Posted: April 30th, 2022

What are the virological aspects of seasonal influenza?

What are the virological aspects of seasonal influenza?
Seasonal influenza, or the flu, is a common infectious disease that affects millions of people worldwide every year. It is caused by different types of influenza viruses that belong to the family Orthomyxoviridae. These viruses can change over time and cause outbreaks of respiratory illness in humans and animals. In this paper, we will discuss the virological aspects of seasonal influenza, including its types, subtypes, lineages, transmission, replication, evolution, and prevention.

Types of seasonal influenza viruses

There are four types of influenza viruses: A, B, C, and D. However, only types A and B cause seasonal epidemics of disease in humans (WHO, 2023). Type C virus is less common and usually causes mild infections, while type D virus mainly affects cattle and has not been reported to infect humans (Ducatez, 2015).

Influenza A viruses are divided into subtypes based on the combinations of two surface glycoproteins: haemagglutinin (HA) and neuraminidase (NA). There are 18 HA subtypes (H1–H18) and 11 NA subtypes (N1–N11) identified so far. Influenza A viruses can infect various animal species, such as birds, pigs, horses, dogs, cats, and bats. Some of these viruses can cross the species barrier and infect humans, sometimes causing pandemics. For example, the 2009 pandemic was caused by a novel influenza A (H1N1) virus that originated from pigs (A (H1N1)pdm09) (ECDC, 2023).

Influenza B viruses are not classified into subtypes but can be divided into two antigenically distinct lineages: Victoria and Yamagata. Influenza B viruses mainly circulate among humans and do not infect animals. They tend to cause less severe disease and fewer complications than some influenza A viruses (WHO, 2023).

Transmission of seasonal influenza viruses

Seasonal influenza viruses are transmitted from person to person through respiratory droplets that are generated when an infected person coughs or sneezes. The droplets can land on the mucous membranes of the nose, mouth, or eyes of a susceptible person who is within 1–2 meters of the source. Alternatively, the droplets can contaminate surfaces or objects that are touched by an infected person or a susceptible person. The virus can then be transferred to the mucous membranes by hand contact. Aerosol transmission can also occur in some settings where small droplets remain suspended in the air for longer periods of time (Killingley, 2013).

The incubation period of seasonal influenza is usually 1–4 days, with an average of 2 days. The infectious period of seasonal influenza is estimated to be from one day before the onset of symptoms to 5–7 days after. However, some people may shed the virus for longer periods, especially children and immunocompromised individuals (ECDC, 2023).

Replication of seasonal influenza viruses

Seasonal influenza viruses enter the respiratory epithelial cells by binding to specific receptors on the cell surface. The receptors are sialic acid molecules that are attached to glycoproteins or glycolipids on the cell membrane. The type and distribution of sialic acid receptors determine the host range and tissue tropism of influenza viruses. For example, human influenza viruses preferentially bind to sialic acid receptors that are linked to galactose by an alpha-2,6 linkage (SAα2-6Gal), while avian influenza viruses preferentially bind to sialic acid receptors that are linked to galactose by an alpha-2,3 linkage (SAα2-3Gal) (Skehel and Wiley, 2000).

After binding to the receptors, the virus is internalized by endocytosis into an endosome. The acidic environment of the endosome triggers a conformational change in HA that exposes a fusion peptide that inserts into the endosomal membrane. This allows the viral envelope to fuse with the endosomal membrane and release the viral ribonucleoprotein (RNP) complexes into the cytoplasm. The RNP complexes consist of eight segments of negative-sense single-stranded RNA (ssRNA) that are associated with nucleoprotein (NP) and three polymerase proteins: PB1, PB2, and PA.

The RNP complexes are transported to the nucleus where they are transcribed and replicated by the viral polymerase complex. The transcription produces messenger RNAs (mRNAs) that are capped and polyadenylated by stealing host cell pre-mRNAs. The mRNAs are exported to the cytoplasm where they are translated into viral proteins by the host cell ribosomes. The replication produces complementary positive-sense ssRNA (cRNA) that serves as a template for the synthesis of more negative-sense ssRNA. The newly synthesized ssRNA segments are assembled with NP and polymerase proteins to form new RNP complexes that are exported to the cytoplasm.

The viral proteins are transported to the endoplasmic reticulum (ER) and the Golgi apparatus where they undergo post-translational modifications, such as glycosylation and cleavage. HA and NA are inserted into the membrane of the ER and then transported to the Golgi apparatus where they are sorted and packaged into vesicles. The vesicles fuse with the plasma membrane and release the HA and NA to the cell surface. M1 and M2 are matrix proteins that form a layer under the viral envelope. M1 binds to the RNP complexes and mediates their incorporation into budding virions. M2 is an ion channel that regulates the pH inside the virion. NS1 and NS2 are non-structural proteins that are involved in inhibiting host cell antiviral responses and facilitating viral assembly and release, respectively. NEP (also known as NS2) is a nuclear export protein that mediates the export of RNP complexes from the nucleus. PB1-F2 is a pro-apoptotic protein that is expressed from an alternative reading frame of PB1. It can enhance viral pathogenicity by inducing cell death and inflammation.

The assembly and release of seasonal influenza viruses occur at the plasma membrane of the infected cell. The RNP complexes, M1, and NEP interact with HA, NA, and M2 at specific lipid rafts that are enriched in cholesterol and sphingolipids. The virus buds from the cell membrane and acquires an envelope that contains HA, NA, and M2. The virus is then released from the cell by the action of NA, which cleaves the sialic acid receptors and prevents the virus from re-attaching to the same cell.

Evolution of seasonal influenza viruses

Seasonal influenza viruses evolve rapidly due to two main mechanisms: antigenic drift and antigenic shift. Antigenic drift refers to the accumulation of point mutations in the genes encoding HA and NA, which result in changes in their antigenic properties. Antigenic drift allows the virus to escape from the host immune system and cause recurrent infections. Antigenic shift refers to the reassortment of gene segments between different influenza viruses, which result in new combinations of HA and NA subtypes. Antigenic shift can lead to major changes in antigenicity and infectivity, and potentially cause pandemics if a novel virus emerges that can efficiently transmit among humans.

Antigenic drift occurs constantly in seasonal influenza viruses due to the lack of proofreading activity of the viral polymerase complex, which introduces errors during RNA replication. The rate of mutation is estimated to be about 10^-3 per nucleotide per replication cycle for influenza A viruses, and about 10^-4 for influenza B viruses (Nobusawa and Sato, 2006). The mutations that affect HA and NA can alter their binding affinity to sialic acid receptors, their susceptibility to neutralizing antibodies, or their enzymatic activity. Some mutations may confer a selective advantage to the virus by increasing its fitness or evading host immunity. These mutations may be fixed in the viral population through natural selection and genetic drift, resulting in antigenic variants that differ from previous strains.

Antigenic shift occurs occasionally in influenza A viruses due to their ability to infect multiple animal species and exchange gene segments through reassortment. Reassortment can occur when two or more different influenza A viruses co-infect the same cell and produce progeny viruses that contain a mixture of gene segments from both parental viruses. Reassortment can generate new combinations of HA and NA subtypes that have not been previously encountered by humans or have not circulated for a long time. These new subtypes may have novel antigenic properties that can evade pre-existing immunity in humans and cause severe disease. Reassortment can also affect other gene segments that may influence viral replication, pathogenicity, or transmissibility.

Prevention of seasonal influenza

The best way to prevent seasonal influenza is by vaccination. Vaccination stimulates the production of antibodies that can recognize and neutralize specific strains of influenza viruses. Vaccination can reduce the risk of infection, severity of illness, complications, hospitalization, and death due to seasonal influenza.

However, vaccination is not 100% effective because seasonal influenza viruses constantly change through antigenic drift and antigenic shift. Therefore, vaccines need to be updated regularly to match the circulating strains. The World Health Organization (WHO) monitors global influenza activity and recommends vaccine strains twice a year: in February for the northern hemisphere season, and in September for the southern hemisphere season. The vaccine strains are selected based on their antigenic similarity to recent isolates, their prevalence and geographic distribution

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