Animal-Human Interface Module-2

Learning Objectives Understand how Influenza A is spread in poultry Understand how highly pathogenic avian influenza outbreaks happen Understand reasons for emergence of novel viruses Understand host restriction of AI in human Upon completion of this module, you will: Understand how Influenza A is spread in poultry; Understand how highly pathogenic avian influenza outbreaks happen; and Understand host restriction of AI in human

Avian Influenza A Viruses Infect respiratory and gastrointestinal tracts of birds Infections do not usually cause disease in wild waterfowl (wild ducks and geese) Genetic re-assortment occurs Viruses are shed in respiratory secretions and feces Can survive at low temperatures and low humidity for days to weeks Can survive in water Disinfection of the environment is needed

Species Infected by Influenza A: HA and NA Subtypes This figure illustrates the range of species that Influenza A sub-types can infect. The species that specific HA subtypes can infect are listed on the left, and the species that specific N1 subtypes can infect are listed on the right. Note that wild migratory waterfowl can be infected with all subtypes. Within the H5 and H7 subtypes, certain strains can be severe. H11 H12 H13 H14 H15,16

Pathogenicity of AI in Poultry Low Pathogenic Avian Influenza viruses (LPAI) Usually do not cause illness in wild birds May cause mild illness in domestic poultry Cause poultry outbreaks worldwide Can evolve into highly pathogenic viruses Highly Pathogenic Avian Influenza viruses (HPAI) Usually cause high mortality in domestic poultry Subtypes: H5, H7 Molecular and pathogenicity criteria

Evolution of Highly Pathogenic Avian Influenza Viruses (HPAI) Usually associated with mutation of the hemagglutinin precursor protein, that results in multiple cleavage sites (conveys pantropism) Other viral proteins may augment pathogenicity (e.g. NS1) All HPAI viruses to date have been H5 or H7, BUT not all H5 or H7 are HPAIs, many are LPAIs

Influenza: Hemagglutinin Cleavage Site for LPAI and HPAI HA0: Precursor Hemagglutinin Protein LPAIs have single basic amino acid cleavage points HPAIs have multiple basic amino acid cleavage points The H0 precursor protein is cleaved to the active form by host cellular proteases Human influenza viruses and LPAIs have single cleavage points Each cell type (respiratory or intestinal epithelium) has a unique protease capable of cleaving at that single point, so the virus only replicates efficiently in that cell type HPAIs have multiple cleavage points that convey “pantropism”, or the ability to replicate in multiple atypical cell types (e.g. liver, spleen, kidney, etc.), so the virus can achieve systemic replication

How does HPAI happens in poultry? Carried by migrating wild birds to domestic poultry or man introduces the virus to the birds Virus changes and becomes more deadly in poultry Difficult to control and eliminate because it spreads rapidly Of most concern when speaking of pandemic possibilities are the so-called highly pathogenic variations of influenza A (HPAI) – H5 or H7. When reassortment occurs and a new virus of the subtype H5 or H7 results, there is cause for great concern. These are the subtypes that have historically proved to be the most deadly. Since these most highly pathogenic subtypes have no natural reservoir, they must arise from a mutation or change that occurs when the HPAI virus is carried by a wild bird and introduced into domestic poultry. Thus, they are called highly pathogenic avian influenza, or HPAI. Through rapid change in the domestic poultry host, the previously stable virus becomes increasingly deadly. This makes the rapid detection of these subtypes of the utmost importance. If infection with the virus can be detected at an early stage, elimination/intervention should be possible. The importance of early detection cannot be overstated. Once the virus mutates into a more lethal form, not only can it cause pandemics in poultry (possibly leading to human infection); health officials might need to work for years to completely clear the virus from a particular geographic area.

Avian Influenza Outbreaks in India: That week in February, 2006 10 countries affected in 6 days from 15th February, 2006 onwards including India! Several thereafter!! Greece - 14.02.06 2. Azerbaizan - 15.02.06 3. Iran - 15.02.06 4. Germany - 16.02.06 (Re-occurrence earlier in 2003) 5. India - 18.02.06 6. Egypt - 18.02.06 7. Austria - 20.02.06 8. Bosina & Herzegovina - 20.02.06 9. France - 20.02.06 10. Italy - 22.02.06 (Earlier had in 2003)

Poultry Outbreaks 2006-2007, India Feb 2006 Outbreak, both commercial and backyard poultry affected Navapur-C 318k Uchhal-C: 90K Jalgaon-B: 613K Ichhapur-B: 9K Cost: >1 mil July 2007 Outbreak in small poultry farm Birds culled: 336K Cost: $165K

Rapidly Evolving Genetic Diversity Evolution of H5N1 HA Gene Rapidly Evolving Genetic Diversity Hong Kong/156/97 Vietnam/JP14/05 ck/Cambodia/013LC1b/05 Vietnam/1194/04 Vietnam/1203/04 Vietnam/HN30408/05 Thailand/16/04 Vietnam/JPHN30321/05 Clade 1 Hong Kong/213/03 Indonesia/CDC523/06 Indonesia/CDC699/06 Indonesia/CDC326/06 Indonesia/5/05 Indonesia/CDC184/05 Indonesia/7/05 dk/KulonProgoBBVET9/04 ck/Indonesia/CDC25/05 Indonesia/6/05 ck/Brebes/BBVET2/05 Indonesia/CDC594/06 ck/Dairi/BPPVI/05 Clade 2 Subclade 1 ck/Yunnan/374/04 ck/Yunnan/115/04 ck/Yunnan/493/05 ck/Yunnan/447/05 dk/Guangxi/13/04 ck/Guangxi/12/04 whooping swan/Mongolia/244/05 bar headed gs/Qinghai/1A/05 * Turkey/65596/06 Turkey/15/06 Iraq/207NAMRU3/06 ck/Nigeria/641/06 mld/Italy/332/06 turkey/Turkey/1/05 Egypt/2782NAMRU3/06 Djibouti/5691NAMRU3/06 ck/Nigeria42/06 migratory dk/Jiangxi/2136/05 gs/Kazakhstan/464/05 ck/Krasnodar/01/06 Azerbaijan/011162/06 swan/Iran/754/06 Subclade 2 dk/Laos3295/06 Anhui/1/05 Anhui/2/05 Japanese white-eye/Hong Kong/1038/06 ck/Malaysia935/06 Vietnam/30850/05 Guangxi/1/05 dk/Hunan/15/04 qa/Guangxi/575/05 dk/Vietnam/Ncvdcdc95/05 Subclade 3 migratory dk/Jiangxi/1653/05 gs/Guangdong/1/96 Indonesia/CDC625/06 India

Avian Influenza A viruses H1 - H16 N1 - N9 Natural Reservoirs for Human Influenza A Virus Subtypes Human Influenza A Viruses Avian Influenza A viruses H1 - H16 N1 - N9 H1 - H3 H5?? Aquatic ducks and Geese

Viral Diversity And New Host Adaptation Viral diversity led by two different ways: antigenic “drift” & “shift” Antigenic Drift: Gene mutations result in new strain variants One variant “predominates” for 1-3 years As viruses evolve, people immune to older viruses become more susceptible to newer strains Necessitates annual updating of vaccine strains Antigenic Shift” Emergence of “novel” influenza A subtypes among humans Current candidates: H2 and H4-16 viruses Relatively Infrequent Potential for pandemic if person to person can be sustained

Implications of “Shift” No one has pre-existing immunity Potentially More infections More serious illnesses among those infected Longer, atypical seasons New “high risk” groups beyond usual groups Potential initiation of a global pandemic 1918 ……..A(H1N1)… Spanish flu 1957 ……..A(H2N2)… Asian flu 1968 ……..A(H3N2)… Hong Kong flu

Circulation of Influenza A Viruses in Humans in the 20th Century H1N1 H1N1 H2N2 H3N2 Spanish Influenza Asian Influenza Hong Kong Influenza 1918 1957 1968 1977 ? 16 HA subtypes 9 NA subtypes Influenza A reservoir Ag drift ? Ag shift

Potential Influenza A Viruses in Humans in the 21th Century H?N? H1N1 H2N2 H3N2 Spanish Influenza Asian Influenza Hong Kong Influenza H5N1 20?? 1918 1957 1968 1977 ? 16 HA subtypes 9 NA subtypes Influenza A reservoir ?

Why is H5N1 (Bird Flu) Important? Lethal to poultry (economic impact) and humans Infects many species of birds (endemic) and mammals Present in healthy waterfowl - shed in feces Potential for evolution to pandemic form No human H5N1 vaccine commercially available Limited supply of expensive antiviral medicines Potential for major economic, social and political impact

Influenza HA Receptor Preference: Distribution of Sialic Acid Human influenza viruses prefer αlpha 2,6 linkages Avian influenza viruses prefer αlpha 2,3 linkages Human Sia(2-6)Gal Avian Sia(2-3)Gal Humans possess predominantly α 2, 6 receptors throughout the respiratory tract, with some α 2, 3 receptors deep in respiratory tract

Bird to Human Transmission Remains a Rare Event (as of yet) Continuing H5N1 evolution in multiple hosts could make spread more common Virus ‘learns’ to use alpha 2-6 linkages commonly found in human upper respiratory tract Mutation or reassortment could transform H5N1 to a virus capable of sustainable human-to-human infection causing a pandemic Can not predict future: other more virulent form of bird virus may emerge

Pandemic Threat of H5N1 in Asia Good news: No evidence of sustained human-to-human transmission of H5N1 viruses Bad news: H5N1 viruses are circulating widely among poultry in Asia - cannot be eradicated soon. Sporadic H5N1 human infections have caused severe illness, high mortality Probable limited person-to-person transmission has occurred When is the pandemic coming? Unknown?????? H5N1 is not the only avian influenza A virus to worry about Circulation of H5N1 viruses among poultry must be controlled WHO Pandemic alert period: Phase 3

Summary HPAI H5N1 is an avian virus HPAI H5N1 prefers to attach to cells with galactose linked in an α 2, 3 orientation Humans possess some receptors with the α 2, 3 orientation in their lower respiratory and gastrointestinal tract HPAI H5N1 currently infects humans with great difficulty Infected poultry (chickens and waterfowl) or poultry products is the only currently known source of spread to humans of the disease except for lateral transmission in rare family cluster outbreaks Certain risk behaviors will predispose individuals to infection