Gastroenteric viruses · Viruses infecting the gut Viruses associated with gastroenteritis •...
Transcript of Gastroenteric viruses · Viruses infecting the gut Viruses associated with gastroenteritis •...
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Jim Gray Professor of Clinical Virology, UEA & Consultant Virologist, NNUH
Gastroenteric viruses
Virus evolution and diversity: Keys to their success.
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Viruses infecting the gut Viruses associated with gastroenteritis
• rotaviruses • caliciviruses
• noroviruses • sapoviruses
• astroviruses • adenoviruses 40, 41
Noroviruses
Sapoviruses
Rotaviruses
Astroviruses
Adenoviruses
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• Family Reoviridae
• Unenveloped, icosahedral,
triple layered capsid (75nm diameter)
• Genome: 11 segments of dsRNA ~ 18,550bp (660bp – 3300bp) • Responsible for more than 500,000 deaths/ year in young children (1 in 285 children)
100nm
Rotavirus
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Rotavirus structure
VP4
VP2
VP6
VP7
Aqueous channel
dsRNA
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Rotavirus evolution
Three mechanisms are important for the evolution and diversity of rotaviruses • Genome rearrangement
• Antigenic drift
• Antigenic shift
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Rotavirus evolution
Antigenic drift: • Rate of mutation within rotavirus genes is relatively high because RNA replication is error-prone. • A rotavirus genome differs from its parental genome by at least one mutation. • Point mutations can accumulate to give rise to intratypic variation.
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DC14 DC2 DC4 S2 DC17 DC15 DC12 DC24 DC3 399/99 625/96 544/96 543/96 617/96 563/96 538/96 621/96 583/96 351/96 366/96 721/99 KU
G2 G2 G2 G2 G2 G2 G2 G2 G2 G2 G2 G2 G2 G2 G2 G2 G2 G2 G2 G2 G2
G1
P[4] P[4] P[4] P[4] P[4] P[4] P[4] P[4] P[4] P[4] P[4] P[4]
P[8]
London London London
London London London London London
Cambridge Cambridge Cambridge Cambridge Cambridge Cambridge Cambridge Cambridge Newcastle Newcastle
Aberdeen
Aberdeen
M11164 Cluster A (1991)
Cluster B (1996-99)
Phylogenetic tree constructed with cDNA sequences of 882bp fragments of the VP7 genes of G2 rotavirus strains.
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G2 rotavirus strains – VP7
Antigenic Site A
87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 DSI A E A K N E I S D D E W N T ES2 . . . . . . . . . . . . . . . HN126 T . . . . . . . . . . . . . . DC2/91 . . . . . . . . . . . . . . . DC3/91 . . . . . . . . . . . . . . . DC4/91 . . . . . . . . . . . . . . . DC12/91 . . . . . . . . . . . . . . . DC14/91 . . . . . . . . . . . . . . . DC15/91 . . . . . . . . . . . . . . . DC17/91 . . . . . . . . . . . . . . . DC24/91 . . . . . . . . . . . . . . . DC24/91 . . . . . . . . . . . . . . . DC22/91 . . . . . . . . . . . . . . . 543/96 T . . . . . . . . N . . . . . 544/96 T . . . . . . . . N . . . . . 536/96 T . . . . . . . . N . . . . . 583/96 T . . . . . . . . N . . . . . 538/96 T . . . . . . . . N . . . . . 621/96 T . . . . . . . . N . . . . . 625/96 T . . . . . . . . N . . . . . 366/91 T . . . . . . . . N . . . . . 617/96 T . . . . . . . . N . . . . . 351/96 T . . . . . . . . N . . . . . 399/99 T . . . . . . . . N . . . . . 721/99 T . . . . . . . . N . . . . .
E
Serotyped
Did not serotype
aa position
Alanine: threonine Aspartic acid: asparagine
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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 combinations • However, reassortment is not a random phenomenon and is influenced by the selection of progeny with viable gene combinations, the host cell and the immune status of the host.
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Dual Infection of an enterocyte by 2 parent viruses (A, B)
Progeny viruses
Rotavirus gene reassortment
G9P[6]
G1P[8]
G9P[6]
G1P[8]
G9P[8]
G1P[6]
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1995/96 G1P[8] 407 G1P[6] 2 G9P[6] 18 G9P[8] 1 G1+G9/P[8] 5 G1+G9/P[6] 2
Parental and daughter stains and multiple type combinations of rotavirus strains 1995/96
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1995/96 3 locations
1996/97 6 locations
1997/98 8 Locations
Geographical Distribution of Rotavirus G9 Strains in the UK during Three Consecutive Seasons
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Several findings suggest that rotavirus G9P[6] strains were introduced into the human population recently
• Relative lack of diversity between the VP7 genes and the
chronological clustering of all G9 strains.
• The associations between infection with G9P[8] strains and; Symptomatic infections in older individuals (older children
and adults) More severe disease requiring hospitalisation and iv-
rehydration Infection in a neonatal unit (lack of maternal protection) Infections predominantly in the urban population
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• G12 found in association with many P-types • G12 found throughout the world • Does this represent multiple introductions? • Can we identify an animal reservoir?
G12 rotavirus strains
100
9896949290
466-96/97892-96/97632-96/97873-96/97884-96/97480-96/97221-96/97
431-96/97414-97/98436-97/98107481-97/98114-97/98
GOS51117-95/96GOS51426-95/96GOS51996-95/96GOS52006-95/96GOS49314-95/96US1205 95/96651-95/96107071-97/98104907-97/98132-97/98422-97/98435-97/98426-97/98MY9919878-97/98MY919877-97/980.10-97/980.7-97/980.9-97/98103053-97/98101647-98/990.8-97/98105041-97/98
116E-L14072
G9G9G9G9G9G9G9G9G9G9G9G9
G9G9G9G9G9G9G9
G9G9G9G9G9G9G9G9G9G9G9G9G9G9G9
G9
P[8]P[8]P[8]P[8]P[8]P[8]P[8]P[8]P[8]P[8]P[8]P[8]
P[6]P[6]P[6]P[6]P[6]P[6]P[6]
P[8]P[6]P[8]P[8]P[8]P[8]
P[6]P[6]P[6]P[8]P[8]P[6]P[6]
P[11]
BirminghamPlymouthReadingBirminghamRhylBirminghamNewcastle
GOS51203-95/96 G9 P[6] London
LeedsLeedsLeedsBirminghamPeterborough
LondonLondonLondonLondonLondonUSALeedsBirminghamBirminghamPeterboroughLeedsLeedsLeedsMysore IndiaMysore IndiaLondon (OB)London (OB)London (OB)BirminghamBirminghamLondon (OB)Birmingham
India
II
III
IA
IB
100
9896949290
466-96/97892-96/97632-96/97873-96/97884-96/97480-96/97221-96/97
431-96/97414-97/98436-97/98107481-97/98114-97/98
GOS51117-95/96GOS51426-95/96GOS51996-95/96GOS52006-95/96GOS49314-95/96US1205 95/96651-95/96107071-97/98104907-97/98132-97/98422-97/98435-97/98426-97/98MY9919878-97/98MY919877-97/980.10-97/980.7-97/980.9-97/98103053-97/98101647-98/990.8-97/98105041-97/98
116E-L14072
G9G9G9G9G9G9G9G9G9G9G9G9
G9G9G9G9G9G9G9
G9G9G9G9G9G9G9G9G9G9G9G9G9G9G9
G9
P[8]P[8]P[8]P[8]P[8]P[8]P[8]P[8]P[8]P[8]P[8]P[8]
P[6]P[6]P[6]P[6]P[6]P[6]P[6]
P[8]P[6]P[8]P[8]P[8]P[8]
P[6]P[6]P[6]P[8]P[8]P[6]P[6]
P[11]
BirminghamPlymouthReadingBirminghamRhylBirminghamNewcastle
GOS51203-95/96 G9 P[6] London
LeedsLeedsLeedsBirminghamPeterborough
LondonLondonLondonLondonLondonUSALeedsBirminghamBirminghamPeterboroughLeedsLeedsLeedsMysore IndiaMysore IndiaLondon (OB)London (OB)London (OB)BirminghamBirminghamLondon (OB)Birmingham
India
II
III
IA
IB
G9 rotavirus strains
• Relative lack of diversity between the VP7 genes and the chronological clustering of all G9 strains. • May suggest single introduction
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G and P Genotype Combinations (%) 1995/96 1996/97 1997/98 1998/99 2005/06 2006/07
G1P[8] 56.9 86.5 73.1 92.1 51.8 59.7
G2P[4] 17.9 1.9 15.9 3.9 5.1 13.0
G3P[8] 6.3 4.2 0.4 0.3 9.8 5.2
G4P[8] 11.6 4.2 4.7 2.0 1.5 1.4
G1P[4] 1.5 1.2 0.8 0.1 0.0 0.3
G2P[8] 0.8 0.0 0.3 0.0 0.5 1.0
G4P[4] 0.1 0.2 0.2 0.0 0.2 0.0
G1P[6] 0.3 0.0 0.0 0.0 0.0 0.0
G1P[9] 0.0 0.1 0.2 0.3 0.0 0.0
G3P[6] 1.5 0.0 0.0 0.0 0.0 0.0
G3P[9] 0.1 0.0 0.0 0.0 0.0 0.0
G4P[6] 0.1 0.0 0.0 0.0 0.2 0.0
G8P[8] 0.0 0.0 0.2 0.0 0.0 0.3
G9P[8] 0.1 1.7 3.7 1.2 22.7 8.8
G9P[4] 0.0 0.0 0.0 0.0 0.0 0.4
G10P[4] 0.0 0.0 0.0 0.0 0.0 0.1
G12P[8] 0.0 0.0 0.0 0.0 2.4 1.0
G9P[6] 2.5 0.0 0.7 0.0 0.0 0.1
G12P[6] 0.0 0.0 0.0 0.0 0.0 0.1
Common genotypes
Reassortment among common genotypes
Zoonotic introduction
Reassortment between animal and human genotypes
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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
Noroviruses
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P domain
S domain
RNA genome
Inner shell
Calicivirus structure
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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 • faecal-oral route of transmission • limited heterotypic protection • absence of long term immunity
Mechanisms generating diversity among noroviruses
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NTPase Vpg Pro RdRp Capsid AAA….A
5 5374 6950 7585
6950 5385
NTPase Vpg Pro RdRp Capsid AAA….A
5 5374 6950 7585
6950 5385
NTPase Vpg Pro RdRp Capsid AAA….A
5 5374 6950 7585
6950 5385
+
Hawaii virus
Mexico virus
Hawaii/Mexico recombinant virus
Norovirus recombination
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GII-1 and GII-3 Recombinant norovirus
Hawaii GII-1
Mexico GII-3
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Mechanisms generating diversity among noroviruses
• Accumulation of point mutations • emergence of variants • antibody escape mutants
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Fort Lauderdale Saint Cloud
Alphatron
Jena
Newbury CH126
Blakemore
Winchester
DSV
Stavanger
KY89 Norwalk Hesse
Sindlesham
Southampton WhiteRose
Musgrove 318/S05/95
Thistle
Chiba
Malta
Koblenz
Bristol Lordsdale
Toronto Mexico
Seacroft
Sw43 Limburg
Leeds 273/Gwyned
M7
Amsterdam
VA97207 Idaho Fall
Fayetteville Kashiwa47
Erfurt 546
Snow Mountain Melksham Hillingdon
290/White River Girlington
Hawaii
Wortley/90 314/S19/94
GGII
GGIII
GGI
GGIV
MNV-1
GGV
Phylogenetic grouping among noroviruses
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Inter- and Intra-seasonal diversity of NoV genotypes during 2003 to 2006. Early, mid and late season outbreaks characterised.
Genotype 2003/04 2004/05 2005/06
Early Mid Late Early Mid Late Early Mid Late
GI-1 0 0 0 0 0 0 0 1 (5%) 0
GI-2 1 (5%) 0 0 0 0 0 0 0 0
GI-3 1 (5%) 0 0 0 0 0 0 1 (5%) 0
GI-4 0 0 0 0 0 0 0 3 (15%) 0
GI-6 2 (10%) 0 0 0 0 0 0 0 0
GII-1 0 0 0 0 0 1 (5%) 0 1 (5%) 0
GII-2 3 (15%) 1 (5%) 0 4 (20%) 2 (10%) 0 0 1 (5%) 0
GII-3 7 (35%) 3 (15%) 2 (10%) 0 0 0 0 2 (10%) 0
GII-4 1 (5%) 14 (70%) 18 (90%) 14 (70%) 18 (90%) 18* (90%) 9 (45%) 7 (35%) 18 (90%)
GII-6 1 (5%) 0 0 2 (10%) 1 (5%) 0 2 (10%) 0 1 (5%)
GII-7 3 (15%) 2 (10%) 0 0 0 1(5%) 6 (30%) 3 (15%) 1 (5%)
GII-8 1 (5%) 0 0 0 0 0 0 1 (5%) 0
Total 20 20 20 20 20 20 20 20 20
Total of
genotypes
3 GI
6 GII
4 GII 2 GII 3 GII 3 GII 2 GII 4 GII 3 GI
6 GII
3 GII
Early = September/October, Middle = December, Late = March, GII = Genogroup II, GI = Genogroup I, * = February and March
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Emergence of GII-4 variants
0%
20%
40%
60%
80%
100%
Sep
-03
Nov
-03
Jan-
04
Mar
-04
May
-04
Jul-0
4
Sep
-04
Nov
-04
Jan-
05
Mar
-05
May
-05
Jul-0
5
Sep
-05
Nov
-05
Jan-
06
Mar
-06
May
-06
Jul-0
6
Sep
-06
Nov
-06
Jan-
07
Mar
-07
May
-07
Jul-0
7
Sep
-07
v11v10v8v6v5v4v3v2
GII-4 variants: September 2003 to September 2007
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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
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A
B
A
B
A
B
A
B
A
B
Pre-2002 2002 epidemic
Structural changes on the P2 domain between GII-4 variants
Molecular surface
Electrostatic surface
Monoclonal antibodies raised against the pre-2002 GII-4 strains do not react with the 2002 GII-4 strain and vice versa.
Pre-2002 2002
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Autum Winter Spring Summer Autum Winter Spring Summer
GII4 variant is selected, out of season outbreaks occur, becomes epidemic
Normal winter season
Narrowing diversity: GII4 predominates
GII4 variants emerge
Return to normal season, wide diversity at the beginning, narrowing as season progresses.
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.
Autum Winter Spring Summer
Normal winter season Normal summer activity
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.
Epidemic winter season Unusual summer activity
2002/03 epidemic
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• Low infectious dose ~ 10-100 virus particles • Noroviruses 107 particles per gram/ml • Rotaviruses 1011 particles per gram/ml
• Stability in the environment • Norovirus survives up to 80oC • Rotavirus survives in the environment for months
• Protected by the matrix – faeces and vomit, which also inactivate chlorine-based disinfectants • Non-enveloped viruses – resistant to many disinfectants and alcohol • Short term immunity ~ 6 months • 16% of the population excrete NoV in the absence of symptoms • 14% of the population excrete rotavirus in the absence of symptoms
Keys to the success of gastroenteric viruses
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• Multiple routes of transmission - person to person contact, through ingestion of contaminated water or food or by contact with contaminated environmental surfaces • RNA genome replication results in the accumulation of point mutations • Segmented rotavirus genome replication results in reassortment • Dual infections can result in recombination or reassortment • Rotaviruses are associated with zoonotic infection • Hospital-acquired infections are predominantly associated with GII-4 • There are multiple introductions into hospitals, of variants of GII-4, throughout the NoV season and many rotavirus strains co-circulate in the human population • Antibody-escape mutants and rotavirus reassortants are selected and driven by herd immunity resulting in epidemics in an immunologically naive population
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Acknowledgements
Centre for Infections, HPA David Brown Miren Iturriza-Gomara Chris Gallimore David Allen Jacqueline Xerry Juliet Adigwe Farah Aladin Sameena Nawaz
Cambridge University Ulrich Desselberger
Norfolk and Norwich University Hospital Sarah Morter Stephen Brolley Emma Meader