Influenza Flashcards
Describe Influenza
Influenza is a specific respiratory syndrome, caused by influenza virus
What are the symptoms of seasonal influenza
- Infections can range from subclinical to severe
- Typical influenza involves fever/chills, cough, headache, muscle aches, fatigue,loss of appetite
- Chest X-ray normal
- Acute infection lasting about 7 days or longer; no persistence of virus; weakness and cough may last for several weeks
What are the at risk groups for severe complications of influenza?
At-risk groups for severe complications and death are the young, the elderly, those with underlying chronic heart, lung, renal or metabolic conditions.
How is the influenza virus spread?
Virus spread by droplet infection from coughing and sneezing
What is the incubation period and infectious period for Influenza?
Incubation period 1 - 5 days; Infectious for 5 - 6 days (depends upon the intake of virus and severity of the strain)
Describe the pathogenesis of Influenza.
- Droplets containing virus enter the respiratory tract
- Virus binds to sialic acid-containing receptors on non-cilliated respiratory epithelium (SA α2-6 linkage to galactose in humans). These receptors are on cells elsewhere in the body but virus remains localised to RT throughout entire infection cycle.
- The virus replicates in epithelial cells of upper and lower respiratory tract but particularly the large airways
- Tissue damage and ensuing inflammatory response -> local symptoms; cytokines and interferon -> fever (IL-1), malaise, head and muscular aches (IFN)
- Pre-existing and developing immunity sufficient to clear the virus in immunocompetent individuals (acute infection)
- Later in infection viral replication can occur in ciliated epithelium of trachea and bronchi -> possibility of secondary bacterial infection (H. influenzae, Staph. aureus, Strep. pneumoniae) -> death from bacterial pneumonia, esp. in elderly
- Rarely, virus replication occurs within lung parenchyma, resulting in primary viral pneumonia; this is partly due to the damage to the cilia which normally sow the progression of microorganisms through the respiratory tract.
Describe the family of influenza viruses.
- Members of the Orthomyxoviridae family
- Enveloped virus with a genome comprising segments of single-stranded RNA of -ve sense (negative sense organisms require their own polymerase which they must bring into the infected cell)
- 3 Types of influenza virus that show no immunological cross-reactivity: A, B and C
- Types are differentiated by antibodies to the internal antigens
- Types A and B cause human influenza (Type C is a minor human pathogen)
- Only Type A influenza viruses infect other species –> poses a danger to us
What is the significance and purpose of HA and NA?
Both HA and NA interact with sialic acid-containing receptors.
HA: the gripper
NA: the snipper
Give some examples of Type A Influenza Virus subtypes:
- Type A influenza viruses all share similar internal proteins but may differ in the form of HA and NA they encode => different subtypes
- 16 different subtypes of HA (H1-H16), 9 different subtypes of NA (N1-N9)
- Different Type A viruses are named after the HA and NA subtypes they express eg. H5N1
- Aquatic birds are the ancestral host of influenza A virus => all different subtypes of HA and NA are found on viruses endemic in avian species
- Certain subtypes also infect pigs, horses and many other mammals including man
- H1N1, H2N2 and H3N2 viruses have circulated in humans in recent decades - currently H1N1 and H3N2
Explain the Replication Cycle of the Influenza Virus.
Viral Haemagglutinin (HA) binds to the receptor (sialic acid linked to galactose) on the surface of respiratory epithelial cell.
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Virus taken into cell by RME
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As the endosome becomes more acid the HA changes conformation leading to fusion of viral envelope with the endosomal membrane
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The 8 viral RNPs escape the endosome and go to the nucleus.
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In the nucleus, viral RNA is replicated and mRNA is synthesised
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Viral protein synthesis occurs
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HA and NA expressed on the cell surface after glycosylation in the ER and Golgi allow the virus to acquire those surface glycoproteins and envelope as they bud out of the cell.
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Viral Neurominadase (NA) cuts sialic acid receptors from the cell surface so that newly budded virus won’t bind back to the dying cell.
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Newly formed virus requires the action of tryptase Clara to become infectious.
Only viruses with HA that has been previously cut can undergo the conformational change required for fusion and endosome escape.
This cut occurs at the ‘cleavage site’ to reveal a hydrophobic fusion peptide.
Normally cleavage of the HA can only be done by an enzyme secreted by Clara cells in the respiratory tract and so influenza is confined to the respiratory tract.
What is the adaptive immune response to influenza?infection.
CD8+ cytotoxic T cells
- kill virus-infected cells
- important in recovery from influenza
- can recognise peptides derived from the internal antigens of the virus, therefore are broadly crossreactive between Type A subtypes but not between Types A and B
- CD8+ T cell immunity is not long-lived but can be boosted by repeated exposure to virus
Antibody
- Developing antibody to HA (and NA) speeds clearance of virus
- Acts by inhibiting attachment (or release) of virus; Ab +C’ lysis of cells; promoting phagocytosis etc
- Pre-existing Ab will protect against infection by neutralising input virus
- the antibody response to the infecting strain is lifelong, however crossreactive CD8+ CTLs might lessen severity of disease but cannot stop the infection.
Explain Antigenic Drift.
- Leads to the creation of new strains within a subtype
- Single amino acid changes in viral proteins arise because of errors of replication of the viral RNA-dependent RNA polymerase (= drift)
- These may be deleterious, neutral or advantageous
- Those that occur in the sites on HA (or NA) where neutralising antibodies bind may be advantageous if the antibody can no longer bind the mutated protein sequence.
- Viruses with such a mutation will be selected for in the presence of antibodies to that site (= antigenic drift)
- Neutralising antibodies to the HA bind to overlapping epitopes within 5 antigenic sites surrounding the receptor-binding pocket (the receptor-binding pocket itself does not change)
- If we sequence the HA of viruses isolated over time we find mutations accumulating in these sites.
- Once all 5 sites have mutated, the vast majority of the population will have no pre-existing antibodies that recognise the new virus strain.
- An epidemic will result
- New strains replace all older strains (so evolution of influenza is a linear process)
What are the targets of vaccine-induced therapy in influenza?
- Antibody to HA to block attachment
- Antibody to NA to block efficient viral release
Give Details about the Influenza vaccine.
- Inactivated trivalent vaccine containing 3 different influenza viruses representing the most recent strains of influenza A H1N1 and H3N2 subtypes, and influenza B.
Given intramuscularly, recommended for those people particularly at risk from the complications of influenza.
This includes people:
- over 65 years of age or
- with chronic lung, heart or kidney disease or
- with diabetes or cancer or
- with immunosuppression and
- health workers who may transmit influenza to those at risk
- The viruses are grown in eggs and purified from allantoic fluid, then chemically inactivated and detergent disrupted
- They are not suitable for people with egg allergies
- Being an inactivated preparation it induces antibody but not cytotoxic T cell responses
- Gives reasonably good protection in healthy young individuals (70%) but less in the elderly
- If significant antigenic variation from the strains included in the vaccine protection may be compromised
- Vaccine has to be updated every year to include the latest epidemic strains isolated during winter outbreaks in the other hemisphere which may appear here in the next season
- Once the vaccine strains have been selected it takes about 6 months to prepare the vaccine
What are some of the targets of antiviral drugs?
Ion channel blockers: Inhibit the function of the M2 ion channel, preventing endosome escape of RNPs
NA inhibitors: blocks efficient viral release.