Flu viruses

Influenza viruses are called the monotypic genus Alphainfluenzavirus, Betainfluenzavirus, Gammainfluenzavirus, Deltainfluenzavirus (until October 2018, they were called Influenza A, B, C and D), each of which consists only of the species of the same name. They belong to the family Ortomyxoviridae , which in addition to these four genera includes Izaviruses, Togotoviruses and Quaranfilviruses ^[3] .

Antigenic properties of the internal proteins of the RNP ( born ribonucleoprotein , RNP) of the virion, which do not provide cross-type serological reactions, determine the belonging of the influenza virus to the genus ^[4] .

Further division, in the case of an “A” virus, is carried out according to the subtypes ( serotypes ) of the surface proteins ( glycoproteins ) hemagglutinin (HA) and neuraminidase (NA) ^[4] .

Since 1980, according to the WHO recommendation, the designation of influenza virus strains includes ^{[5] [6]} :

1. type of;
2. place of selection (geographical origin of strain);
3. the index assigned in the laboratory (the serial number of the strain);
4. separation year;
5. (for animal viruses only) the name of the animal that is the natural host of the virus (from which the virus was isolated).
6. the index of surface proteins, placed last and enclosed in parentheses, makes sense only for a virus of type “A”;

Examples: “A (Brazil) 11/78 (H1N1)” (an influenza virus “A” of a person with hemagglutinin H1, neuraminidase N1, isolated in Brazil in 1978), “A / Moscow / 10/99 (H3N2)”, “A / New Caledonia / 120/99 (H1N1)”, “B / Hong Kong / 330/2001”, “A / Fujian / 411/2002 (H3N2)”.

Influenza A and B viruses cause seasonal epidemics in humans ^[7] .

Alphainfluenzavirus

Monotypic genus, former name: "Influenza A". Type A influenza virus.

Annually causes outbreaks of influenza, often - epidemics, periodically - pandemics ^{[8] [9]} . This is due to the high degree of variability of the virus: a virus of type “A” is subject to both antigenic shift (shifta) and antigenic drift ^[10] . In 2018, flu viruses of the A (H1N1) and A (H3N2) subtypes circulate among people ^[7] .

The natural reservoir of influenza A virus are waterfowl. Sometimes it is transmitted to other birds, as a result, it can infect domestic birds, from them - domestic animals and then people, leading to epidemics and pandemics ^[11] .

In birds, the virus infects the epithelial cells in the digestive tract, in humans - the epithelial cells of the respiratory tract ^[12] .

Within the Influenza A species, several serotypes have been isolated (observed in nature) ^{[8] [9]} :

• H1N1 , which caused pandemics of the Spanish flu in 1918 and swine flu in 2009 (according to the old classification, there are three serospecies in it: Hsw1N1, H0N1 and H1N1 ^[6] );
• H1N2 , Endemic to humans, pigs and birds;
• H2N2 , Which caused the pandemic of the Asian flu in 1957;
• H3N2 , Which caused the pandemic of the Hong Kong influenza in 1968;
• H5N1 , which caused the avian flu pandemic in 2004;
• H6N1 , Detected in a single patient, was cured;
• H7N2
• H7N3
• H7N7 , is associated with human conjunctivitis and has a high potential for epizooty ^[13] ;
• H7N9 , Responsible for six epidemics in China, now has a high pandemic potential among other influenza A serotypes ^[14] ;
• H9N2
• H10N7
• H17N10 ^[15]
• H18N11 ^[15]

As of 2016, 18 hemagglutinin (HA) subtypes and 11 neuraminidase (NA) subtypes are known, with a possible total of 198 variants of the virus ^[3] .

Type A virion contains eight segments of viral RNA ^[16] .

Betainfluenzavirus

Monotypic genus, former name: Influenza B. Influenza virus type "B".

Type B influenza virus varies in type of drift, but not in shift ^[10] . It is not divided into subtypes, but can be subdivided into lines. In 2018, influenza viruses of type B lines B / Yamagata and B / Victoria circulate ^[7] .

The natural reservoir of Influenza B is man. The virus infects the upper and lower respiratory tract, the symptoms are similar to those caused by an A-type virus. It has a limited number of lines, which is probably why most people acquire immunity to Influenza B at an early age. Influenza B is variable only in hemagglutinin, antigenic drift of HA is not as active as that of Influenza A ^{[17] [18]} .

Influenza virus “B” causes epidemics, but quite rarely, once every 4–6 years, they develop slowly compared to those caused by the virus “A” and, as a rule, cover 8–10% of the population ^[19] . There are two epidemics in the USSR with highs in the spring of 1963 and in the spring of 1974. In addition, the "B" virus was present in many epidemics together with the "A" virus ^[20] .

Influenza virus type "B" is similar to the virus type "A", they are difficult to distinguish under an electron microscope. The virion envelope "B" contains 4 proteins: HA, NA, NB and BM2. BM2 is the proton channel used when the virus is digested (into the cell). Protein NB is considered an ion channel, but this is not a prerequisite for viral replication in cell culture. The genome of the virus consists of eight fragments of RNA ^[21] .

Gammainfluenzavirus

Monotypic genus, former name: Influenza C Influenza virus type "C".

Influenza virus “C” is detected in patients less frequently than “B” and “A”, it usually leads to mild infections, is not dangerous for humans and does not pose a problem for public health ^{[7] [8]} .

Influenza C’s natural reservoir is human, it also infects pigs and can be transferred between pigs in experiments. It affects the upper respiratory tract, mainly in children, the clinical symptoms are mild. Serological studies have revealed a global prevalence of type “C” virus. Most people get immune to it at an early age ^[17] .

The type C virus does not exhibit an antigenic shift and it changes little ^[10] . Influenza C is antigenically much more stable than type A virus and the high degree of transverse reactivity observed among them isolates these species from each other ^[17] .

Influenza virus “C” causes scattered diseases and almost never causes epidemic outbreaks ^[19] .

Contains 7 genome fragments. It has only one envelope (penetrating through the wall of the victim cell) glycoprotein HEF ( eng. Hemagglutinin esterase fusion - hemagglutinin and esterase fusion), which plays the role of both glycoproteins (HA and NA) of types A and B viruses ^[21] . Not divided into subtypes. Six genome lines have been identified, but due to the frequent recombinations of different lines, new variants have recently emerged that present an epidemic threat ^[17] .

Deltainfluenzavirus

Monotypic genus, former name: Influenza D Influenza virus type "D".

Viruses of the “D” group mainly infect cattle. According to reports, they do not infect people and do not cause them disease ^[7] .

Influenza D strikes cows, which are a natural reservoir, and pigs. It is found in small ruminants (sheep and goats). There are signs of transmission of the type “D” virus from cows to humans - people exposed to cows have antibodies to it, but no infected people have been detected. Structurally similar to a type-C virus, instead of HA and NA it contains HEF ^[22] .

Influenza D contains 7 single-stranded RNA fragments ^[23] , at least 50% of the amino acids coincide with the type C virus, but one of the main proteins, M1, in the type D virus differs from the type C virus. This virus was isolated in a separate form, because when its genetic material is mixed with the “C” virus, they do not give tenacious descendants ^[24] .

The first influenza virus was isolated from birds (chickens) in 1901 in Italy, but was identified as the causative agent of “bird plague” or “chick plague”. (Publication of 1902: Centanni, E .. Die Vogelpest. Zentbl. Bakt. Paraskitkde, Abt. 1, 31, 145-152, 182-201. ^[25] ) 50 years after this, it was established that the bird plague virus is one of the viruses of influenza "A" birds. Then the flu virus “A” was isolated from pigs by an American scientist Richard Shoup ( born Richard Shope ) in 1931 . The human influenza virus was isolated in 1933 in England at the National Institute for Medical Research by virologists Wilson Smith, Christopher Andrews and Patrick Leidlow. In 1940, the influenza virus "B" was isolated. In 1951, according to the technology of cultivating viruses “on chicken embryos”, the influenza virus “C” was isolated. In 2003, as a result of four years of work in the laboratories, the pandemic virus "Spaniard" of 1918 was obtained (restored) and studied ^[9] .

Influenza virus type "D" was first isolated in 2011 in the United States in pigs ^[22] .

In 2013, A-type influenza virus was detected in bats living in Central America with the most recent HA and NA variants: serotype H18N11 ^[15] .

The virion (infectious particle) of influenza has the shape of a sphere ^[26] or approaching a spherical one, its diameter is 100-120 nm ^[19] .

The influenza virus is an enveloped virus: the outer layer is a lipid membrane into which “spikes” are inserted: glycoproteins and the M2 matrix protein, which forms ion channels. Under the lipid membrane, the matrix (matrix) M1 protein is located; it forms the inner layer of the virus envelope, gives stability and rigidity to the outer lipid envelope ^{[26] [27]} .

Hemagglutinin and neuraminidase glycoproteins are key proteins for virus reproduction of types “A” and “B”. Hemagglutinin is used to penetrate the cell, neuraminidase - to exit from it. ^[8] .

Inside the virion is the genome of the virus, which carries genetic information about the envelope and internal proteins of the virus. The genome is presented in the form of a ribonucleoprotein complex vRNP (nucleoprotein in complex with viral genomic RNA), which contains RNA fragments attached to the nucleoprotein protein (NP), and three proteins of the polymerase complex: PB1, PB2 and PA. The interior of the virion also includes the NEP protein ^{[26] [27]} . The virus of type “A” has 8 proteins that encode 11 RNA fragments: HA, M1 ( English matrix 1 ), M2, NA, NP ( English nucleocapsid protein ), NS1 ( English non-structural protein 1 ), NS2 (or NEP, eng. Nuclear export protein , PA ( eng. Polimerase acid ), PB1 ( eng. Polymerase basic 1 ), PB1-F2 ( eng. Polymerase basic 1 frame 2 ), PB2 ^[28] .

Upon infection, cells of type “A” viruses are attached by the outer part of HA to sialic acids on the surface of target cells and virions penetrate into the cell through endocytosis. The low pH inside the endosome causes a change in the second part of the HA, resulting in a change in the conformation of the HA and the viral membrane fuses with the membrane of the endosome. The ion channels formed by M2 protein further lower the pH inside the endosome, as a result, the vRNP complex dissociates from the M1 matrix protein and fragments of viral RNA penetrate into the cytoplasm of the cell and further into the cell nucleus ^[27] .

Replication of viral RNA occurs in the cell nucleus using the viral polymerases PA, PB1 and PB2, synthesis of viral proteins is performed in the cytoplasm, processing of M1, HA and NA proteins occurs in the endoplasmic reticulum and the Golgi apparatus. The synthesized proteins M1, HA, and NA are directed to the membrane ^[27] .

The synthesized NP protein is sent to the nucleus, where it forms a complex with fragments of replicated viral RNA and synthesized polymerases, then with the help of the matrix protein M1 is sent to the cytoplasm and further to the cell membrane ^[27] .

On the cell membrane, new viral particles are assembled from the synthesized proteins, vRNP complexes and the membrane itself, which are budded from the cell with the help of the NA glycoprotein (the “A” virus). NA cleaves sialic acids that prevent the separation of the HA of the viral envelope from the cell ^[27] .

The eighth segment of the RNA virus type "A" encodes non-structural proteins NS1 and NS2. The NS1 protein inhibits the translation of mitochondrial RNA cells, as well as the synthesis and operation of interferon, and is a major factor in the pathogenicity of the influenza virus. The NS2 protein, also known as NEP, provides nuclear export of viral RNA in combination with NP ^[27] .

Influenza virus does not destroy every cell. The following typically occurs: the virus enters the cell, multiplies and goes out of it in an organized manner - the cell remains whole and sometimes alive. In this case, the virus is able to exploit the cell several times ^[8] .

In addition to replicating viral RNA, viral particles in the cell synthesize proteins, one of which, PB1-F2, is released from the cell, in the human body through the bronchi enters the lungs and destroys the macrophages of the lung tissue, thus causing pulmonary infections, in particular, pneumonia ^[8] .

Influenza virus type "A" is characterized by high variability, due to two features of the genome.

The first property, the fragmentation of the genome of a virus, makes it possible to exchange genes between two viruses of the same type, if both of them are infected with the same cells. In this case, two sets of the same genes of two different viruses are synthesized in the cell, and viruses with different combinations of the same genes and with a different set of surface antigens appear in the progeny. Such viruses are called recombinants or reassortants (viruses with reassorted genes), and antigenic shift or shear into the phenomenon. For example, when co-cultivated in H1N1 and H3N2 cells, both initial forms and recombinants are formed in the progeny: H1N1, H3N2, H1N2, H3N1. Gene recombination processes are easily reproduced in the experiment and are often observed in natural conditions. Such a spasmodic change causes a pandemic: people who had previously suffered from the flu are completely susceptible to the new virus, and without meeting collective immunity, it quickly spreads among the world's population. Recombination is one of the main causes of influenza virus variability and is used in the preparation of influenza virus strains for the preparation of vaccines ^[29] .

The second property of influenza viruses - the variability of their glycoproteins (NA and HA) as a result of mutations, antigenic drift - antigenic differences are small at first, but gradually increase ^[29] .

Influenza viruses survive in the air for up to 4 hours, while type “A” viruses are more resistant than “B”. In dried and settled aerosol droplets, the virus remains on bed linen for up to 2 weeks, in room dust - for up to 5 weeks. Wet cleaning with disinfectants completely disinfects the room ^[30] .

The common properties of cultures carrying the influenza virus are ^[31] :

1. intermittent cellular degeneration;
2. a pronounced increase in the life of primarily trypsinized infected cultures compared to non-infected ones;
3. significant changes in the properties of the virus in the process of persistence.

The peculiarities of the epidemic spread of influenza viruses are determined by the highest variability of influenza virus type "A" and significant - type "B". Each new shift or drift version of the virus “A” or “B” is able to overcome the immunity acquired by a person to the previously circulating variants of the same virus ^[6] .

The cause of the global spread of influenza is in the unique features of its pathogens, which have no analogues among other viruses: genome fragmentation and protein variability (glycoproteins), which are associated with influenza immunity ^[19] .

Different serotypes (serological varieties - varieties of the same virus, differing in antigenic composition) do not provide cross-immunity. Antibodies produced in response to the glycoproteins of the virus form the basis of immunity against a particular subtype of the influenza pathogen. Recombination of genes and antigenic shift cause the emergence of new forms of the virus and lead to epidemics and pandemics. Then antigenic drift contributes to the continuation of the epidemic ^[19] .

For 1984, the reasons for the emergence of new or return of old viruses are not completely clear. Some researchers believe that the disappeared viruses remain hidden in the human population, others believe that new viruses arise as a result of recombinations between human influenza viruses and animal influenza viruses, which is confirmed by the identification of viral proteins in birds and birds that are similar or identical to those of the virus, later caused an epidemic ^[19] .

Human influenza A viruses are easily transmitted to domestic animals and birds and cause illness. In nature, there are epizootic flu "A", often among birds. The largest reservoir of influenza "A" animals - birds, and it can be transmitted from birds to mammals. There is an outbreak of a deadly epizootic of influenza, like the plague of birds, among seals in 1979–80 in the American coast of the North Atlantic ^[32] .

Cases of human infection with animal flu are described. Such flu has never been widely spread ^[32] .

The history of antigenic shifts of influenza A virus from 1918 to 1981 ^[33] :

• from 1918 to 1957, three main drift variants Hsw1N1, HON1, H1N1 dominated;
• from 1957 to 1968 - H2N2;
• from 1968 to 1977 - H3N2;
• from 1977 to 1981, two viruses circulate simultaneously: H3N2 and H1N1.

As a result of antigenic drift under the pressure of collective immunity, the most pronounced mutations are selected, and an epidemic is developing. In the first half of the 20th century, such epidemics were observed every 3–5 years, now, with a sharp increase in the population of the planet — almost every year ^[19] .

Type “B” viruses cause the same diseases as type “A”, do not cause pandemics, but lead to greater mortality ^[21]

Contrary to popular belief, the influenza virus causes a person's strong immunity. Repeated incidence of influenza is the result of variability of influenza virus (antigenic drift and antigenic shifts) ^[9] .

• H1N1 flu virus
• H5N1 flu virus
• Orthomyxoviruses
• Influenza A virus (Eng.)
• Influenzavirus B (Eng.)
• Influenzavirus C (English)
• Influenzavirus D (Eng.)
• Flu
• Vaccine for the prevention of influenza
• Antigen drift
• Antigenic variability

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