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Enteric viruses. Mechanisms for generating diversity. Jim Gray Enteric Virus Unit CfI, HPA. Viruses infecting the gut. Viruses associated with gastroenteritis rotaviruses caliciviruses noroviruses sapoviruses astroviruses adenoviruses 40, 41. Rotaviruses. Sapoviruses.

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slide1

Enteric viruses

Mechanisms for generating diversity

Jim Gray

Enteric Virus Unit

CfI, HPA

slide2

Viruses infecting the gut

  • Viruses associated with gastroenteritis
    • rotaviruses
    • caliciviruses
      • noroviruses
      • sapoviruses
    • astroviruses
    • adenoviruses 40, 41

Rotaviruses

Sapoviruses

Adenoviruses

Astroviruses

Noroviruses

slide3

Viruses infecting the gut

  • Viruses associated with systemic infections
    • enteroviruses
    • parechoviruses

enteroviruses

  • Viruses associated with infection in the immunocompromised
    • adenovirus types 42-48
    • cytomegalovirus
    • human immunodeficiency virus
slide4

Viruses infecting the gut

  • Presumptive enteric viruses
    • Torovirus
    • Coronavirus
    • Parvovirus
    • Picobirnavirus
    • Aichi virus

Torovirus

Coronavirus

Parvovirus

slide5

Viral gastroenteritis – testing strategies

  • Outbreak investigation
  • Sporadic cases
  • Environmental contamination
  • Contamination of food
  • Recombinants, reassortants and variants
  • Zoonosis
slide6

Rotavirus

  • Family Reoviridae
  • Unenveloped, icosahedral,
  • triple layered capsid (75nm diameter)
  • Genome: 11 segments of dsRNA
  • ~ 18,550bp (660bp – 3300bp)

100nm

slide7

Virus diversity

Rotavirus Genotype distribution

This extrapolates to 57,265 cases out of the 3,579,070 expected in the population under surveillance by EuroRotaNet

Potential reservoir for reassortment

slide8

Rotavirus evolution

  • Three mechanisms are important for the evolution and diversity of rotaviruses
  • Genome rearrangement
  • Antigenic drift
    • the possible vaccine-induced emergence of antibody escape mutants
  • Antigenic shift
    • the possible emergence in the general population of reassortants between two co-circulating rotavirus strains
  • Zoonosis
    • the possible emergence of animal/human
    • rotavirus reassortants
slide9

Rotavirus evolution

  • Antigenic shift
  • Shuffling of gene segments through reassortment can occur during dual infection of one cell
  • If reassortment occurs at random, the 11 segments of the 2 parental strains can reassort into 211 possible gene combination
slide10

G9P[6]

G1P[8]

G9P[8]

G1P[8]

G1P[6]

G9P[6]

Rotavirus gene reassortment

Dual Infection of an enterocyte

by 2 parent viruses (A, B)

Progeny

viruses

slide12

1995/96

1997/98

1997/98

1996/97

1996/97

In 2005/2006 G9P[8] was the predominant strain in some European countries and the second most common strain in the UK

8 Locations

8 Locations

6 locations

6 locations

3 locations

Geographical Distribution of Rotavirus G9 Strains

Geographical Distribution of Rotavirus G9 Strains

in the UK during Three Consecutive Seasons

in the UK during Three Consecutive Seasons

slide13

Identification of zoonotic infections

zoonosis

Animal

Human

  • This segregation or interspecies clustering is observed with the genes encoding NSP4 and VP6
geographical distribution of g12 and g8 strains
Geographical distribution of G12 and G8 strains

G12

G8P[4]

G8P[8]

26 strains clustered within Yorkshire in 2009

g8 vp7 encoding gene three genetic clusters
G8 VP7 encoding gene: Three genetic clusters

Bovine and human strains

associated with P[6] or P[14]

Australia, Argentina, Itly, Japan, US, Japan and UK

1980-2007

Multiple zoonotic introductions

Bovine, porcine, simian and human strains

associated with P[6], P[10] or P[14]

Malawi, Kenya, Congo, Cameroon, South Africa, Egypt, India, Thailand and Tajikistan

1990-2007

Human strains

Associated with P[6], P[4] or P[8]

Cameroon, Tunisia, Ivory Coast, Ethiopia, Slovenia and UK

2000-2009 with less diversity seen in the last 3 years

Reassortment leading to adaptation in the human host

slide17

Noroviruses

Noroviruses

  • Family : Caliciviridae
  • Non-enveloped small round structured viruses (27-32 nm diameter)
  • Genome: pos sense ssRNA ~ 7.5kb
  • Predominantly epidemic
  • The most common cause of outbreaks of gastroenteritis
slide18

Alphatron

Fort Lauderdale

Saint Cloud

Phylogenetic grouping among noroviruses

Fayetteville

Snow Mountain

Melksham

Kashiwa47

Hillingdon

Erfurt 546

290/White River

GGIII

Girlington

Idaho Fall

Hawaii

VA97207

314/S19/94

Wortley/90

Amsterdam

Jena

M7

273/Gwyned

Leeds

GGIV

Limburg

Sw43

Seacroft

Newbury

Mexico

CH126

Toronto

GGII

Bristol

Lordsdale

Blakemore

Chiba

Winchester

Koblenz

Thistle

MNV-1

Malta

GGV

Virus diversity

GGI

318/S05/95

DSV

Musgrove

Stavanger

WhiteRose

Norwalk

Southampton

KY89

Hesse

Sindlesham

slide19

Mechanisms generating diversity among noroviruses

Genetic Recombination

  • Requirements
  • co-infection of a single cell
  • relatedness of parental strains
  • Noroviruses
  • endemic co-circulation of genotypes
  • multiple infections associated with food and water borne spread
  • environmental contamination and virus survival
  • faecal-oral route of transmission
  • limited heterotypic protection
  • absence of long term immunity
slide20

ARGUS outbreak

  • Thirty-seven (10%) of the ships
  • company presented with abrupt
  • onset of gastrointestinal illness
  • The presentation was watery
  • diarrhoea, colicky abdominal pain,
  • and nausea with and without vomiting
  • Clinically the illness was consistent with a viral aetiology
  • Outbreak was controlled by standard infection controls measures
  • Routine bacteriology on board was negative for the common enteric bacteria
  • Specimens were sent to CfI(Colindale) and six enteric viruses were detected in six patients; including noroviruses, sapoviruses and rotavirus

RFA Argus, Falmouth 2004

slide21

Patient

Virus

Genotype

Strain designation

1

Rotavirus

Group A rotavirus

2

Nvd

3

Norovirus

GII-6 (Seacroft/1990/UK)

Argus-3/2003/IQ

4-7

Nvd

8

Norovirus

GI-6 (Sindlesham/1995/UK)

Argus-4/2003/IQ

9

Sapovirus

Argus-2/2003/IQ

Argus-2/2003/IQ

10

Nvd

11

Norovirus

GI-3 (Desert Shield/1990/SA)

Argus-1/2003/IQ

12

Nvd

13

Norovirus

GI-6 (Sindlesham/1995/UK)

Argus-5/2003/IQ

A common food source was implicated in the outbreak and epidemiological analysis showed a statistically significant association with eating salad on a date 24-48 hours preceding the outbreak

slide22

Environmental monitoring for noroviruses in food outlets

  • Environmental swabs
  • Dipped in 0.1M PBS pH 7.2
  • Applied to sites within toilet facilities
  • Toilet flush handle
  • Toilet door handle
  • Wash basin taps
  • Applied to sites within kitchens
  • Fridge door handles
  • Preparation sites
  • Norovirus detected and characterised using
  • Real-time RT-PCR
  • DNA sequencing
slide23

Premises

  • A total of 39 premises in Hertfordshire were sampled
  • Noroviruses were detected in 16/39 (41%)
  • Noroviruses were detected on more than one visit in
  • 4/16 (25%) contaminated premises
  • Two norovirus genotypes were predominant, GII-3 and GII-4
  • Virus genotypes and variants were those seen in the
  • community at the same time
slide24

Contaminated sites within 16 premises

  • Toilet flush 10
  • Toilet door handle 7
  • Wash hand basin taps 7
  • Fridge handle 6
  • Fridge door 3
  • Preparation surfaces 5
  • 24 sites associated with the toilets and 14 with kitchen areas
  • Virus detected on one site on 11 occassions and on multiple sites on 8 occasions
slide25

Mechanisms generating diversity among noroviruses

  • Accumulation of point mutations
    • emergence of variants
    • antibody escape mutants
slide26

Inter- and Intra-seasonal diversity of NoV genotypes during 2003 to 2006. Early, mid and late season outbreaks characterised.

Highlights the fitness of GII-4 to infection the human population against a background of herd immunity

slide28

pre-2002

  • 2002 epidemic
  • 2006 epidemic

Molecular Surface

Homology modelling of amino acid changes at sites A and B on VA387 model structure

Monoclonal antibodies against sites A and B of the 2002 epidemic strain did not bind to sites A and B of the pre-2002 strains suggesting that the 2002 epidemic strain was an antibody-escape mutant

Electrostatic Surface

slide29

Neutral Networks: A model for NoV evolution

Method of representing random neutral drift between related proteins

Genotype populations that are linked by point mutation but are selectively neutral

Groups are defined by epitope structure, not sequence diversity

* as in Gallimore et al (2007)

  • 3 neutral networks
    • blue pre-2002 epidemic 2 clusters
    • orange 2002 epidemic – 2006 7 clusters
    • yellow 2006 epidemic 4 clusters

Time

Evolution

Allen DJ et al. PLoS One, 2008

slide30

2002/03 epidemic

Autum

Autum

Autum

Winter

Winter

Winter

Spring

Spring

Spring

Summer

Summer

Summer

Unusual summer activity

Normal summer activity

Epidemic winter season

Normal winter season

Normal winter season

Narrowing diversity:

GII4 predominates

GII4 variants emerge

GII4 variant is selected, out of season outbreaks occur, becomes epidemic

Return to normal season, wide diversity at the beginning, narrowing as season progresses.

Lack of short-term herd immunity to a new variant

  • Population protected in the short term against variant GII4
  • Population susceptible to other genotypes due to short-term immune protection.
  • GII4 dominate and have an advantage over other co-circulating genotypes.
  • replicative advantage
  • greater transmissibility associated with a lower infectious dose
  • larger proportion of the population susceptible through inherited genetic factors,
  • better survival of the virus in the environment,
  • a mechanism that allows the virus to evade immune surveillance to some degree.

Strain diversity

slide31

Factors associated with enteric virus diversity and disease transmission

  • Associated with endemic and epidemic
  • patterns of disease
  • The ability of the viruses to survive in the
  • environment
  • Multiple transmission routes – food, water,
  • person-to-person, environmental – infection with multiple
  • strains
  • Low infectious dose (Norovirus: 10 virus particles)
  • Short term immunity may allow infection by multiple strains
  • Diversity through genetic recombination or reassortment
  • Lack of proof reading during RNA replication – leads to
  • genetic variants
  • Re-infections and asymptomatic infections are common –
  • large reservoir of infection
  • Enteric virus infections are common in children and their carers