Respiratory Viruses I - Influenza Flashcards
1
Q
Mechanism of systemic symptoms in influenza viral infections
A
- 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
2
Q
Influenza virus hemagglutin (HA) glycoprotein + role in disease
A
- 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.
3
Q
Protease cleavage of HA impact on virus virulence
A
- 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
4
Q
HA role in viral entry
A
- 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.
5
Q
Characteristics of changes in antigenicity of HA
A
- 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
6
Q
Vaccine strategies for influenza
A
- 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.
7
Q
Neuraminidase characteristics and role in disease
A
- 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
8
Q
MOA of oseltamivir and zanamivir
A
- 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.
9
Q
Influenza replication cycle and drug targets
A
- HA is cleaved by host cell protease
- Endosomal uptake after cleavage
- Endosomal pH drops triggering…
- Conformational change allowing fusion of viral envelope with endosomal membrane,
- Genome is released into cytoplasm
- 8 segment genome heads to nucleus for transcription;
- Virus replicates, Only RNA virus that replicates in the nucleus.
- Nucleocapsids assemble in nucleus, move to cytoplasm with NS1.
- NA removes receptor from infected cell, allows for budding and release
- While budding at plasma membrane the virion acquires HA, NA, 8 genome segments
10
Q
General drug targets in influenza tx
A
Block entry, block uncoating, prevent release
11
Q
Amantadine & Rimantadine MOA
A
- 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
12
Q
Epidemiology of influenza
A
- Risk factors:
- ≥ 65
- Chronic disease
- Pregnancy
- Immunocompromised status
- Several pandemics over time.
- 36,000 deaths/year in US
13
Q
Epidemiology of antigenic drift
A
- 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
14
Q
Epidemiology of antigenic shift
A
- 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
15
Q
Rationale for global surveillance of influenza strains
A
- 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
