By Chandan Sekhon - Medicine Student @ Peterhouse, Cambridge
Introduction
Influenza is a virus that takes over 8,000 lives annually. Resulting in hospitalisations, respiratory problems and possibly death, it is a virus that is commonly underestimated in its strength and power to cause damage. Understanding the details of the virus allows us to understand more about how to help those infected with this easily transmissible virus.
Influenza is a virus that has a negative sense of a single-stranded RNA genome. This means the RNA genome is complementary to the mRNA required to synthesise influenza virions. The capsid surrounding the genome consists of two key glycoproteins - haemagglutinin (HA) and neuraminidase (NA), and an ion channel called M2.
Other key proteins in the virus are PA, PB1 and PB2, which make up the viral RNA-dependent RNA polymerase. This is important to transcribe the genome into a functional mRNA allowing the virus to become infectious. There are three types of influenza - A, B and C with type A causing the most disease in humans.
The way influenza enters a cell involves HA and the process of endocytosis. HA binds to sialic acid on the cell membrane and is endocytosed. After this, the inside of the cell becomes acidified, causing a conformational change in the shape of HA promoting fusion of the virus and endosomal membrane.
This lowering of pH allows protons to be imported into the virion via the M2 proton channel. This causes the core of the virion to destabilise, promoting the uncoating of the outer layer. HA is a trimer of three subunits. The HA1 subunit forms the globular head of the protein and includes the sialic acid binding site. HA2 forms the stalk connecting HA1 to the envelope. At neutral pH, the fusion peptide at the end of HA2 is buried within the HA molecule, but upon acidification, the HA1 moves aside allowing the HA2 fusion peptide to be exposed. This allows it to insert into the endosomal membrane, promoting fusion.
After this, the virus replicates. Using the RNA-dependent RNA polymerase, the mRNA forms and has eight segments. At the 5’ end of the viral mRNA, they have a cap and a few nucleotides taken from the host cell DNA-dependent RNA polymerase II - this process is called cap snatching. Viral mRNAs are incomplete copies of the virus RNA, so they can’t function in genome replication. In order to replicate the genome, extra copies of the complete genome are needed.
The new nucleocapsids then escape the cell - they bud through the membrane to acquire an envelope. This release requires NA which cleaves sialic acid from proteins. Since sialic acid is needed for virus entry, this cleavage prevents the virus from binding back to the cell, allowing it to spread.
Slightly altering the influenza genome is one-way influenza continues to spread. The two main ways this happens are antigenic drift and antigenic shift. Gradual ‘drift’ can occur through amino acid mutations in HA and allow the virus to go undetected by circulating antibodies.
Antigenic shift is more extreme and occurs when an entirely new HA protein is acquired from a different influenza virus. This can occur if one cell is infected by two different sets of influenza- for example, human and avian strains. Both genomes are replicated, but during assembly, reassortment can occur, creating new influenza variants.
One specific combination is particularly dangerous for humans - all the genes of the human strain remain the same, but the HA is taken from the avian virus. This means the virus can replicate effectively in humans, but existing immunity to influenza is of no value since we would have antibodies to human strains of HA. This combination has the potential to give rise to pandemics.
There are various drugs available for influenza. Amantadine and rimantadine target the M2 proton channel, and so inhibit influenza entry into the cell. At the late stage, they also interfere with HA processing. Another key drug that is used to combat influenza is Tamiflu. This is an analogue of sialic acid and inhibits NA. This means influenza virions cannot leave the host cell and so cannot spread.
To conclude, influenza is a tricky virus to fight, because of its genetic variability and persistence. Understanding the structure and replication of the virus allows us to develop new treatments and drugs to combat it. As such, pandemics and spread can be limited.
Further Reading:
1. This is an excellent read (it is a little difficult) about the clinical aspect of influenza and determining whether a patient has it or not. <https://jamanetwork.com/journals/jama/article-abstract/200419?casa_token=5RM-hfUDKiQAAAAA:7VR-2bIXUYxmywbkwumo3MR86m5ov-qbaujQMvKlZfDRFlitwXPmOzjaxaghjsoS37jVwC-LoNk>
2. This is a very long and comprehensive guide to influenza and its action. I wouldn’t recommend reading the entire document but is worth having a look at for some higher-level information. <https://www.annualreviews.org/doi/pdf/10.1146/annurev.mi.37.100183.002525?casa_token=LmOEf-NL1_MAAAAA:cjMoL2p0G4OIoe9QZAR1SlwbeJpeNCrxdBdoCwwzzl_a0iAcLgc5p9-ZB3myr5MEvd4DrMfJhgMiVQ>
3. A more historical overview of influenza and its past pandemics, outbreaks and records of the virus. A very interesting read that gives an excellent idea of public health in the past. <https://cssh.northeastern.edu/pandemic-teaching-initiative/wp-content/uploads/sites/43/2020/10/j.1365-2672.2001.01492.x.pdf>
4. Outlining Tamiflu as a drug, its structure, uses and mechanism of action to a very high level of detail, this is a great read (albeit extremely high level) to give a good description of influenza treatments. <https://onlinelibrary.wiley.com/doi/full/10.1002/anie.200602623?casa_token=wsF2EfTQUNgAAAAA%3AiENGWap0-6XrS0BEA-3WgTNttW5Fj6F1og6D3AFXQll6oThKDFfc-g4B_sjAU-dv59dob2ngcVvfreQ>
5. A bit of a different type of literature – this is a study for one of the alternative uses of amantadine – a treatment for Parkinson’s disease. So a bit of a different take on the drug. <https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003468/full>