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Virology > Lecture 33 - Rotavirus Pathogenesis and Disease > Flashcards

Lecture 33 - Rotavirus Pathogenesis and Disease Flashcards

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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
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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
Most common P serotypes in humans
VP4 1A8, 1B6, 2A4
26
How is serotype diversity generated in rotavirus?
Genome reassortment
27
Do VP4 and VP7 serotypes reassort dependently?
No. They reassort independently
28
Multiplicity of infection
Proportion of infectious viral particles to a single cell
29
Is affinity of a viral ligand/receptor interaction normally high?
No. Normally low, but increases in avidity due to multivalent interactions with one or more receptors
30
Rotavirus binding and entry to host cell 1) 2) 3)
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
Sialidase-sensitive rotaviruses
Attach to terminal sialic acids. | These can be cleaved by sialidase.
32
Sialidase-resistant rotaviruses
Attach to branched (internal) sialic acids. | These normally can't be cleaved by sialidase
33
Main human sialidase-resistant rotaviruses
Wa, RV-3
34
Human rotavirus that attaches to A-type histo-blood group antigen
RV-3
35
Two groups of sialidase-sensitive rotaviruses
1) Acetyl. 2) Glycolyl Based on group attached to terminal sialic acid
36
What do human rotaviruses Wa and RV-3 bind to?
Branched sialic acid on ganglioside GM1
37
Gangliosides
Glycolipids
38
What on a rotavirus determines the glycan class that it binds to?
VP8 architecture
39
VP4 conformation change in call entry
Hydrophobic domain is revealed upon attachment, fuses with cell membrane
40
``` Methods of defining viral receptor specificity 1) 2) 3) 4) 5) ```
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
VP5, VP7 integrin ligands
Type I collegen, fibrinogen
42
VP5 integrin natural ligand
Integrin alpha2beta1 in type I collagen
43
VP7 integrin natural ligand
Integrin alphaXbeta2 in fibrinogen
44
What determines rotavirus ability to use integrins as cell receptors
VP4 serotype. | Independent of glycan, ganglioside usage
45
Alpha2beta1 integrin in rotavirus infection
Rotavirus cellular receptor. Bound by VP4
46
AlphaXbeta2 integrin in rotavirus infection
Rotavirus coreceptor. Bound by VP7
47
Motif in VP4 that binds to alpha2beta1 integrin
DGE
48
Relationship between type 1 diabetes and rotavirus infection 1 2 3
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
Effect of rotavirus infection at 5 days on non-obese diabetic mice
1) Diarrhoea, extra-intestinal spread | 2) Reduction in diabetes rate of development
50
Effect of rotavirus infection at 12 weeks on non-obese diabetic mice 1 2 3
1) No diarrhoea. 2) Virus found extra-intestinally in mesentaric, pancreatic lymph nodes only 3) Increased rate of diabetes development
51
``` Proposed mechanism of diabetes acceleration by rotavirus in NOD mice 1 2 3 4 ```
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
Proportion of infants infected by rotavirus by one year in developing and developed nations
80% in developing, 65% in developed
53
Aim of rotavirus vaccines
Prevent severe gastro in first two years of life
54
Where do rotavirus vaccines need to be administered?
Mucosally. | Secreted IgA in gut at time of rotavirus infection correlated with best outcomes in animals
55
Most effective way to stimulate mucosal immune response in GIT against rotavirus
Infection involving local site
56
Rotavirus vaccines 1 2 3
1) Heterologous lamb rotavirus 2) Partially heterologous reassortment rotaviruses - Rotashield, Rotateq 3) Culture-adapted rotavirus - Rotarix
57
Rotashield 1 2
1) Partially-heterologous reassortment rotavirus 2) Rhesus rotavirus (RRV) with human rotavirus VP7. Seotypes G1, G2, G4 3) Quadravalent, live-attenuated vaccine
58
Rotateq 1 2
1) Partially-heterologous reassortment rotavirus | 2) Bovine rotavirus WC3 with culture-adapted human rotavirus P1 VP4 and G1-4 VP7
59
Problem with Rotashield
Strong correlation between Rotashield and intussusception in infants (1 excess case per 20,000 infants vaccinated)
60
Relationship between Rotashield and intussusception
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
``` Rotarix 1 2 3 4 ```
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
Rotavirus strain that Rotarix is less-effective against
G2P4
63
``` Rotateq 1 2 3 4 ```
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
Rotateq efficacy under 2 years in Australia 1 2
1) 93% decline in rotavirus hospitalisations | 2) 53-65% decline in rotavirus notifications
65
Rotarix efficacy under 2 years in Australia
75% decline in rotavirus hospitalisations (93% in infants under 1 year)

Virology (29 decks)

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