Respiratory Viruses I - Influenza Flashcards Preview

Infectious Disease: Unit 2 > Respiratory Viruses I - Influenza > Flashcards

Flashcards in Respiratory Viruses I - Influenza Deck (22):

Mechanism of systemic symptoms in influenza viral infections

  • Viral replication at the initial site of the initial infection ==> early sx
    • Respiratory epithelial cells
  • The Innate response senses infection==> immune mediators ==> systemic sx
    • Cytokines induce fever and myalgias    
    • Interferon (IFN) → “interfere” with viral replication within host cell,
      • ↑ APC ability of T-lymphocytes,
      • ↑ resistance of unaffected cells 


Influenza virus hemagglutin (HA) glycoprotein + role in disease

  • Hemagglutinin (HA) binds to cell surface receptor which are N-acetyl neuraminic acid (sialic acid) moieties.
  • Cleavage of HA0 into H1 and H2 by host cell proteolytic enzymes is required for viral infectivity.


Protease cleavage of HA  impact on virus virulence


  • The cleavability of HA is required for virulence. Without cleavage the virus will not be able to enter the cell.
  • If it is susceptible to cleavage by any old trypsin, then it will be highly virulent


HA role in viral entry

  • conformational change in cleaved HA2 occurs upon shift to low pH (5.5).
  • Normally occurs in the endosomes following endocytosis of attached virions.
  • Conformational change is required for fusion of the viral envelope with endosomal membrane to introduce viral genome into cells.


Characteristics of changes in antigenicity of HA

  • antigenic drift = adaptation to host ab ==> new strains/antigenicity
    • NO changes subtype virus (i.e. H2N2)
    • Occurs in A, B, C
  • antigenic shift = type A influenza virus with a completely novel HA or NA gene segment is introduced into human
    • gene segment usually acquired from other host species (e.g. bird, swine)
    • occurs when two virus infect a single human or animal and swap genes
    • ONLY type A
    • can lead to pandemics


Vaccine strategies for influenza

  • Vaccines are made to target whichever combination of HA and NA that epidemiologists predict will be the most prevalent strain for a given year, ex. H1N1.
  • Thus, if the virus drifts/shifts away from predicted strains it will not effectively protect the population.


Neuraminidase characteristics and role in disease

  • NA is a tetravalent spike protein on the surface of the virion; it constitutes only 5% of all spikes on virion
  • It helps to bind virion to receptors on host cell surface for HA-dependent entry
  • It also acts by Cleaving N-acetyl neuraminic acid from host cell membranes, thus destroying its normal receptors
  • The removal of receptors allows newly budding virions to detach and infect other cells.
  • There are 9 serotypes of NA


MOA of oseltamivir and zanamivir

  • Neuraminidase inhibitors → inhibition of NA enzyme activity
  • Zanamivir and Oseltamivir
    • Block release of new virions from the cell from which they budded
    • Prevens the spread of influenza A/B viruses to other cells
    • Shorten the period and amount of virus shedding
  • ==> reduces and shorten the signs and symptoms of flu.


Influenza replication cycle and drug targets

  1. HA is cleaved by host cell protease
  2. Endosomal uptake after cleavage
  3. Endosomal pH drops triggering...
  4. Conformational change allowing fusion of viral envelope with endosomal membrane,
  5. Genome is released into cytoplasm
  6. 8 segment genome heads to nucleus for transcription;
  7. Virus replicates, Only RNA virus that replicates in the nucleus.
  8. Nucleocapsids assemble in nucleus, move to cytoplasm with NS1.
  9. NA removes receptor from infected cell, allows for budding and release
  10. While budding at plasma membrane the virion acquires HA, NA, 8 genome segments


General drug targets in influenza tx

Block entry, block uncoating, prevent release



Amantadine & Rimantadine MOA

  • Amantadine + Rimantadine target M2
  • Amantadine blocks viral particle uncoating and nucleic acid release, inhibiting viral replication. 
  •  M2 = located in the viral envelope
    • enables hydrogen ions to enter the viral particle (virion) from the endosome, thus lowering the pH inside of the virus, which causes dissociation of the viral matrix protein M1 from the ribonucleoprotein RNP.
    • This is a crucial step in uncoating of the virus and exposing its content to the cytoplasm of the host cell.
  • However, most strains are resistant to amantadine and rimantadine, so they aren’t used anymore


Epidemiology of influenza

  • Risk factors:
  • ≥ 65  
  • Chronic disease
  • Pregnancy
  • Immunocompromised status
  • Several pandemics over time.
  • 36,000 deaths/year in US


Epidemiology of antigenic drift

  • Antigenic drift: very common
  • Simply Stated: Selection Pressure and cause for new vaccine yearly
  • Antibodies in respiratory secretions select against virions that express HA and NA antigens that the patient has seen previously, so viruses with point mutations in HA/NA gene segment, have a selective advantage.
  • Antigenic drift occurs in influenza A, B and C viruses
  • Gradual antigenic change without a change in subtype, ex. 4 different H3N2 viruses


Epidemiology of antigenic shift

  • Simply Stated: Entirely New HA or NA protein (New Virulence)
  • Reassortment of viral RNA segments from human and non-human influenza viruses
    • Importing a genome segment from an influenza virus of another species
    • ==> new HA or NA protein into virions
    • Most from avian strains, after passage through pigs.
  • Antigenic shift occurs only in influenza A
  • We only care if the new strain can be transmitted easily from person to person


Rationale for global surveillance of influenza strains 

  • Vaccine makers are always trying to catch up
  • Have 16 HAs to track and 9 NAs to track
  • Must track animal (mostly pig) population to identify viruses that might jump to humans


Normal influenza epidemice: patients @ risk, resistance, illness, other

  • Risk:
    • ≥ 65, Chronic disease, Pregnancy,
    • Immunocompromised status
  • Resistance: none
  • Illness: Flu
  • Other
    • Yearly drift


1918 pandemic: patients @ risk, resistance, illness, other

  • Risk:
    • Healthy young adults died suddenly 1 or 2 days
  • No resistant people
  • Illness
    • Sudden onset,
    • Prostration and death or bacterial pneumonia
  • Other
    • > 50 million deaths world wide in 2 year period
    • Virus introduce new hemaggultinin and Neuraminidase


2009-2010 pandemic: patients @ risk, resistance, illness, other

  • Risk
    • Initially, lethal in young adults
    • 2009- influenza strain more lethal in children
    • Risk Factors include - obesity and underlying neurological disease
  • Some resistant people
  • Ilnness
    • Regular flu like illness
    • 7-10 days duration
  • Other
    • PCR showed not like the 1918 strain
    • New data suggest drug resistant strains
    • Outbreak earlier in the year than normal
    • highly transmissible in human and pigs


Characteristics of trivalent vaccine

  • Trivalent, Inactivated Vaccine (TIV) is made in eggs - one egg/vaccine!
  • Composed of 3 influenza strains (2A, 1B) that circulated in previous winter.
  • Parenteral (IM).
  • Systemic IgG production/booster


Characteristics of subunit vaccine

  • Split vaccines
  • Recombinant viral proteins
  • Injectable
  • Systemic IgG production/booster


Characteristics of LAIV vaccine

  • Made in eggs
  • Made by reassortment of epidemic strain HA and NA genome segments with other genome segments from virus strains that grow well in eggs.
  • Cold-adapted strains that cannot grow in lower respiratory tract.
  • Best at making secretory IgA in respiratory tract
  • Respiratory secratory IgA and Systemic IgG production/booster
  • Nasal Spray


Difficulties w/development of influenza vaccine

  • Need to induce neutralizing type-specific neutralizing anti-HA and anti- NA antibodies in respiratory secretions.
  • Many different antigenic combinations are possible → 16 HA’s * 9 NA’s = 144 combinations!
  • The long time between selection of viruses in the vaccines and the preparation and use of vaccines for a new strain of flu
  • Vaccine side effects; antigenic variability of the epidemic influenza virus strains; shortages in vaccine; prioritization of limited vaccine for risk groups
  • We just don’t know which one is going to happen next