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The Threat of Influenza

The Threat of Influenza. Damara Gebauer Sai Jahann Bonnie Hart. Influenza . Overview Molecular Biology Clinical Bioweaponization. Influenza Overview. Commonly called “the flu”. It is a highly contagious disease caused by the influenza virus.

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The Threat of Influenza

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  1. The Threat of Influenza Damara Gebauer Sai Jahann Bonnie Hart

  2. Influenza • Overview • Molecular Biology • Clinical • Bioweaponization

  3. Influenza Overview • Commonly called “the flu”. It is a highly contagious disease caused by the influenza virus. • It is a disease of the respiratory system, namely the throat, nose and lungs. • Can affect people of all ages including healthy people and symptoms are seen suddenly.

  4. Influenza Overview • People most susceptible are the elderly, small children and immuno-compromised, although anyone can develop complications. • Complications include pneumonia, bronchitis, nose and ear infection. • “Stomach Flu” Myth • No aspirin for children or teenagers

  5. Influenza Overview • 10-20% of the US population come down with the flu each year. • ~36,000 Americans succumb to complications of the disease. 250,000 people die world wide. • Vaccines are the first line of defense. • Antiviral medication is also available • Viral receptor proteins are primary targets of vaccines and antivirals • Hemagglutinin (HA) and Neuraminidase (NA) are targeted viral proteins

  6. Influenza Strains • Single negative-stranded RNA virus • 3 Types: A, B, C http://web.uct.ac.za/depts/mmi/stannard/fluvirus.html

  7. Influenza Strains

  8. Type A www.omedon.co.uk/.../beans/ influenza%20virus.jpg

  9. Beware of Type A • 15 known HA subtypes: H1-H15 • 9 known NA subtypes: N1-N9 • While all subtypes can be found in birds, only H1-H3 and N1-N2 are known to circulate widely in humans. • H1-H3 are the only types known to have caused pandemics in humans • Pandemics arise from flu strains that have novel HA and NA proteins that people have no immunity to

  10. Beware of Type A • New strains can form by genetic re-assortment between animal and human strains. 1956 (Asian) and 1968 (Hong Kong) were formed this way. • Recently been discovered that wholly avian strains CAN directly infect humans • Epidemic occurred in 1997 in Hong Kong. 18 people were infected and 6 died from complications.

  11. Beware of Type A • Previously it was thought that humans could not be infected by wholly avian flu and that an intermediary step was required • Pigs were thought to be this intermediary step. • Avian or some other animal flu infected pigs, re-assortment occurs creating new strain which then has potential to infect humans. • 1997 Hong Kong incident showed pigs are not required to be intermediary step since re-assortment can occur directly in humans

  12. Avian flu: Why such a threat? • HA and NA surface proteins are generally not recognized by human respiratory cells • Wholly avian flu infects humans at a low frequency but has huge pandemic potential. • 1997 Hong Kong incident was first case of wholly avian flu infecting humans. Fortunately, flu could not spread from person to person.

  13. Avian flu: Why such a threat? • If avian strain were to spread from person to person, most of the population will have no prior immunity to the HA and NA proteins and a devastating pandemic could occur. • Also, if avian strain and common human strain infect host simultaneously, could get re-assortment and creation of a super influenza strain. • WHO and other organizations are watching Asia and other countries with avian flu outbreaks very closely

  14. Three Pandemics in 20th Century • 1918 Spanish Influenza– A(H1N1) • 1957Asian Influenza—A(H2N2) • 1968 Hong Kong Influenza—A(H3N2)

  15. Spanish 1918 Pandemic Influenza A H1N1 http://www.stanford.edu/group/virus/uda/

  16. Spanish Influenza 1918 • The most devastating flu pandemic the world had seen. • Named Spanish influenza because of the severe loss in Spain. 8 million people died in May 1918. • In the U.S, first signs were seen in early spring in military camps in Kansas, but received little attention because of the war in Europe.

  17. Spanish Influenza 1918 • By the fall, hospitals were overwhelmed with patients, many of whom were dying 2-3 days after exhibiting symptoms. • The pandemic was extremely sudden. No one was prepared. In the US, the average life span was reduced by 10 years. • ~675,000 American deaths.

  18. Spanish Influenza 1918 • 40 million people worldwide were dead from the flu. • Most striking was the high morbidity of young people (20-40 years old). • Influenza's full impact: millions of hospitalizations, secondary bacterial pneumonias, and middle ear infections in infants and young children. • Caused by H1N1 strain that resembled most closely swine origin.

  19. 1957 Asian Influenza—A(H2N2) • Re-assortment of avian and human strains. • Re-assortment thought to have occurred in pigs. • 70,000 deaths in America. First identified in China in February 1957, it spread to the US by June 1957

  20. 1968 Hong Kong Influenza—A(H3N2) • Also re-assortment of avian and human strains. • 34,000 deaths in America. Started in Hong Kong in early 1968 and spread to America by the end of the year. • A(H3N2) is still circulating in human population today.

  21. Influenza Today • Kills an average of 36,000 Americans every year and 250,000 around the world. • ~115,000 Americans are hospitalized for the flu each year http://www.nlm.nih.gov/medlineplus/news/fullstory_16132.html

  22. Recent News: Revenge of the Birds • 1997 Hong Kong A(H5N1)- First reported case of direct transmission from bird to human. • 1999 Hong Kong A(H9N2)- 2 children infected with avian flu and transmission was believed to be direct bird to human. Both children recuperated. • 2003 Hong Kong A(H5N1)- a father and son traveling to mainland came down with flu, father did not survive. Source of infection remains unknown.

  23. Recent News • 2003 Netherlands A(H7N7)- Outbreak of avian flu in farmed poultry. 80 poultry workers and their families became ill. There seemed to be some human to human transmission. One patient died. • 2003 Hong Kong A(H9N2)- One child became ill with avian flu but recovered. • Present day- Several Asian countries including China, Thailand, Vietnam, Indonesia and others are having outbreaks of avian flu among farmed poultry.

  24. Influenza: Molecular Biology • What differentiates influenza from other viruses? • How does an influenza virus particle interact with a host cell? • Why is it so contagious? So dangerous?

  25. Characteristics of viruses • Genome enclosed in protein shell • Can only reproduce within host cell • Each type of virus has specific “host range” • Reprogramming of cell • Copy viral genes • Manufacture viral proteins

  26. Structure of Influenza • Viral envelope • Surface studded with spikes • Matrix protein (M1) • 8 RNA segments • Non-structural proteins • Nuclear export protein (NEP) • NS1 protein • Nucleocapsid protein (NP) • Polymerase components

  27. Surface proteins of influenza A/B • Hemagglutinin (HA) • Rod-shaped • Binds virus to host cell to initiate infection • Brings about fusion • 15 types • Neuraminidase (NA) • Mushroom-shaped • Prevents viral aggregation upon release • 9 types

  28. Genome segments of influenza A

  29. Genome segments – encoding • 4: HA • 6: NA • 7: M1/M2 Matrix proteins • 5: Nucleoprotein (NP) • 1,2,3: Polymerase machinery (PB-2, PB-1, PA) • 8: Non-structural proteins: NS1, NEP

  30. Genetic variation of influenza A • Causes introduction of new, pandemic strains • Mutational frequency comparable to other viruses • Can’t be the only explanation • Unique ability to undergo antigenic variation • Antigen: interacts with cell and antibody • Antigenic drift: minor changes • Antigenic shift: major differences; new strains

  31. Genetic Variation: Antigenic Drift • Accumulation of point mutations eventually result in amino acid substitutions • HA glycoprotein: • Results in differences in key antigenic sites at which the host antibody binds • Prevent binding of antibodies induced by previous infection • Also occurs in NA glycoprotein

  32. Genetic Variation: Antigenic Shift • Involves replacement of entire gene segments • Results in novel viruses • Occurs suddenly in association with pandemics • Through dual infection: different influenza viruses infect a single cell • Does not occur in NA glycoprotein

  33. Genetic Variation: Antigenic Shift • One cell is infected by two different influenza A viruses • Not necessarily human flu • Inside the cell, spontaneous self-assembly can produce recombinant viruses • Those viruses bud out of cell and infect other host cells • A new flu strain is born!

  34. Infection cycle of influenza • Binding of virus to cell • Cell engulfs virus via endocytosis • Membrane of virus fuses with endosome; RNA released into cell • Viral polymerase produces mRNA from viral RNA • Protein, new RNA produced • Self-assembly produces virions • Virions bud off cell membrane

  35. Infection cycle: Binding and endocytosis • HA contains receptor binding site for virus • Binds to sialic acid residue on cell surface glycoprotein • Binding triggers receptor-mediated endocytosis • Virus is taken into endosome • Low pH of endosome causes fusion of viral and endosome membranes

  36. Infection cycle:Endocytosis and membrane fusion

  37. Infection cycle:Fusion of viral and cell membranes • Cleavage of HA is necessary • This allows fusion of membranes • HA cleaved at arginine in cleavage site • More arginines = more proteases cleaving • Mutated viruses can be cleaved by more proteases • Virus is more infective • More of the cells it attaches to will get exposed to viral genome.

  38. Infection cycle:Viral replication • Negative-sense viral RNA is transcribed to mRNA by viral polymerase (PB1, PB2, PA) • mRNA complements made for incorporation into new virions • mRNA translated to produce viral proteins • For incorporation into virions • For use in infected cell (NEP, NS1)

  39. Infection cycle:Viral budding • HA and NA incorporated into host cell membrane • M1 matrix protein forms shell, bound to: • Cytoplasmic tails of HA, NA • Viral ribonucleoproteins • Other M1 molecules • Virus buds off via exocytosis

  40. Host cell v. influenza A virus • Human cell has initial antiviral defenses • Interferon-α/β-independent response • Protein kinase R • Interferon-α/β response • Virus needs to counteract these to reproduce • NS1A protein

  41. Host cell v. influenza A virus • Interferon-α/β-independent protection • Upon infection by virus, activate transcription factors that control expression of antiviral genes • Interferon regulatory factor-3 (IRF-3), IRF-7 • Combine with coactivators to form virus-activated factor (VAF) • VAF induces transcription of genes that code for antiviral proteins

  42. Host cell v. influenza A virus • Protein Kinase-R (PKR) protection • Activated by presence of double-stranded RNA • Consequence of RNA virus presence in cell • Activated PKR inhibits protein synthesis and therefore viral replication • Phosphorylates translation initiation factor eIF2

  43. Host cell v. influenza A virus • Interferon-α/β response • Infected cell produces IFN-α/β • Signal travels to neighboring uninfected cells • In infected and neighboring cells, induces transcription of antiviral proteins • Protects infected cell against current infection • Prepares at-risk cells to withstand infection • Induces production of MxA protein • Largely responsible for inhibition of influenza A

  44. Host cell v. influenza A virus • Influenza NS1A protein inhibits 3’-end processing of cell mRNA • Prevents addition of poly-A tail • Doesn’t affect viral mRNA processing • Inhibits activation of PKR • Mechanism not clearly understood • Enough IFN-β produced to protect neighboring cells

  45. Influenza effect on host cells • Turns off protein function • NS1A protein • Causes cell death • Induces apoptosis • Dead cells shed off respiratory tract lining • Can cause shedding down to basement membrane layer • Infects respiratory tract; causes clinical symptoms

  46. Flu-Clinical

  47. Influenza Virus Types • Type A • humans and other animals • all age groups • moderate to severe illness • Type B • milder epidemics • humans only • primarily affects children • Type C - uncommon strain, no epidemic

  48. Common Flu Symptoms • High Fever • Headache • Extreme-tiredness/weakness • Dry cough • Sore throat • Stuffy/runny nose • Muscle aches • Diarrhea and vomiting

  49. Cold v. Flu • Flu is worse than common cold • Symptoms more intense in flu (fever, body aches, tiredness, and dry cough) • Colds- more likely to have runny or stuffy nose • Colds don’t result in serious health problems (pneumonia, bacterial infections, or hospitalizations)

  50. Increased Risk • Age 65 and older • Any age with chronic medical conditions • Pregnant women • Children 6-23 months

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