Over the years of active development of the information space, citizens have already got used to the mysterious names H1N1 or H5N1, and some already even know that the first is swine flu, and the second is bird flu. But until now, few of the ordinary patients - former and future - understand how the influenza virus works and exactly how it works.
How does the flu virus work?
Influenza viruses belong to a separate family of orthomyxoviruses. Their genome does not contain a double-stranded DNA strand, as in humans, but a single-stranded RNA. Moreover, this chain consists of 8 separate fragments encoding a total of only 11 proteins. RNA fragments even replicate, that is, they multiply independently of each other. This is an important point that explains why influenza viruses change so easily and form new varieties. If two different strains of the influenza virus penetrate into the same cell, then they can exchange separate sections of the genome, thus giving birth to new reassortant viruses that did not exist before.
The virus is a sphere in shape. At the very heart of this sphere are fragments of an RNA strand, each of which is associated with a set of proteins responsible for replication of this particular fragment of the genome, that is, they are 8 nucleoproteins. All these nucleoproteins are packaged in a nucleocapsid - a protein shell gracefully twisted with a screw. And on top - and this is a special feature of the so-called enveloped viruses - there is another coating called the supercapsid.
The supercapsid is a critical entity for the influenza virus. In fact, it is a lipid bilayer membrane, which includes several types of glycoproteins - complexes of proteins and carbohydrates. It is by the glycoproteins that scientists determine what kind of strain of the influenza virus got into the test tube. It is thanks to these compounds that the virus enters the cell and multiplies. And finally, it is precisely on contact with glycoproteins that some effective anti-flu drugs are targeted.
Flu virus surface proteins are the key to world ownership
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What unique compounds can be found on the surface of the influenza virus supercapsid?
Hemagglutinin
This is a compound by which the virus, firstly, recognizes the receptors of the cells of the host organism, and secondly, attaches to them. Antibodies to hemagglutinin are formed when a person becomes ill with a certain strain of influenza virus and provide protection against it in the future. There are 16 subtypes of hemagglutinin.
Neuraminidase
This is an enzyme that, firstly, destroys the components of the protective mucus layer on the mucous membranes of the respiratory tract and thereby facilitates the passage of the virus to the target cell. Secondly, neuraminidase takes part in the fusion of a viral particle with a cell. Finally, it ensures the release of new viral particles from the infected cell. If there was no neuraminidase, then the reproduction cycle would be limited to just one cell, and even without the manifestation of any symptoms of the disease. Antibodies to neuraminidase are formed in our body as a result of vaccination - they prevent the influenza virus from spreading throughout the body. There are 9 subtypes of neuraminidase in influenza A viruses and one each in influenza B and C.
M2 protein
This is the so-called ion channel, that is, an adjustable "hole" in the membrane of the virus through which ions can move. Since we are talking about ions, it means that we are also talking about the charges that they carry, that is, during the operation of the ion channel, the pH inside the viral particle will change. The M2 protein is designed to transfer protons, that is, the nuclei of the hydrogen atom with a positive charge (H +).
Reproduction and viremia
So, with the help of neuraminidase, the influenza virus made its way through the mucus layer in the respiratory tract and reached the surface of the epithelial cell, more precisely, to the ciliated epithelium lining them. Neuraminidase has a special "pocket" through which it binds to small carbohydrate residues (oligosaccharides) sticking out of the cell membrane.
In this case, the supercapsid of the virus comes into contact with the cell membrane and their lipid layers merge. As a result, the nucleocapsid, which contains, as we recall, 8 RNA segments, enters the cell, into its cytoplasm.
While the process of penetration of the virus nucleocapsid into the cell is underway, the M2 protein is actively working. It pumps protons inside the virus, which means that the environment inside it becomes more and more acidic. As a result of these manipulations, the contents of the nucleocapsid penetrate into the cell nucleus. At the same time, the viral RNA segments are released in the form of complexes with proteins, which receive all the necessary resources of the cell at their disposal and start the production of new viruses. This is also a very thoughtful process during which "temporary" mRNAs are formed, sent from the nucleus to the cytoplasm in order to organize the synthesis of viral proteins there. Then these proteins are transported to the nucleus, where the viral particles are finally assembled. Some of the new genomic RNAs are used for additional replication of the viral genome.
One can only admire the precision of assembling 8 different viral RNA segments into one future viral particle. It is impossible for two identical segments to enter the same nucleocapsid, and the mechanism of this process is still unknown. At this moment, the formation of reassortant viruses, which we talked about above, can take place. Finally, ready-made nucleocapsids move into the cytoplasm. When passing through the cell membrane, the freshly assembled nucleocapsid receives a supercapsid envelope with the entire set of glycoproteins.
The entire cycle from the penetration of the virus into the cell to the release of new viral particles from it takes from 6 to 8 hours. Numerous viruses come out and infect neighboring cells. Less commonly, virions enter the bloodstream and are carried throughout the body. The spread of the virus through tissues and organs is called viremia. The peak of influenza virus replication is observed in the interval from 24 to 72 hours from the moment the viral particles enter the epithelium of the respiratory tract.
How does the virus affect the body?
When new virions are released, the cells in which they reproduced die. The inflammatory process breaks out. Therefore, with the flu, the upper respiratory tract is primarily affected, gradually the inflammation covers the trachea and bronchi. If viruses enter the bloodstream and spread throughout the body, the infection becomes generalized, and intoxication of the body develops.
The danger of influenza lies in the fact that it affects the blood vessels and the nervous system. Against the background of infection with the influenza virus, there is a massive formation of reactive oxygen species (ROS), that is, free radicals that tend to oxidize everything that gets in their way.
It should be understood that the flu virus itself does not contain toxins. The toxic effect is exerted by compounds that our body produces in an attempt to protect itself from the virus. This reaction is so violent, and the place for the introduction of the virus is chosen so "well" that the person suffers from his own immune system. According to research data, ROS trigger proteolysis processes - the destruction of proteins. This occurs in the airway at the border of the air, resulting in a "respiratory" or "metabolic" explosion.
Since the process of introduction and reproduction of the virus occurs in the respiratory tract, the walls of the capillaries located there (small blood vessels) are affected, first of all. They become more brittle, permeable, which in severe cases leads to disruption of local blood circulation, the development of hemorrhagic syndrome and the threat of pulmonary edema. Against the background of damage to the vascular system, the blood supply to the brain may deteriorate and, as a result, a neurotoxic syndrome is formed.
The immune system at this time activates the production of a huge amount of cytokines - substances that trigger inflammatory reactions and have a cytotoxic effect. Normally, they should deal with the inactivation and elimination of infectious agents. But the scale of the process is so great that a systemic inflammatory reaction develops.
As a result, due to damage to the mucous membrane of the respiratory tract and blood vessels, the ability of the immune system to resist external threats decreases, the activity of protective blood cells of neutrophils decreases. In general, this leads to the activation of existing chronic diseases and increases the threat of bacterial infection. The most severe and common complication of influenza is pneumonia.
Different strains of influenza differ from each other, in particular, in the ability to activate massive ROS production. Therefore, some types of influenza are more severe, while others are easier. To a large extent, the state of the patient's body, his immune status, experience of acquaintance with other strains play a role. Some types of influenza are more dangerous for the elderly and children, while others more often affect the population in their prime.
Influenza Virus Vulnerabilities
To stop the process of virus replication in cells and its spread throughout the body, substances are needed that can interrupt its evolutionary reproduction cycle.
In 1961, scientists proposed combating influenza viruses with amantadine. This compound was approved for use in 1966, and in 1993 rimantadine, its analogue, appeared. Amantadine (and rimantadine) are able to block the ion channels of the M2 protein. This stops virus replication at the initial stages.
The drug was very effective against group A viruses, but had no effect on group B and C viruses. up to 90%. The cause was point mutations in the genome of the virus that occurred during treatment with adamantanes. So today rimantadine and its other analogs are considered ineffective drugs. Moreover, they were initially useless against viruses of groups B and C.
In 1983, neuraminidase inhibitors were developed - substances that block the ability of an enzyme to start the process of leaving an infected cell for new virions. This stops the virus from replicating and spreading.
Neuraminidase inhibitors include oseltamivir (Tamiflu) and zanamivir (Relenza). Since 2009, another drug from this group, administered intravenously, paramivir, has been approved for use in the United States. These drugs are, in fact, the only drugs designed specifically to fight the influenza virus. But they should be taken within 24-48 hours from the moment of the first manifestations of the disease. Later, they will be ineffective - numerous new viruses have already spread throughout the body.
All other so-called antiviral agents do not act on the influenza virus itself or at certain stages of its penetration into the body, reproduction and spread.
conclusions
- The influenza virus is a construct designed by nature to enter the body through the respiratory tract and equipped for this with all the necessary "master keys".
- There are only a few types of drugs that act specifically on the influenza virus, taking into account the characteristics of its life cycle and structure. But one of these drugs is already ineffective, since the virus has adapted to it. And drugs of another type are effective only for a very short period from the moment the first symptoms appear. The anti-influenza effect of other drugs has not been proven.
- Therefore, symptomatic therapy and monitoring of the patient's condition are used to treat influenza. In most cases, with the flu, it is enough just to lie down at home, taking medications to reduce the high temperature, if it has grown to 39 ° C, and other means to alleviate the patient's condition. It is important not to allow the development of complications - for this you just need to create all the conditions for the body to fight the virus.
- Vaccination remains the best way to fight the virus. Even if a person is vaccinated against one strain and picked up another, the available antibodies can provide at least minimal protection and facilitate the course of the disease.
Author: Nesterova Julia