
Q

What is associated with poliovirus replication?

A

Induction of large intracellular vesicular clusters that house the replication complex

26
Q

Another name for the clusters of vesicles in poliovirus-infected cells

A

Rosettes

27
Q

Where does poliovirus RNA replication occur?

A

On the surface of rosettes (clusters of vesicles in cytoplasm)

28
Q

Role of COPI and COPII

A

Regulate intracellular vesicle traffic between the ER and the Golgi.

COPI decorates exterior of vesicles going from Golgi to ER (retrograde traffic)
COPII decorates exterior of vesicles going from ER to Golgi (anteretrograde traffic)

29
Q

Vesicle surface markers responsible for traffic between the ER and Golgi

A

COPI and COPII

30
Q

Degradation of which organelle is particularly associated with poliovirus infection?

A

Golgi

31
Q

Drug that has similar effects on Golgi as poliovirus infection

A

Brefeldin A

32
Q

Poliovirus protein that recruits COPII to form replication complex rosette

A

2BC

33
Q

Poliovirus protein that impairs the function of GTPases that regulate COP transfer

A

3A

34
Q

Why does poliovirus impair host cell secretory pathway?
1)
2)
3)

A

1) Virus requires membrane for biogenesis of replication complex
2) Prevents surface expression of MHC-I (prevents CTL killing)
3) Prevents secretion of cytokines, IFN

35
Q

Does interference with cell secretory pathway negatively affect poliovirus?

A

No. Makes no glycoproteins, doesn’t have an envelope

36
Q

Hypothesis for cause of ebola/Marburg virus shock

A

Release of cytokines form infected macrophages

37
Q

Where was Ebola first identified?

A

Sudan

38
Q

Where is Ebola traditionally endemic?

A

Central Africa

39
Q

Countries affected by the 2014 ebola outbreak

A

Guinea, Liberia, Sierra Leone, Nigeria

40
Q

What is the 2014 ebola virus related to?

A

97% identical to Zaire species ebolavirus

41
Q

Ebolavirus symptoms
1)
2)
3)

A

1) Abrupt, unexpected symptoms
2) Starts with red eyes
3) Progresses to fever, headache, flu-like symptoms, fatigue, internal, external bleeding, haemorrhage

42
Q

Ebolavirus incubation period

A

2-21 days

43
Q

Ebolavirus transmission

A

Body fluids, direct contact with infected people.

Often first infects people who handle or eat monkeys.

44
Q

Ebolavirus natural host

A

Thoguht to be fruit bats

45
Q

Essential proteins in ebolavirus pathogenesis
1)
2)
3)

A

1) Glycoprotein (GP) is a major structural component
2) VP35 is an essential polymerase cofactor
3) VP24 plays a role in virus assembly and budding

46
Q

What does ebola use transcriptional editing for?

A

Two forms of ebola GP.
75% of ebola GP are unedited, result in secreted GP that acts as a decoy for antibodies.
25% of GP is edited via addition of an adenosine. This changes the reading frame, making GP with a transmembrane domain and is incorporated into virion.

47
Q

How is ebola surface GP made?
1)
2)
3)

A

1) Adenosine added to GP mRNA transcript to alter the reading frame. A transmambrane domain is now added.
2) Host furin cleaves GP, activates it.
3) GP is incorporated into viral capsid

48
Q

Ebola VP35 roles
1)
2)

A

1) Polymerase cofactor

2) Inhibits IRF3, thereby preventing transcription of IFN

49
Q

Ebola VP24 roles
1)
2)

A

1) Role in virus assembly and budding

2) Prevents STAT1 nuclear translocation, to impede the production and stimulation of interferon-stimulated genes

50
Q

How can macrophages make ebola more pathogenic?

A

Infected macrophages release a large amount of TNFa.

Vascular instability and destruction might be a result of macrophage-released TNFa

Virology (29 decks)

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