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Enteric viruses

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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Enteric viruses

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  1. Enteric viruses Mechanisms for generating diversity Jim Gray Enteric Virus Unit CfI, HPA

  2. Viruses infecting the gut • Viruses associated with gastroenteritis • rotaviruses • caliciviruses • noroviruses • sapoviruses • astroviruses • adenoviruses 40, 41 Rotaviruses Sapoviruses Adenoviruses Astroviruses Noroviruses

  3. 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

  4. Viruses infecting the gut • Presumptive enteric viruses • Torovirus • Coronavirus • Parvovirus • Picobirnavirus • Aichi virus Torovirus Coronavirus Parvovirus

  5. Viral gastroenteritis – testing strategies • Outbreak investigation • Sporadic cases • Environmental contamination • Contamination of food • Recombinants, reassortants and variants • Zoonosis

  6. Rotavirus • Family Reoviridae • Unenveloped, icosahedral, • triple layered capsid (75nm diameter) • Genome: 11 segments of dsRNA • ~ 18,550bp (660bp – 3300bp) 100nm

  7. 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

  8. 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

  9. 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

  10. 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

  11. Parental and daughter stains and multiple type combinations of rotavirus strains 1995/96

  12. 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

  13. Identification of zoonotic infections zoonosis Animal Human • This segregation or interspecies clustering is observed with the genes encoding NSP4 and VP6

  14. Rotavirus Surveillance in the UK

  15. Geographical distribution of G12 and G8 strains G12 G8P[4] G8P[8] 26 strains clustered within Yorkshire in 2009

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. Mechanisms generating diversity among noroviruses • Accumulation of point mutations • emergence of variants • antibody escape mutants

  26. 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

  27. GII-4 variants: September 2003 to September 2007

  28. 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

  29. 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

  30. 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

  31. 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

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