Micro Test 4: Orthomyxoviruses

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BrookeNH10
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198922
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Micro Test 4: Orthomyxoviruses
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2013-02-08 15:02:04
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Micro Test Orthomyxoviruses
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Micro Test 4 Orthomyxoviruses
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  1. Name 7 Orthomyxoviruses
    • Influenza A, B, C
    • Thogoto Virus
    • Dhori Virus
    • Isavirus
  2. # of gene segments:
    Influenza A & B?
    Influenza C?
    Thogoto and Dhori?
    Isavirus?
    • A, B= 8
    • C= 7
    • Thogoto and Dhori= 6
    • Isavirus= 8
  3. Major human pathogens
    Influenza A & B

    *Influenza C is a non-repeated mild infxn, usually in childhood
  4. Tick-borne viruses
    • Thogoto Virus
    • Dhori Virus
  5. Orthomyxovirus:  Genome structure
    • - sense RNA
    • Each segment encodes only 1-2 genes (Most other RNA viruses have a single genomic RNA encoding multiple genes)
  6. Orthomyxovirus:  RNA replication
    • RNA replication occurs in the nucleus
    • (Most RNA viruses replicate in the cytoplasm- negative strand viruses; or attached to cellular membranes- many positive strand viruses)
  7. Flu virus mutates rapidly
    • Pts. should be revaccinated every year
    • Flu disease generally characterized by rapid onset of symptoms, especially fever
  8. Flu A and B can be treated with antiviral drugs
    • Zanamivir and Oseltamivir
    • (Amantadine is for 'flu A only)
  9. Orthomyxo vs. Paramyxo: RNA Segments
    • Ortho= 8 RNA segments
    • Paramyxo= 1 RNA segment
  10. Orthomyxo ('flu) vs. Paramyxo:  Attachment and Fusion
    • O= HA (attachment and fusion), NA (neuraminidase)
    • P= HN (attachment and neuraminidase), F (fusion
  11. Orthomyxo ('flu) vs. Paramyxo:  Entry into cell
    • O= Receptor-mediated endocytosis
    • P=  Fusion at plasma membrane
  12. Orthomyxo ('flu) vs. Paramyxo:  RNA synthesis location
    • O= nucleus
    • P= cytoplasm
  13. Orthomyxo ('flu) vs. Paramyxo:  Subtypes
    • O= Multiple, serologically distinct subtypes
    • P=  Few subtypes
  14. Influenza with multiple subtypes
    Influenza A

    (Influenza A is also the only influenza w/ antigenic drift)
  15. Influenza surface antigens
    • A= HA, NA
    • B= HA, NA
    • C= HEF
  16. Influenza with antigenic shift
    A, B, and C (all three have antigenic SHIFT, but only A has antigenic DRIFT)
  17. Annually recurrent infxn by closely related viruses. 
    Obtained by 5%-20% of the US population every year.
    Can reach epidemic proportions
    Seasonal 'flu
  18. Infection by "new" flu virus
    Most people will have no immunity
    Expect severe disease in ~25% of population
    Death rates could be as high as 2-5% of entire population
    Pandemic 'flu
  19. 2 things that determine type (A, B, C) of flu
    • Nucleocapsid (NP)
    • Matrix (M1)

    *Traditionally done serologically, but no often done using NP sequence
  20. Subtype (H1N1, H3N2, etc) is determined by
    HA (H1-H16) and NA (N1-N10)
  21. Nomenclature:  Type/locale/isolate #/ year (subtype)
    Human 'flu
  22. Nomenclature:  Type/species/isolate #/ year (subtype)
    Non-human 'flu
  23. Influenza A:  # of ORFs
    10
  24. HA and NA are randomly distributed on surface of virus
    HA >>> NA
  25. Gene segments are exchanged between two viruses infecting the same cell
    Reassortment

    • Causes Antigenic Shift (flu A only)
    • Can cause pandemics
    • Ocassionally see internal antigenic shifts, but don't lead to pandemic strains
  26. Antigenic drift is due to the fact that
    Influenza Polymerase is error prone (most change are deleterious, but some confer selective advantage- i.e. resistance to antibody binding)
  27. Hemagglutinin is required for
    Receptor binding AND membrane fusion
  28. Required for Hemagglutinin fusion step
    Proteolytic processing
  29. Hemagglutinin processing in vivo probably caused by
    Clara tryptase (secreted by Clara cells in bronchial epithelium)
  30. High pathogenic viruses may contain cleavage sites for other enzymes
    furin, plasminogen, elastase

    *allows virus to grow in broader range of cells
  31. Avian flu receptor
    a2,3 sialic acid
  32. Human flu receptor
    a2,6 sialic acid
  33. pH-dependent conformation change in HA
    activates fusion
  34. Activates fusion
    pH-dependent conformational change
  35. Fusion peptide
    • Hydrophobic
    • Inserts into lipid bilayer of host cell
  36. Neutral pH:  Interactions btw acidic and basic residues stabilise
    HA1 and HA2

    HA2 N-terminus forms "hairpin"
  37. Forms hairpin
    HA2 N-terminus
  38. Low pH:  Addition of H+ neutralizes acidic residues
    • Breaks bond between HA1 and HA2
    • "Spring loaded" HA2 N-terminus forms long alpha helix
    • Fusion peptide is displayed
  39. Fusion peptide is displayed
    at low pH

    • Triggered by pH drop as endosome get acidified
    • Essential for viral infxn
  40. Antibodies block receptor binding sites
    Nautralizing Abs bind to HA
  41. Mutations retained in succeeding strains
    Fixed mutations
  42. Tetrameric type II membrane glycoprotein
    Neuraminidase
  43. NA is targeted to
    apical domain
  44. Required to prevent virus aggregation after budding
    Sialidase activity (receptor destroying enzyme)
  45. Target of Relenza, Tamiflu
    Sialidase activity
  46. B-propellar structure
    Neuraminidase (NA)
  47. Subtypes of NA
    9 subtypes (N1-N9)
  48. Active site of NA is _____
    Ab binding site of NA is ____
    • Active site = buried
    • Ab binding site= on surface
  49. Neuraminidase Inhibitors
    • Oseltamivir
    • Zanamivir

    Bind in active site (buried) and mimic structure of rxn intermediate
  50. Allows H+ to pass from lumen of acidified endosome to lumen of virus
    M2 ion channel

    This is required to release NP from M
  51. Amantadine blocks
    H+ (inhibits wild type flu A)

    *locks ion channel to prevent H+ movement
  52. AmaR associated with what mutations
    D24, S31, and H37
  53. Influenza: Transmission
    • Aerosols (can spread up to 3 ft away)
    • Droplets
    • Solid surfaces
  54. Influenza:  Symptoms
    • Abrupt onset
    • High fever
    • Myalgia
    • headache
    • malaise
    • nausea/vomiting
  55. Influenza complications
    • Febrile seizure (mainly in children)
    • Primary viral pneumonia
    • Secondary bacterial pneumonia
    • Sinusitis
    • Secondary bacterial otitis media
    • Transient dementia
  56. Influenza:
    Incubation?
    Duration of Symptoms?
    Virus Shedding?
    • Incubation= 1-4 days
    • Duration of Symptoms= 2-5 days
    • Virus Shedding= S-1 to S+3
  57. Cells targeted by influenza
    Ciliated and mucous-producing cells of the respiratory tract
  58. Flu:  Immunity
    • Mucosal IgA- protects airways against infxn
    • Serum IgG- Titer >40 HAI are considered to be protective
    • Influenza virus-specific CTL- resolves ongoing infxn
  59. De novo anti-influenza response is ineffective in very young and very old
    • Neonates- Maternal IgG provides some protection (don't get IgA)
    • Very old due to poor Th response
  60. Influenza:  Diagnosis
    Point of Care Tests (ZstateFlu)
  61. Where did Swine Flu come from?
    HA most closely related to viruses circulating in North American Swine since 1940s (probably related to Spanish Flu)
  62. Older pts. and swine flu fulnerability
    • Older patients have protective cross-reacting antibodies
    • Presumably due to prior exposure to antigenically related seasonal strains
  63. Patients at risk of have severe disease of complications due to flu
    • Children
    • Elderly
    • Immunocompromised
    • Patients with lung disease
    • Obese
  64. Influenza:  Tx of low-risk patient
    • Supportive care
    • Antiviral drugs where likely to be efficacious
  65. Only work on influenza A
    • Amantadine and Rimantadine
    • (Also have potential for use in Parkinson's disease)
  66. NA inhibitors that block the release of viruses from infected cells
    • Relenza (Zanamivir)- inhalation device
    • Tamiflu (Oseltamivir)- capsule
  67. NA inhibitors must be given within
    48 hours of onset (has been used prophylactically)

    • *More expensive than Amantadine
    • Shorten the duration of illness by 1.5 days
  68. Effective against both influenza virus A and virus B
    Relenza, Tamiflu
  69. New option for flu tx
    Peramivir:  Neuraminidase Inhibitor (can be administered IV)
  70. Influenza Prevention
    • Hygiene (handwashing)
    • Public health measures (closing public places, wearing masks, etc.- Spanish flu)
    • Prophylaxis w/ antivirals
    • Vaccination
  71. Flu vaccine types in current use
    • Subunit (killed) vaccine
    • Live Attenuated vaccine
  72. Subunit (killed) Vaccine
    • Grown in eggs
    • Ab response
    • Ok for young, old, immunosuppressed
    • Given IM
  73. Live Attenuated Vaccine
    • Defective virus grown in eggs
    • Will replicate weakly in pts.
    • Both T and B cell response
    • Healthy children and adults only
    • Given intranasally
  74. Aim of flu vaccines
    HA1 titre >40 after two weeks
  75. Problems w/ influenza vaccines
    • Current vaccines are not cross-protective (can only protect against like viruses- aka same subtype)
    • Most current vaccines are grown in eggs- 6 month lag to vaccine production, production capability is limited
    • Anaphylaxis in pts. allergic to eggs
  76. Guillain Barre Syndrome associated with
    H1N1 Swine Flue vaccine
  77. Flu Vaccine Efficacy
    • Population as a whole= ~62%
    • Healthy young people= ~90%
    • Vaccination does NOT significantly reduce risk of infxn
    • Vaccination DOES reduce the risk of hospitalization and death due to influenza
  78. H5N1 Influenza in humans (Bird flu)
    • Identified in Hong Kong
    • Almost all due to direct contact w/ infected domestic poultry or wildfowl
  79. H5N1 (bird flu) in humans:  Clinical
    • Longer incubation time (2-3 days)
    • Initial symptoms as for seasonal flu (high fever, pts. decline rapidly)
    • Oseltamivir tx is effective if started early

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