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Virology > Lecture 33 - Rotavirus Pathogenesis and Disease > Flashcards

Lecture 33 - Rotavirus Pathogenesis and Disease Flashcards

1
Q

How was rotavirus discovered?

A

Reovirus-like particles in intestinal epithelial cells

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2
Q

Infectious agent that causes most severe diarrhoea and dehydration than others

A

Rotavirus

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3
Q

Annual deathrate of rotavirus in developing countries

A

1/200

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4
Q

Total annual deaths from rotavirus in 2008

A

500, 000

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5
Q

Effect of rotavirus vaccination

A

45% reduction in rotavirus hospitalisations since 2006

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6
Q 
Other disease manifestations of rotavirus
1
2
3
4
A

1) Low-level viremia common
2) ~4% develop CNS disease (encephalitis)
3) Occasional liver involvement
4) Autoimmune. Type 1 DM, coeliac disease

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7
Q

Rotavirus family

A

Reoviridae

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8
Q

Rotavirus genome

A

Segmented, dsDNA (11 segments)

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9
Q

Rotavirus capsid symmetry

A

Icosahedral

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10
Q

Rotavirus core protein

A

VP2

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11
Q

Rotavirus VP4

A

Trypsin-cleaved into VP5 and VP8.

VP5 and VP8 are receptor ligands

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12
Q

Rotavirus inner capsid protein

A

VP6

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13
Q

Rotavirus outer capsid proteins

A

VP4, VP7

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14
Q

Rotavirus protein important in serotyping

A

VP6

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15
Q

Proportion of rotovirus proteins that are structural

A

~1/2

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16
Q

How can individual rotavirus isolates be distinguished?

A

Electropherotyping

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17
Q

Rotavirus gene arrangement on genome

A

Each segment encodes a single protein, except for one segment (VP1, 2, 3, 4, 6, 7, NSP1-5)

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18
Q 
Laboratory diagnosis of rotavirus 
1
2
3
4
5
6
7
A

1) ELISA with antibodies against group antigens (EG: VP6)
2) RT-PCR
3) Electron microscopy
4) Electropherotyping
6) Seroconversion
7) IgA conversion in stools

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19
Q

Aspect of rotavirus infection that leads to diarrhoea

A

Destruction of absorptive capacity of vili

NSP4 (viral toxin)

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20
Q

What are rotavirus neutralising antibodies directed against?

A

Either outer capsid protein (VP4 or VP7)
VP4 = P serotype
VP7 = G serotype

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21
Q

Serotyping of stool rotaviruses

A

ELISA to VP4 or VP7 give serotypes

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22
Q

Genotyping of stool rotaviruses

A

Nested-set RT-PCR

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23
Q

Most-common rotavirus G serotypes in humans

A

VP7 type 1, 2, 3, 4, 9

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24
Q

Number of G types in humans

A

Over 27

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25
Q

Most common P serotypes in humans

A

VP4 1A8, 1B6, 2A4

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26
Q

How is serotype diversity generated in rotavirus?

A

Genome reassortment

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27
Q

Do VP4 and VP7 serotypes reassort dependently?

A

No. They reassort independently

28
Q

Multiplicity of infection

A

Proportion of infectious viral particles to a single cell

29
Q

Is affinity of a viral ligand/receptor interaction normally high?

A

No. Normally low, but increases in avidity due to multivalent interactions with one or more receptors

30
Q

Rotavirus binding and entry to host cell
1)
2)
3)

A

1) VP4 cleaved by trypsin to VP5 and VP8
2) Initial attachment of VP8 to glycans (sialic acids or histo-blood group antigens)
3) Binding and entry via endocytosis. Mediated by VP5 and VP7 interactions with integrins. Complexes of glycans and/or integrins in lipid rafts may be involved

31
Q

Sialidase-sensitive rotaviruses

A

Attach to terminal sialic acids.

These can be cleaved by sialidase.

32
Q

Sialidase-resistant rotaviruses

A

Attach to branched (internal) sialic acids.

These normally can’t be cleaved by sialidase

33
Q

Main human sialidase-resistant rotaviruses

A

Wa, RV-3

34
Q

Human rotavirus that attaches to A-type histo-blood group antigen

A

RV-3

35
Q

Two groups of sialidase-sensitive rotaviruses

A

1) Acetyl.
2) Glycolyl
Based on group attached to terminal sialic acid

36
Q

What do human rotaviruses Wa and RV-3 bind to?

A

Branched sialic acid on ganglioside GM1

37
Q

Gangliosides

A

Glycolipids

38
Q

What on a rotavirus determines the glycan class that it binds to?

A

VP8 architecture

39
Q

VP4 conformation change in call entry

A

Hydrophobic domain is revealed upon attachment, fuses with cell membrane

40
Q 
Methods of defining viral receptor specificity
1)
2)
3)
4)
5)
A

1) Receptor ligand (EG: anti-receptor antibody) blocks virus attachment
2) Structural studies of receptor-ligand complexes
3) Cell expression of DNA for receptor confers susceptibility
4) Glycan array analysis of virus receptor protein-glycan complexes
5) Bioinformatics - Presence of amino acid sequence in a virus protein

41
Q

VP5, VP7 integrin ligands

A

Type I collegen, fibrinogen

42
Q

VP5 integrin natural ligand

A

Integrin alpha2beta1 in type I collagen

43
Q

VP7 integrin natural ligand

A

Integrin alphaXbeta2 in fibrinogen

44
Q

What determines rotavirus ability to use integrins as cell receptors

A

VP4 serotype.

Independent of glycan, ganglioside usage

45
Q

Alpha2beta1 integrin in rotavirus infection

A

Rotavirus cellular receptor. Bound by VP4

46
Q

AlphaXbeta2 integrin in rotavirus infection

A

Rotavirus coreceptor. Bound by VP7

47
Q

Motif in VP4 that binds to alpha2beta1 integrin

A

DGE

48
Q

Relationship between type 1 diabetes and rotavirus infection
1
2
3

A

1) Correlation between rotavirus seroconversion and development of type 1 diabetes.
2) If infection occurs at 5 days - Increased Treg production, reduction in diabetes
3) Infection at 12 weeks - Increased diabetes incidence.

49
Q

Effect of rotavirus infection at 5 days on non-obese diabetic mice

A

1) Diarrhoea, extra-intestinal spread

2) Reduction in diabetes rate of development

50
Q

Effect of rotavirus infection at 12 weeks on non-obese diabetic mice
1
2
3

A

1) No diarrhoea.
2) Virus found extra-intestinally in mesentaric, pancreatic lymph nodes only
3) Increased rate of diabetes development

51
Q 
Proposed mechanism of diabetes acceleration by rotavirus in NOD mice
1
2
3
4
A

1) Plasmacytoid DCs activated by rotavirus
2) Viral RNA triggers TLR, pDCs release IFN1
3) T-, B-cells activated by IFN1.
4) Autoreactive CD8+ T cell presented autoantigen, begins killing beta cells in pancreas

52
Q

Proportion of infants infected by rotavirus by one year in developing and developed nations

A

80% in developing, 65% in developed

53
Q

Aim of rotavirus vaccines

A

Prevent severe gastro in first two years of life

54
Q

Where do rotavirus vaccines need to be administered?

A

Mucosally.

Secreted IgA in gut at time of rotavirus infection correlated with best outcomes in animals

55
Q

Most effective way to stimulate mucosal immune response in GIT against rotavirus

A

Infection involving local site

56
Q

Rotavirus vaccines
1
2
3

A

1) Heterologous lamb rotavirus
2) Partially heterologous reassortment rotaviruses - Rotashield, Rotateq
3) Culture-adapted rotavirus - Rotarix

57
Q

Rotashield
1
2

A

1) Partially-heterologous reassortment rotavirus
2) Rhesus rotavirus (RRV) with human rotavirus VP7. Seotypes G1, G2, G4
3) Quadravalent, live-attenuated vaccine

58
Q

Rotateq
1
2

A

1) Partially-heterologous reassortment rotavirus

2) Bovine rotavirus WC3 with culture-adapted human rotavirus P1 VP4 and G1-4 VP7

59
Q

Problem with Rotashield

A

Strong correlation between Rotashield and intussusception in infants (1 excess case per 20,000 infants vaccinated)

60
Q

Relationship between Rotashield and intussusception

A

1) Under 1 excess case per 20,000 infants vaccinated

2) Vaccination at 4-6 months of age associated with increased risk. Better to vaccinate younger

61
Q 
Rotarix
1
2
3
4
A

1) Monovalent, live-attenuated vaccine
2) Human G1 isolate with most-common VP4
3) 85-100% efficacy vs severe disease
4) 75% efficacy against any rotavirus disease

62
Q

Rotavirus strain that Rotarix is less-effective against

A

G2P4

63
Q 
Rotateq
1
2
3
4
A

1) Pentavalent, human-bovine reassortment vaccine
2) Has most-common human VP4 (P1A8) and VP7 (G types 1-4)
3) 98% efficacy vs severe disease
4) 41-92% efficacy against any rotavirus disease

64
Q

Rotateq efficacy under 2 years in Australia
1
2

A

1) 93% decline in rotavirus hospitalisations

2) 53-65% decline in rotavirus notifications

65
Q

Rotarix efficacy under 2 years in Australia

A

75% decline in rotavirus hospitalisations (93% in infants under 1 year)

Virology (29 decks)

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