The Evolution of Influenza Viruses: Mutations Mechanisms

Posted on 2024-12-16

Overview

Influenza viruses, of the Orthomyxoviridae family, are characterised by negative-sense, single-stranded, segmented RNA genomes (1). Seasonal influenza, commonly referred to as flu, is primarily caused by influenza A (IAV) and B (IBV) viruses (2). IAVs are classified into subtypes based on their surface glycoproteins, haemagglutinin (HA) and neuraminidase (NA), with 18 HA and 11 NA subtypes identified (3). Currently, IAVs A/H1N1 and A/H3N2 are the predominant seasonal subtypes (4).

Notably, only IAVs can infect a variety of hosts (i.e., humans, pigs, horses), resulting in a high transmissibility rate and leading to global pandemics, particularly through avian IAVs circulating in wild birds, which pose a major pandemic threat (3). In contrast, IBVs, lacking an animal reservoir, are only divided into B/Victoria and B/Yamagata subtypes (5).

The influenza genome consists of eight gene segments encoding key proteins, such as polymerase subunits (PB1, PB2, PA), matrix proteins (M1, M2), non-structural proteins (NS1, NEP), and the surface glycoproteins (HA and NA). HA mediates cell entry by binding to sialic acid on host cells, whereas NA facilitates the release of new virions and mucus penetration (6). 

Historical IAV pandemics over the last century, such as the 1918 “Spanish flu”, and the 1957 “Asian flu”, and the “1968 “Hong Kong flu” caused an estimated cumulative of more than 50 million deaths globally. Its continual evolution underscores the importance of understanding viral mechanisms to inform prevention and treatment strategies (7). 

Genetic Drift vs. Genetic Shift

The segmented genome and error-prone RNA-dependent RNA polymerase (RdRP) enable rapid evolution through antigenic drift and antigenic shift., driving immune evasion and pandemic potential (8).  

Antigenic drift is the process by which minor changes are introduced into key viral epitopes through point mutations in the viral genome (9). These mutations can occur during replication due to the lack of proofreading by the RNA-dependant RNA polymerase. Most mutations are inconsequential or render the virus nonviable, but those that alter the HA or NA glycoproteins enable the virus to evade host immunity, driving antigenic drift. Although mutation rates are consistent across the genome, antigenic regions drift more rapidly due to immune-driven selection (10). 

In humans, antigenic drift leads to the gradual replacement of older viruses by new variants, though turnover rates vary. A(H3N2) viruses show rapid turnover, whereas A(H1N1) and IVBs often co-circulate for longer periods (4). 

On the other hand, antigenic shift involves the complete exchange of HA and/or NA genes, resulting in entirely new subtypes. Antigenic shifts can only occur in IVAs due to their extensive animal reservoirs, which may harbour antigenically distinct strains (10). IVBs, lacking such a reservoir, do not undergo an antigenic shift. In humans, antigenic shift introduces viruses against which there is limited immunity, increasing transmission and raising the risk of a pandemic (11).

Abbexa in Research: Temporal proteomic analyses of human lung cells distinguish high pathogenicity influenza viruses and coronaviruses from low pathogenicity virus" by Rashid et al.

(Image adapted from the paper by Rashid et al. The figure on the left illustrates the temporal expression patterns of ZSWIM8 during infection. The Western blot panel shows ZSWIM8 protein levels at 12h, 24h, and 48h post-infection under mock (M) and infected (I) conditions. On the right, the bar graph quantifies the fold-change in ZSWIM8 expression, normalized to mock and GAPDH, as measured by mass spectrometry and Western blot)

The Abbexa ZSWIM8 Antibody (abx126815) was instrumental in validating the downregulation of ZSWIM8 at multiple time points during infection, underscoring its utility in studying key host proteins and their roles in viral pathogenesis (12).

Read the full article here.

Abbexa in Research: “Development of a Rapid Fluorescent Diagnostic System to Detect Subtype H9 Influenza A Virus in Chicken Faeces” by Tuong et al.  

(Image extracted from the paper by Tuong et al. The figure demonstrates the use of Abbexa’s Avian Influenza H9 Virus Antigen Rapid Test Kit (RDT). The kit was tested with five H9 subtype strains (L428, L95, W757, SU-11, and HCO09) at 64 HAU/25 µL. )

Abbexa’s Avian Influenza H9 Virus Antigen Rapid Test Kit (abx092107) was utilised as a benchmark in a study evaluating diagnostic tools for H9N2 influenza, demonstrating its role as a reliable reference for comparing novel assay performance (13). 

Read the full article here.

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References

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5. Chen R, Holmes EC. The evolutionary dynamics of human influenza B virus. J Mol Evol [Internet]. 2008 Jun 27 [cited 2024 Dec 13];66(6):655–63. Available from: https://link.springer.com/article/10.1007/s00239-008-9119-z

6. Jagger BW, Wise HM, Kash JC, Walters KA, Wills NM, Xiao YL, et al. An overlapping protein-coding region in influenza A virus segment 3 modulates the host response. Science (1979) [Internet]. 2012 Jul 13 [cited 2024 Dec 13];337(6091):199–204. Available from: https://www.science.org/doi/10.1126/science.1222213

7. Russell CA, Kasson PM, Donis RO, Riley S, Dunbar J, Rambaut A, et al. Improving pandemic influenza risk assessment. Elife. 2014;3:e03883. 

8. Renegar KB, Small PA, Boykins LG, Wright PF. Role of IgA versus IgG in the Control of Influenza Viral Infection in the Murine Respiratory Tract. The Journal of Immunology [Internet]. 2004 Aug 1 [cited 2024 Dec 13];173(3):1978–86. Available from: https://dx.doi.org/10.4049/jimmunol.173.3.1978

9. Both GW, Sleigh MJ, Cox NJ, Kendal AP. Antigenic drift in influenza virus H3 hemagglutinin from 1968 to 1980: multiple evolutionary pathways and sequential amino acid changes at key antigenic sites. J Virol [Internet]. 1983 Oct [cited 2024 Dec 13];48(1):52. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC255321/

10. Koel BF, Burke DF, Bestebroer TM, Van Der Vliet S, Zondag GCM, Vervaet G, et al. Substitutions near the receptor binding site determine major antigenic change during influenza virus evolution. Science (1979) [Internet]. 2013 Nov 22 [cited 2024 Dec 13];342(6161):976–9. Available from: https://www.science.org/doi/10.1126/science.1244730

11. Chai N, Swem LR, Reichelt M, Chen-Harris H, Luis E, Park S, et al. Two Escape Mechanisms of Influenza A Virus to a Broadly Neutralizing Stalk-Binding Antibody. PLoS Pathog [Internet]. 2016 Jun 1 [cited 2024 Dec 13];12(6):e1005702. Available from: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005702

12. Rashid MU, Glover KKM, Lao Y, Spicer V, Coombs KM. Temporal proteomic analyses of human lung cells distinguish high pathogenicity influenza viruses and coronaviruses from low pathogenicity viruses. Front Microbiol. 2022 Oct 10;13:994512. 

13. Tuong HT, Jeong JH, Choi YK, Park H, Baek YH, Yeo SJ. Development of a rapid fluorescent diagnostic system to detect subtype h9 influenza a virus in chicken feces. Int J Mol Sci [Internet]. 2021 Aug 2 [cited 2024 Dec 13];22(16):8823. Available from: https://www.mdpi.com/1422-0067/22/16/8823/htm