# SİMGE SÜRMEN - 16056038, INFLUENZA VIRUSES

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> [name=Simge Sürmen]

> [time= Thurs, June 03 2021, 01:00 PM]

**Influenza: [Virology by P. Saravanan, 2017]**
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# Influenza Viruses

## Morphology

* Influenza is an infectious respiratory disease; in humans, it is caused by influenza A (genus influenzavirus A) and influenza B (genus influenzavirus B) viruses (influenzavirus C and influenzavirus D genera are also known).
* Influenza A and B cause influenza in humans.

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**Graphic 1: Influenza A viruses are further classified into subtypes, while influenza B viruses are further classified into two lineages.**

**Both influenza A and B viruses can be further classified into specific clades and sub-clades.**

Source: https://www.cdc.gov/flu/about/viruses/types.htm

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**Figure 1: Influenza Virus Types.**
Source: https://www.researchgate.net

* Influenza A and B are morphologically similar, on the contrary, Influenza C has different morphology from them.
* The most important distinctive feature of C is in particular having only a single glycoprotein spike.

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**Table 1: Influenza Virus Types and Features.**


Source: https://www.researchgate.net/figure/1-Characteristics-of-Influenza-Virus_tbl1_316634161

* Influenzavirus A is divided into subtypes, based on their differences in H and N proteins. Fourteen subtypes of H protein (H1–H14) and 9 of N proteins (N1–N9) are known in birds.

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**Figure 2: Influenza Virus.**
Source: wikipedia.com

* Influenza virions are spherical and 80–120 nm in diameter.
* Some forms may be length than 1000 nm in diameter.
* The nucleocapsid has helical symmetry with a core of 8 segmented ssRNA (–), ~9kb (about 5000 kDa).

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**Picture 1: Influenza Virus.**
https://www.healio.com/news/infectious-disease/20200917/efforts-to-prevent-covid19-led-to-global-decline-in-flu

* RNA genome is associated with an RNA polymerase (PA, PB1, PB2) proteins to form a ribonucleoprotein (RNP) arranged in a helix.

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**Figure 3: Influenza Virus Structure.
The nucleocapsid is surrounded by a matrix protein (M1) layer. This layer is surrounded by a lipid bilayer envelope derived from the host plasma membrane.**

**The M2 protein crosses the envelope to form ion channels that allow pH changes in the endosome.**

Source: https://www.nature.com/articles/s41572-018-0002-y
Krammer, F., Smith, G.J.D., Fouchier, R.A.M. et al. Influenza. Nat Rev Dis Primers 4, 3 (2018). https://doi.org/10.1038/s41572-018-0002-y

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**Table 2: Targeting and Protein Description of Influenza Virus.**
Source: https://www.cusabio.com/infectious-diseases/influenza-virus.html

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* The envelope of influenza virus A and B has two types of glycoprotein projections or spikes, the haemagglutinin (H) and the neuraminidase (N) proteins.
* The H' peplomers have 500 tapered projections.
* Their wide ends are out. Their narrow ends are located inside and embedded in the lipid membrane.
* The ‘N’ peplomers are 100 mushroom shaped projections per virion measuring 9 nm in length.
* The virus particles bind to host cell through sialic acid receptor by ‘H’ peplomers.

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**Figure 4: Components of Influenza Virus Virion.**
https://www.nature.com/articles/s41572-018-0002-y
Krammer, F., Smith, G.J.D., Fouchier, R.A.M. et al. Influenza. Nat Rev Dis Primers 4, 3 (2018). https://doi.org/10.1038/s41572-018-0002-y

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## Antigenic Structure and Variation

* Influenza virus, antigenic structure include haemagglutinin (H) glycoprotein composed of two polypeptides HA1 and HA2 strain specific.
* Neuraminidase (N) glycoprotein enzyme which destroys cell receptors by hydrolytic cleavage and strain specific like H,
* Matrix (M) protein which is genus specific, and ribonucleoprotein (RNP) that is genus specific.

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**Figure 5: Influenza Virus Antegenic Structure.**
* 5A: Antigenic Drift Process, is defined as antigenic drift, the gradual sequential change that occurs regularly at frequent intervals in the antigenic structure. This process is due to mutations in the H or N genes. As a result, they may react with antisera against the previous virus strain.
* 5B: Antigenic Shift Process; This is an abrupt, drastic, discontinuous variation in the antigenic structure resulting in a new virüs strain unrelated antigenically to predecessor virus strain. It may involve both H and N genes. This is a result of genetic recombination in doubly infected cells.

Source: http://frontiersmag.wustl.edu/2017/12/15/the-challenges-of-neutralizing-influenza-and-the-quest-for-a-universal-vaccine/

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* Influenza vaccines are formulated every year to match the circulating strains, as they evolve antigenically owing to antigenic drift.
* But, vaccine efficacy is not optimal and is dramatically low in the case of an antigenic mismatch between the vaccine and the circulating virus strain.

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## Replication

* After attachment to the specific receptors on the cell membrane, virions are taken into the cell by endocytosis and then transported to vacuoles (endosomes), where the acid pH induces a change in the configuration of the HA.
* This rearrangement of the HA brings a special set of catalytic amino acids, the ‘fusion sequence’, in contact with the lipid of the vacuole Wall.
* Fusion of the viral and vacuole lipids triggers release of the virus ssRNA, which is transported immediately to the host-cell nucleus.

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**Figure 6: Influenza Virus Replication Cycle.**

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* Simultaneously protons pass along the M2 ion channel to the interior of the virion and cause M1 protein to be released from the RNP complex.
* Thus the RNP : RNA complex can enter the cell nucleus for transcription and replication.
* The new influenza virions are assembled at the host cell surface membrane and released by a process of budding in which both HA and NA are involved.
* Viral NA has the important function of cleaving sialic acid from viral and cellular glycoproteins, thus preventing virus aggregation and allowing individual virions to be released from the cell.

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**Figure 7: Genomes of influenza viruses.**

Source:https://www.intechopen.com/books/current-issues-in-molecular-virology-viral-genetics-and-biotechnological-applications/gene-constellation-of-influenza-vaccine-seed-viruses
**DOI: 10.5772/55289**

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## Pandemic Influenza

* The severity of pandemic influenza depends on multiple factors, including the virulence of the pandemic virus strain and the level of pre-existing immunity.

**Figure 8: Development of Influenza Virus**

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**Figure 9: History of Influenza.**
Source: https://www.researchgate.net/figure/Schematic-of-Influenza-A-B-and-C-virus-structure-Influenza-A-is-defined-by-its-surface_fig2_330745030

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**Table 3: Strains of influenza virus that caused pandemics.**
Source: https://www.researchgate.net/figure/Schematic-of-Influenza-A-B-and-C-virus-structure-Influenza-A-is-defined-by-its-surface_fig2_330745030

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## Pathogenisis

* The route of entry of the virus is the respiratory tract. The viral neuraminidase facilitates attachment by hydrolyzing the mucous film lining the respiratory tract exposing the cell receptors.
* Incubation period is short varying from 1–4 days. Influenza virus symptoms: fever, sore throat, runny nose, cough, headache, muscle pain and fatigue.

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## Prophylaxis

* Prophylaxis Vaccination is the main preventive measure for influenza, but difficulty in immunoprophylaxis attribute to frequent antigenic variation.
* Both inactivated and live vaccines are available.

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**Table 4: Inactivated influenza vaccines.**
Source: [Virology by P. Saravanan, 2017]

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**Table 5: Releated Proteins for Vaccination**
Source: https://www.cusabio.com/infectious-diseases/influenza-virus.html