Avian Influenza - Causes and Pathogenesis

Causes of bird flu

The cause of bird flu in humans is the influenza A virus of the Influenzavirus genus of the Orthomyxoviridae family. It is classified as an enveloped virus. The virion has an irregular or oval shape, covered with a lipid membrane penetrated by glycoprotein spikes (spicules). They determine the hemagglutinating (H) or neuraminidase (N) activity of the virus and act as its main antigens. There are 15 (according to some data, 16) variants of hemagglutinin and 9 - neuraminidase. Their combination determines the presence of virus subtypes, and 256 combinations are theoretically possible. The modern "human" influenza virus has combinations of H1, H2, H3 and N1, N2 antigens. According to seroarchaeological studies, the severe pandemic of 1889-1890. was caused by the subtype H2N2, the moderate epidemic of 1900-1903 - by the subtype H3N2, the "Spanish flu" pandemic of 1918-1919 - H1N1, containing an additional protein obtained from the avian influenza virus. Epizootics of avian influenza in recent years are associated with subtypes H5N1, H5N2, H5N8, H5N9, H7N1, H7N3, H7N4. H7N7. Subtypes H1, H2, H3, N2, N4 circulate in wild bird populations, i.e. similar to the human influenza A virus.

Under the lipid membrane there is a layer of matrix protein M-protein. The nucleocapsid, located under the two-layer membrane, is organized according to the type of helical symmetry. The genome is represented by single-stranded RNA consisting of eight separate segments. One of the segments codes for non-structural proteins NS1 and NS2, the rest code for virion proteins. The main ones are NP, which performs regulatory functions, M-protein, which plays an important role in the morphogenesis of the virus and protects its genome, and internal proteins - P1-transcriptase, P2-endonuclease and B3-replicase. Differences in the structural proteins of the "bird" flu virus and human flu represent an insurmountable species barrier that prevents the replication of the bird flu virus in the human body.

Different subtypes of this virus have different virulence. The most virulent is the H5N1 subtype, which has acquired a number of unusual properties in recent years:

• high pathogenicity for humans;
• the ability to directly infect humans;
• the ability to cause hyperproduction of proinflammatory cytokines, accompanied by the development of acute respiratory distress syndrome;
• the ability to cause multi-organ damage, including damage to the brain, liver, kidneys and other organs;
• resistance to the antiviral drug rimantadine;
• resistance to the effects of interferon.

The bird flu virus, unlike the human flu virus, is more stable in the environment. At a temperature of 36°C, it dies in three hours, at 60°C - in 30 minutes, and instantly during heat treatment of food products (boiling, frying). It tolerates freezing well. It survives in bird droppings for up to three months, in water at a temperature of 22°C - four days, and at 0°C - more than a month. It remains active in bird carcasses for up to a year. It is inactivated by conventional disinfectants.

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Pathogenesis of avian influenza

At present, the mechanism of development of influenza caused by the H5N1 virus in humans has not been sufficiently studied. It has been established that the site of its replication is not only the epithelial cells of the respiratory tract, but also enterocytes. Taking into account general biological and immunopathological processes, it can be assumed that the pathogenesis of influenza A (H5N1) in humans will develop according to the same mechanisms.

Various hemagglutinins of avian influenza viruses differ in their ability to recognize and bind to the receptor - sialic acid linked in the oligosaccharide of cell membranes with galactose. Hemagglutinins of human influenza viruses interact with residues of this acid, united by a 2,6 bond with galactose, and hemagglutinin of avian influenza viruses recognizes it in a 2,3 bond with galactose residues. The type of bond of the terminal sialic acid and the conformational mobility of the oligosaccharides of surface lectins are the main elements of the interspecies barrier for avian and human influenza viruses. Lectins of human tracheal epithelial cells include lectins with a 2,6 bond type and do not contain oligosaccharides with a 2,3 bond type, characteristic of epithelial cells of the intestinal tract and respiratory tract of birds. Changes in the biological properties of the highly pathogenic strain of the A (H5N1) virus, its ability to overcome the interspecies barrier can lead to damage to various types of human cells with the development of more severe forms of the disease. In the clinical picture of such pathologies, along with catarrhal syndrome, damage to the gastrointestinal tract develops.

Epidemiology of avian influenza

The main reservoir of the virus in nature are migratory waterfowl belonging to the orders Anseriformes (wild ducks and geese) and Charadriiformes (herons, plovers and terns). Wild ducks are of the greatest importance. Influenza viruses in Eurasia and America evolve independently, so migration between continents does not play a role in the spread of the virus; flights by longitude are of decisive importance. For Russia, the Central Asian-Indian and East Asian-Australian migration routes are important in this regard. They include routes going to Siberia through Malaysia, Hong Kong and China, i.e. regions where new variants of the virus are intensively forming. The East African-European and West Pacific routes are less significant.

In wild waterfowl, the virus does not cause clinically evident disease, although a large-scale severe influenza epizootope has been described in Arctic terns. Replication of the virus in birds occurs primarily in the intestines and, accordingly, it is released into the environment with feces, and to a lesser extent with saliva and respiratory material. 1 g of feces contains enough virus to infect 1 million heads of poultry.

The main mechanism of virus transmission in birds is feco-oral. Waterfowl (ducks) are capable of transmitting the virus transovarially and, thus, serve as its natural reservoir and spread it along their migration routes. They are the main source of infection for domestic birds, which, on the contrary, suffer from severe forms of flu, accompanied by their mass death (up to 90%). The most dangerous subtype is H5N1. Infection occurs in conditions of free keeping and the possibility of contact with their wild counterparts. This is especially characteristic of the countries of Southeast Asia (China, Hong Kong, Thailand, Vietnam and other countries). There, along with large poultry farms, there are many small peasant farms.

The bird flu virus can affect mammals: seals, whales, minks, horses and, most importantly, pigs. Cases of the virus penetrating the population of the latter were noted in 1970, 1976, 1996 and 2004. These animals can also be affected by the human flu virus. Currently, human susceptibility to such bird viruses is low. All cases of infection were recorded in those who had long-term and close contact with sick birds. An experiment conducted in the UK on introducing various subtypes of the virus into the body of volunteers gave a negative result.

In Thailand, where the population is 60 million people, during an epizootic that affected two million birds, 12 cases of the disease in people were reliably established. In total, by 2007, about 300 episodes of "bird" flu in people were registered. Two cases of infection from a sick person were officially recorded.

These data indicate that circulating strains of avian influenza virus do not pose a serious threat to humans. Thus, it can be concluded that the interspecies barrier is quite strong.

However, there are facts that allow us to consider that bird flu is a global threat. Firstly, the above information can be interpreted from other positions.

• Even isolated cases of infection of people from birds and from sick people indicate that the insurmountability of the interspecies barrier is not absolute.
• The actual number of cases of infection from poultry, and possibly from sick people, given the real situation in regions where epizootics are raging, may be many times higher. During the H7N7 flu epizootic in Holland, 77 people fell ill, one died. High antibody titers were found in people in contact with sick people, which also indicates the possibility of transmission of the virus from person to person, but with a loss of virulence.

Secondly, the mutagenic potential of the avian influenza virus, especially the H5N1 subtype, is very high.

Thirdly, pigs are susceptible to avian and human influenza viruses, so it seems theoretically possible for the pathogens to meet in the animal's body. Under these conditions, they can hybridize and produce assortant viruses that are highly virulent, similar to avian influenza viruses, and at the same time can be transmitted from person to person. Due to the widespread spread of avian influenza, this probability has increased dramatically. Cases of humans becoming infected with swine influenza have also been described, but the simultaneous penetration of the two viruses into the human body is still less likely.

Fourthly, genetic methods have proven that the Spanish flu pandemic of 1918-1919 had an “avian” origin.

Fifthly, in modern conditions, due to globalization processes and the availability of fast modes of transport, the possibility of the spread of the assortant virus increases sharply. Thus, it is fair to conclude that the probability of the emergence of a new variant of the influenza A virus and the emergence of a severe pandemic is very high.

Mathematical modeling methods have shown that in a city with a population of seven million (Hong Kong), the number of people infected at the peak of the epidemic could reach 365 thousand people daily (for comparison, in Moscow during the flu pandemic in 1957 this number did not exceed 110 thousand people per day). According to WHO experts, it is possible that the rapid culling of birds during the epizootic in Hong Kong in 1997 prevented a flu pandemic. US experts predict that in the event of a pandemic in America, 314 to 734 thousand people will need to be hospitalized, and 89 to 207 thousand will die.

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