Virology - Influenza Flashcards
Outline influenza.
- Family: Orthomyxoviridae, species: Influenza A, B, and C.
- -ve sense RNA, segmented genome (A and B eight, C seven), enveloped virus.
- 80-120nm diameter, helical nucleocapsid
- B and C occur almost exclusively in humans, whereas A has many subtypes and can infect many different species, including humans.
- Viral subtypes are distinguished by their surface proteins, haemagglinin (HA) and neuraminidase (NA).
- Cause of major outbreaks of acute respiratory infection
- Can undergo antigenic shift and antigenic drift
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What are the surface proteins of influenza? Which ones affect humans?
How is birdflu spread to humans?
Name some influenza pandemics.
- First reported case: America 1918, spread through the rest of the world by June 1918, infected 50% of the World’s population.
Pandemics occurred in 1918, 1957 and 1968 with the emergence of H1N1 Spanish influenza, H2N2 and H3N2 respectively, and most recently in 2009, with the emergence of H1N1 from swine (H1N1 2009pdm) into the human population. The great pandemic of 1918–1919 was particularly severe, killing 20–40 million people as it spread over a few years. In 1957, the emergence of H2N2 as a pandemic virus displaced circulating H1N1, which disappeared until 1977, when it re-emerged after 20 years
Outline the structural proteins of influenza.
The nucleocapsid is surrounded by the M1 protein shell, immediately exterior to which is a lipid envelope derived from the host cell. The viral M2 protein projects through the envelope to form ion channels, which assist virus entry through an endosomal route which involves pH changes. Two types of spike project from the lipid envelope, the haemagglutinin (HA) and theneuraminidase (NA) enzyme.
The HA, so-called because the virus agglutinates certain species of erythrocyte, is about 10 nm in length and consists of trimers of identical glycoprotein subunits, each consisting of two polypeptide chains, HA1 and HA2 joined by a linkage site that may be a single basic amino acid, usually arginine, or a string of basic amino acids.
What does haemagglutinin interact with on cell membranes?
Influenza viruses bind to cells by the HA interacting with cell membrane receptors containing N-acetylneuraminic acid (sialic acid).
What is the role of neuraminidase?
Between the HA spikes on the virus surface are the mushroom-shaped NA spikes. The NA protein is assembled from four subunits attached by a stalk containing a hydrophobic region which is anchored in the viral lipid envelope. The NA enzyme catalyses the cleavage of sialic acid and an adjacent sugar residue from glycoproteins found in mucus. This action allows the virus to permeate through the mucin overlying host epithelial surfaces. Neuraminidase activity is also important in the release of new virus particles from infected cells.
Outline the difference between antigenic drift and antigenic shift.
Antigenic shift is the slow genetic change of the influenzavirus over time, whereas antigenic shift is a major change in the surface protein composition of influenza, caused by the combining of strains.
Major pandemics are associated with antigenic shifts – when the viral HA or NA (or both) is changed. Antigenic shift results from the acquisition of a complete new RNA segment 4 and/or 6, either as a result of reassortment or infection of humans with an animal virus.Epidemics occurring regularly in winter months between pandemics are associated with genetic drift in the HA antigen.
Amino acid changes arising as a result of genetic mutation provide a selection advantage for the virus if they occur on the globular head of the HA protein, where host antibody binds. Mutation at these sites allows the virus to infect despite the presence of antibody to previous strains, a phenomenon known as antigenic drift.
What is the difference between influenza virus types?
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Influenza A:
- Causes epidemics and occasionally pandemics
- Animal reservoir (e.g. birds)
- Moderate-severe disease
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Influenza B:
- only causes epidemics
- No animal reservoir
- Moderate disease
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Influenza C:
- Does not cause epidemics (very mild illness)
Name some pandemics with specific influenza causes.
What are the possible pathways for generation of pandemic influenza viruses?
Pigs have receptors for both human and avian strains, and this mammalian host has long been considered a key ‘mixing vessel’ for reassortment following simultaneous infection with human and avian viruses.
What are the risk factors for the acquisition of zoonotic avian, or non human influenza?
- close or direct contact with diseased poultry or other domestic fowl
- close or direct contact with other mammalian species infected with unusual influenza A viruses (swine, seals)
- inhalation, ingestion or mucosal contact with infectious material.
Outline the clinical features of human seasonal influenza A infection.
Influenza is an acute infection of the human respiratory tract. Disease is characterized by the sudden onset of fever, chills, headache, muscle pain and extreme fatigue. Other common symptoms include a dry cough, sore throat and stuffy nose.
For otherwise healthy individuals, influenza is an unpleasant but usually self-limiting disease with recovery usually within 2-7 days.
Serious illness and mortality are highest among newborns, older people and those with underlying disease, particularly chronic respiratory or cardiac disease, or those who are immunosuppressed.
What are some complications of human seasonal influenza? What groups are at risk?
At risk groups: more severe depending on age, with both ends of the age spectrum most at risk.
- Primary influenza pneumonia is an unusual complication that may occur at any age and carries a case fatality rate of 1–5%, depending on age and underlying conditions. This can be fatal, especially in young adults during an outbreak, after a very short illness of sometimes less than 1 day. A similar rapid illness can occur in the elderly.
- More commonly a bacterial pneumonia caused by Staphylococcus aureus, Streptococcus pneumoniae or Haemophilus influenzae occurs late in the course of the illness, often after a period of improvement, resulting in a classical biphasic fever pattern.
- Very rare complications include myocarditis, encephalitis or meningoencephalitis.
Outline the pathogenesis of influenza.
- Inhaled virus is deposited on the mucous membrane lining the respiratory tract or directly into the alveoli
- The virus is exposed to mucoproteins containing sialic acid that can bind to the virus, thus blocking virus attachment to respiratory tract epithelial cells. However, the action of viral neuraminidase allows the virus to break any bonds formed.
- Specific local secretory immunoglobulin (Ig) A antibodies, if present from a previous infection, may neutralise the virus before attachment occurs, provided the antibody corresponds to the infecting virus type. If not prevented by one of these immune defence mechanisms, virus attaches to the surface of a respiratory epithelial cell and the intracellular replication cycle is initiated.
- The major site of infection for seasonal influenza in humans is the ciliated columnar epithelial cell. New viruses bud from the apical membrane, the cilia are lost and viruses spread to other areas of the respiratory tract. The cell damage initiates an acute inflammatory response with oedema and the attraction of phagocytic cells.
- The earliest response is the synthesis and release of interferons from the infected cells: these can diffuse to and protect both adjacent and more distant cells before the virus arrives. It appears that interferons released in this way cause many of the systemic features of the ‘flu-like’ syndrome.
A key control strategy for reduction of morbidity and mortality due to influenza is immunization. Outline the influenza vaccine.
The aim is to produce haemagglutination inhibiting or neutralizing antibody in all vaccinees. This protects against infection, but only with strains closely related to those in the vaccine, and limits transmission.
Whole virus, split and subunit inactivated influenza vaccines for intramuscular injection have been widely available for many years, and live attenuated vaccines have been available more recently for use in children in the USA.
Inactivated vaccines are trivalent and contain the H and N subunits from two type A strains and one type B strain. The strains are updated annually on the recommendation of the WHO and, in the UK, are recommended for use in people aged over 65 years, and in those of any age who suffer from chronic cardiorespiratory problems, diabetes, renal or liver failure or an immunosuppressive illness.
How are influenza vaccines made? [3]
- Vaccine seed strains need to be grown in cell or egg substrates to make inactivated vaccines.
- Separated whole virus particles are inactivated by either formalin or β-propiolactone, and may be used at this stage as ‘whole virus vaccines’. Whole virus vaccine should not be given to those who are allergic to egg protein.
- The H and N antigens may be separated from the whole virus by treatment with detergent, and such subunit or split-virus vaccines are better tolerated, especially by young children.
- Other types of vaccines have been tried, such as cold-adapted live-attenuated vaccines given intranasally. These have been generally effective in provoking a good local (IgA) antibody response and are particularly good at developing protective efficacy in children, though less so in adults, but are not widely used at present.
