Norovirus

Question 1

What is the impact of gastroenteritis?

Answer 1

Causes deaths of 1.45 million a year, many in under 5s in africa and SE asia
Is the second most common cause of child deaths

Question 2

What is the classification of Norovirus?

Answer 2

Positive sense RNA virus. Is a Caliciviridae of which there are 5 subtypes, including Norovirus and Sapovirus (which is similar but we get life long immunity to it).

Question 3

How was Norovirus identified?

Answer 3

Faecal material was filtered and mixed with immune sera pre and post challenge to pull down the virus. This was then analysed with an electron microscope

Question 4

What are the sub categories of norovirus?

Answer 4

There are 7 genogroups, genogroups 1, 2, 4 infect humans

Question 5

What is the structure of Nororviruses?

Answer 5

Are icosahedral with a single protein VP1

Question 6

What is the impact of Norovirus infection in the UK?

Answer 6

Loads of infections but some are asymptomatic. Many hospitalisations occur with beds being taken - is a high cost. Virus also spreads easily in the close environment of a hospital

Question 7

What is the infection pattern of norovirus?

Answer 7

Is seasonal (peaks in weeks 5-8 of the year). Unsure why - could be due to spending more time indoors (transmission opportunities) or UV sensitivity or lower temperature and rainfall (spillovers) or slow population immunity or emergence of variants.

Question 8

How does norovirus spread?

Answer 8

By droplets in vomit. Virus is very stable. Also through shellfish (virus accumulates in the intestine and is infectious if eaten uncooked), food watered with decal contaminated water, infected food handlers.

Question 9

What features of norovirus makes it so problematic?

Answer 9

Low infectious dose (20 particles)
Prolonged asymptomatic shedding (over 3 weeks)
Environmentally stable (can survive low chlorine doses and heating to 60)
Strain diversity (antigenic shift and drift)
Lack of lasting immunity

Question 10

How does norovirus evolve?

Answer 10

Through antigenic drift and shift. Isn’t segmented but can recombine with each other in the subgenomic region to get a brand new capsid

Question 11

Why is norovirus immunity short lasting?

Answer 11

Infection is short and limited to the intestine so there is no time to generate potent antibodies

Question 12

What is the problem of norovirus to the immunocompromised?

Answer 12

Can have chronic norovirus infections and can die from complications due to malnutrition - get a smooth intestine so can’t absorb nutrients.
This can be due to genetics or cancer therapy or stem cell therapy

Question 13

How can we study norovirus?

Answer 13

Can grow inefficiently in B cells and can to organoid cultures. Can look at murine norovirus in mice (where a lot of studies were done) but it is a persistent long term infection and don’t tend to get diarrhoea. Can also use other Caliciviruses e.g. RHDV (Lago virus) and FCV (a Vesivirus - feline calicivirus)

Question 14

Describe the norovirus genome

Answer 14

Single positive strand mRNA of 7.5kb, covalently attached to VPg at the 5’ end. 3 ORFs (sometimes 1 and 2 are fused). ORF 1 produces a polyprotein similar to picornaviruses which is cleaved by an internal protease. ORF 2 encodes the capsid, ORF 3 encodes the minor capsid. Murine norovirus has ORF 4 which is to do with the interferon response

Question 15

How does norovirus enter cells?

Answer 15

Binds the histoblood group antigens as the receptor to get the RNA into the cytoplasm

Question 16

How does norovirus synthesis its proteins?

Answer 16

The genome recruits ribosomes to the 5’ end for protein synthesis. VPg acts as a cap substitute and the mRNA is bicistronic with an IRES. VPg binds eIF4G gin the central domain

Question 17

How does norovirus replicate its genome?

Answer 17

Makes full length genomic and subgenomic RNA (subgenomic only encodes VP1 and VP2, promoter is a small stem loop on the antisense RNA). The polymerase and VP1 is necessary and this makes a dsRNA intermediate.

Question 18

How is norovirus packaged?

Answer 18

The full length genome is packaged with 180 copies of VP1 and at least 2 copies of VP2 (unpublished data suggests maybe 6)

Question 19

What is the case for a norovirus vaccine?

Answer 19

Doesn’t really kill people in the developed world, but if we had a vaccine that was 50% effective and only lasted 12 months we would be predicted to save a lot of money if it was under £50.

Question 20

How can a norovirus vaccine be produced?

Answer 20

Can’t really do attenuated vaccine as have only just been able to grow the virus
Subunit vaccine is possible - can express VP1 in large quantities and can form virus like particles.

Question 21

Can you get an immune response to norovirus?

Answer 21

Is difficult - in a study 12 people were challenged, but only 6 became clinically ill. Of those 6, they all fell ill again when challenged 1-2 years later. Suggests there is no such thing as long lasting immunity and that not everyone is equally susceptible

Question 22

What determines the susceptibility for an individual to norovirus?

Answer 22

Blood group type and secretor status - if don’t secrete blood group then are more resistant and need a high infectious dose.

Question 23

What is the hope of controlling norovirus?

Answer 23

Have had some vaccine trials with limited success - found that vaccine didn’t reduce number of people infected significantly, but did reduce signs of clinical illness and viral shedding (just about significant…).
However, we need antivirals to treat chronic cases, and vaccines can’t be rolled out in a year so aren’t suitable for an outbreak.