Influenza viruses Holly Shelton holly.shelton@pirbright.ac.uk
Preventing and controlling viral diseases
Influenza Viruses • Orthomyxoviridae • Negative sense RNA virus • 7 or 8 segments • Enveloped • 4 Subtypes; A,B, C, D Electronmicrograph of influenza virus particles. (Courtesy of Linda M. Stannard, University of Cape Town). http://virology- online.com/viruses/Influenza.htm Subtype Natural Host Disease Other Species Infected Frequent, Mild – Severe, A Wild aquatic birds Humans, Poultry, Horses, pandemic potential Pigs, Dogs, Tigers, Cats, Ferrets, Seals, Whales & others B Humans Frequent - Mild Seals Rare – Mild C Humans Pigs D Cattle Mild Pigs
Influenza virus structure A transmission electron micrograph of MDCK cells infected with influenza A/Netherlands/602/2009 (H1N1) virus is shown at a magnification of ×40,000. (Seladi-Schulman et al. Journal of Virology Nov 2013, 87 (24) 13343-13353; DOI: 10.1128/JVI.02004-13 )
Influenza A virus proteins Core Accessory Proteins Proteins HA PB1-F2 NA PB1-N40 M2 PA-X M PA-N155 PB1 PA-N182 PB2 M3 PA M42 NS1 NS3 NEP NEG8 NP PB2-S1
Birds are natural hosts for influenza viruses Haemagglutinin Neuraminidase N10 N11 H16 H17 H18
Influenza A virus host range Bat H17N10 H18N11 Swayne, D.E. Epidemiology if Avian Influenza in Agricultural and Other Man-Made Systems. In: Avian Influenza. Wylie-Blackwell (www.blackwellpublishing.com). 2008
Human Infection H1N1 and H3N2 co-circulate in humans. 1977 1957 2009 ‘Russian flu’ 2003 ‘Asian flu’ ‘Pandemic H1N1 2009’ H1N1 H2N2 H7N7 H1N1 1918 1968 1997 2006 H5N1 ‘Spanish flu’ ‘Hong Kong flu’ H7N3 H3N2 H1N1 Symptoms • Fever & Chills • Lethargy • Aches – headache & muscular • Coughing & Sneezing • General discomfort • Conjunctivitis = pandemic • Pneumonia • Death
1918 – Spanish flu pandemic The influenza pandemic of 1918 killed 50 million people. Case fatality rate of 2%.
2009 - Swine flu pandemic The influenza pandemic of 2009 killed 250,000 people. Case fatality rate of 0.03%.
Treatment M2 inhibitors • Amantidine & Rimantadine No use as most viruses resistant. Neuramidase inhibitors • Oseltamivir (Tamiflu) • Zanimivir (Relenza) Increasing resistance being observed. Inhibitors of RNA-dependent RNA polymerase • Favipiravir; Pimodivir; Baloxavir acid
Vaccines UK Annual influenza vaccine Split virion inactivated vaccine 2 Influenza A strains and 1 Influenza B strain. Grown in hens eggs Live attenuated vaccines Intra-nasal administration Routine in the USA for years 2013 first introduction in the UK for children 2+ (Fluenz). Grown in hens eggs
Influenza virus entry is blocked by antibodies
Error prone replication leads to mutation accumulation. x x x Antigenic Drift • Slow accumulation of mutations • Can alter the epitopes which Abs recognise. • Immune evasion results.
Human impact from human virus infection Report from Norway published in 2012 suggests that influenza virus sick leave rate is around 1950 per 100,000 with around 10,300 days of work lost annually. ECDC 10 th Oct 2012. USA Centre for disease control reported in Feb 2018 that influenza causes US employees to miss approximately 17 million workdays which is estimated at $7 billion a year in sick days and lost productivity. Research by Longevity Centre UK (ILCUK) found that influenza vaccination prevents up to 626,000 infections per year in England and therefore approximately 6,000 premature deaths.
Avian influenza in birds Aquatic birds inc. shorebirds Domesticated Natural avian poultry influenza cycle Farm animals
Avian Disease Wild aquatic bird symptoms • No outward disease symptoms • Sudden death Poultry symptoms • Coughing/ sneezing • Decreased egg production • Soft shells and misshapen eggs • Nasal discharge • Swelling of eyelids, head, comb & wattle • Cyanosis • Diarrhoea • Lethargy • Fever • Lack of coordination (neurological signs) • Sudden death without warning
Prevalence of avian influenza in domesticated birds H9N2
H5Nx outbreaks in Europe 2017-2018
Wild bird migration brought the H5Nx virus to Europe from Asia.
Impact of H5Nx in Europe - During October 2016 and August 2017 29 European countries experienced poultry outbreaks. - 1.6 million birds culled in Europe over the 2016/2017 winter because of H5N8 outbreaks. - In winter 2016/2017 mandatory to keep poultry inside resulting in free-range status of some eggs and chicken being affected.
Chickens are one of the major livestock species used for food Economic Impact - H5N1 caused >$20 billion in economic losses since 2003 - H7N9 resulted in $6.5 billion loss for china in 2013 - LPAI losses often incalculable
How do we deal with outbreaks of avian influenza virus? Control mechanisms; - Stamping out – culls and quarantine • Can only take place in non-endemic countries • Leave livestock susceptible to future incursions - Vaccination in endemic countries • Virus variability means a limited to what protection is afforded • Cost of vaccination • How long it takes for immunity to develop, average meat birds have a life span of 6 to 8 weeks. • Differentiation between infected and vaccinated animals (DIVA) hard meaning certain trading routes cut off.
Making better vaccines – viral vectors HVT – Herpes Virus of Turkeys DEV – Duck Enteritis Virus Vector
Making better vaccines – protecting against multiple strains or pathogens
Zoonotic risk from avian influenza virus LPAI Natural Reservoir HPAI Humans Wild Aquatic Birds Domestic Poultry
Human cases of avian influenza infection since 2003. Virus Number of Number of Case fatality rate human cases human deaths H5N1 860 454 52.8% H7N9 1625 623 38.3% H6N1 1 0 0% H9N2 42 0 0% H10N8 1 0 0% H7N7 85 1 1.1% H5N6 19 6 31.5% H7N3 2 0 0% H7N4 1 0 0%
No human to human transmission of avian influenza viruses
What characteristics do Influenza viruses require to replicate and transmit efficiently in the human population?
Receptors Attachment – HA binds sialic acid receptors. Sialic acid
Linkage of sialic acid to the sugar chain OH COOH OH OH H O H O O O O OH AcHN O H O H O H O H O OH OH OH Sialic Acid Lactose OH COOH OH H O OH O O O Avian AcHN O Protein H O H O O H O OH OH OH Sialic Acid-(a-2,3)-Lactose OH COOH H O Human O O OH AcHN H O H O H O O O O H O Protein H O OH OH Sialic Acid-(a-2,6)-Lactose
Avian and human influenza viruses bind to different types of sialic acid receptors. α -2,3 2,3 α -2,6 2,6 Cell Cell Why are the receptors different for human and avian influenza viruses? Site of replication differs Avian infection: Human infection: Intestinal tract - Colon Upper respiratory tract
Sialic acid in chickens Trebbien et al., Virology (2011) 8:434
Sialic acid in humans Eriksson et al., Scientific reports (2018) 8:12215
Amino acid residues in the HA receptor binding site can alter the preference for sialic acid linkage. H3 subtype (1968) – Matrosovich et al. 2000 a 2,3 a 2,6 Amino acid 226 228 Avian Q G ++ - Human L S + + H1 subtype (1918) – Tumpey et al . 2007 Amino acid 190 225 Avian E G ++ - Human D D + + Source: Stevens et al ., Science, 2004
Some H5N1 avian strains found in Egypt and some H7N9 isolates contain molecular signatures that predict binding to human receptors.
Stability Transmission mechanism is different between human and birds - Humans - respiratory droplets Aquatic birds – Faecal/ oral. - PH 5-6 PH 7.5-8.4
Influenza virus membrane fusion Figure with thanks to Dr Thomas Peacock: Schematic for proposed mechanism of influenza A HA- membrane fusion. A) Binding of HA to SA on surface of host cell. B) as pH drops HA head domain moves away and fusion peptide is inserted into host membrane. C and D) The HA fusion peptide and transmembrane domain contract together pulling the host and viral membrane together forming the fusion pore.
Host Range Restriction of Influenza A virus – Stability Human viruses more stable at low PH. Shelton et al 2013
Host Range Restriction of Influenza A virus – Replication mRNA mRNA cRNA vRNA Temperature Sensitivity • Polymerase complex is a enzymatic complex – Optimal temperature for activity. • Human upper respiratory tract is ~ 33°C. • Avian gut is ~ 41°C. Interaction with host factors • Polymerase complex recruits host factors in the nucleus. • Differences between interaction partners in humans verus birds.
Changes in PB2 adapts avian influenza for growth in mammalian cells. Avian virus Avian virus Avian virus Human virus + PB2 (human) + PB2 (human) E627K mutation in avian PB2 sufficient to allow growth in mammalian cells
Some H5N1 and H7N9 strains already contain the E627K mutation.
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