Influenza Flashcards

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1
Q

Describe Influenza

A

Influenza is a specific respiratory syndrome, caused by influenza virus

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2
Q

What are the symptoms of seasonal influenza

A
  • 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
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3
Q

What are the at risk groups for severe complications of influenza?

A

At-risk groups for severe complications and death are the young, the elderly, those with underlying chronic heart, lung, renal or metabolic conditions.

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4
Q

How is the influenza virus spread?

A

Virus spread by droplet infection from coughing and sneezing

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5
Q

What is the incubation period and infectious period for Influenza?

A

Incubation period 1 - 5 days; Infectious for 5 - 6 days (depends upon the intake of virus and severity of the strain)

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6
Q

Describe the pathogenesis of Influenza.

A
  • 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.
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7
Q

Describe the family of influenza viruses.

A
  • 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
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8
Q

What is the significance and purpose of HA and NA?

A

Both HA and NA interact with sialic acid-containing receptors.

HA: the gripper
NA: the snipper

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9
Q

Give some examples of Type A Influenza Virus subtypes:

A
  • 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
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10
Q

Explain the Replication Cycle of the Influenza Virus.

A

Viral Haemagglutinin (HA) binds to the receptor (sialic acid linked to galactose) on the surface of respiratory epithelial cell.

Virus taken into cell by RME

As the endosome becomes more acid the HA changes conformation leading to fusion of viral envelope with the endosomal membrane

The 8 viral RNPs escape the endosome and go to the nucleus.

In the nucleus, viral RNA is replicated and mRNA is synthesised

Viral protein synthesis occurs

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.

Viral Neurominadase (NA) cuts sialic acid receptors from the cell surface so that newly budded virus won’t bind back to the dying cell.

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.

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11
Q

What is the adaptive immune response to influenza?infection.

A

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.
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12
Q

Explain Antigenic Drift.

A
  • 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)
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13
Q

What are the targets of vaccine-induced therapy in influenza?

A
  • Antibody to HA to block attachment

- Antibody to NA to block efficient viral release

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14
Q

Give Details about the Influenza vaccine.

A
  • 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

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15
Q

What are some of the targets of antiviral drugs?

A

Ion channel blockers: Inhibit the function of the M2 ion channel, preventing endosome escape of RNPs

NA inhibitors: blocks efficient viral release.

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16
Q

Discuss the antiviral therapy: Amantadine and Rimantadine (adamantanes)

A

Amantadine and Rimantadine (adamantanes) block the M2 ion channel; inhibit the uncoating of influenza A virus in the endosome during entry, preventing infection (not active against Type B).

  • Orally administered, given daily
  • Have been used for treatment in children and for prophylaxis in nursing homes etc to prevent widespread outbreaks following a clinical case of influenza
  • They are not used widely in the community, however, because drug resistant mutants of influenza virus readily arise
17
Q

Discuss the antiviral therapy: Relenza (Zanamivir) and Tamiflu (Oseltamivir)

A

Relenza (Zanamivir) and Tamiflu (Oseltamivir) block the action of NA

  • Active against influenza A and B. Reduces duration and severity of disease, but only fully effective if given within 2 days of developing symptoms.
  • Must be given 2 x daily.

Relenza: Developed from work at the Biomolecular Research Institute in Parkville
- Administered by inhalation by mouth to RT

Tamiflu: Orally administered prodrug Circulating seasonal H1N1 strains are showing resistance

18
Q

Discuss the antiviral therapy: “Designer drugs”

A

small molecule (analogue of sialic acid) designed to bind irreversibly in the active site of the viral neuraminidase (NA) and block its enzymic activity, thereby interfering with release of new virus particles from cells

19
Q

What is antigenic Shift?

A
  • Refers to the sudden appearance of an influenza A virus of a new HA (and sometimes NA) within the human population
  • Usually HA is of a new subtype and is derived from birds
  • Complete lack of protective immunity leads to rapid global spread, high morbidity and mortality = pandemic
  • Pandemics are rare because the human virus receptor sees SA α2-6 Gal and avian virus receptor sees SA α2-3 Gal. The receptors in the human upper respiratory tract are mainly SA α2-6 Gal
  • A single amino acid change in the receptor-binding pocket of HA can lead to a change in receptor-binding specificity

Usually the existing subtype of virus will be replaced

One way to create a new human subtype is by reassortment - swapping of gene segments upon co-infection of a single cell in a mixing vessel.

Antigenic shift has resulted from:

  • direct infection with avian virus in 1918 (followed by adaption via mutation)
  • genetic reassortment in 1957 and 1968
  • reintroduction of previous human strain in 1977
20
Q

Describe the 1918-1919 Influenza Pandemic.

A
  • 25-30% of world population clinically infected
  • 20-50 million deaths worldwide
  • Deaths unusually high in 15-35 age group, often rapid, < 5 days, and associated with pulmonary oedema, haemorrhage and cyanosis
  • Why so lethal? Virus not available for analysis but gene sequences have been obtained by reverse transcriptase (RT)-PCR from museum specimens and samples from victims frozen in permafrost in Alaska
  • The genetic basis for virulence is currently being studied using viruses created by reverse genetics
21
Q

Describe the Swine-origin H1N1 Influenza virus.

A
  • First human cases of the new H1N1 virus 26th April 2009 in Mexico
  • Viral genes derived from swine viruses that had reassortments and mutated in pigs before entering man
  • Respiratory symptoms as in seasonal influenza; not systemic
  • Now spread person-to-person across 213 countries (including Australia).
  • Overall not highly lethal to humans compared to H5N1: >10,000 deaths so far. Most deaths in people may have had underlying conditions.
  • BUT virus has greater ability to replicate in lungs compared to seasonal influenza so some young healthy adults getting viral pneumonia
  • Deaths in younger people (like 1918). Possibly some immunity in those born before 1920 induced by earlier seasonal H1N1.
  • Particularly susceptible are: Pregnant women, Obese individuals, Indigenous populations
  • In Australia closure of schools did little to halt the spread of the virus
  • Virus is susceptible to NA-inhibitors; potential for Tamiflu-resistant mutants to arise as with recent seasonal H1N1
  • Appears to have replaced previous seasonal H1N1 strain in community and now included in vaccine
22
Q

Avian H5N1 Influenza Virus

A
  • The H5N1 subtype has mutated in birds to become very virulent and has spread rapidly to many countries and become endemic
  • This H5N1 HPAI (highly pathogenic avian influenza) can infect systemically and rapidly kill poultry
  • Mammals, including man, can also be infected by H5N1 and it can be lethal
  • The more virus in the bird population, the greater chance of it adapting to efficiently infect man (either by drift or reassortment). Hundreds of millions of birds died or were culled.
    Highly pathogenic avian virus strains have a different cleavage site that can be cut by an enzyme found in all cells
    => potential for systemic spread to other tissues including brain
    => highly lethal (even to eggs in which the vaccine is grown)
  • First human case of H5N1 virus in 1997 followed by a further 18 cases. Epidemic halted by culling of poultry.
  • In 2003 human infections associated with H5N1 re-emergence and spread among poultry in Asian countries.
  • Cases appear only to be infected directly from birds or spread within small family clusters -? genetic component
  • Highly lethal to humans: 440 cases, 262 deaths (60% case fatality rate compared to 0.01% for seasonal epidemic influenza)
  • Deaths now reported in 15 countries. Indonesia has most cases and extremely high fatality rate (82%).
  • Severe respiratory disease and evidence for replication outside the respiratory tract
  • Virus susceptible to NA-inhibitors but people not always treated in time.