Abstract
The traditional concept of development of highly contagious forms of flu virus assumes that flu virus with pandemic potential arises as result of mutation and/or genetic recombination events in flu viruses of avian, human or other origin. A significant role in the development of a flu epidemic (pandemic) can be attributed to the appearance in the human population of a large group of people who have never had previous contact with the new variant of flu virus. On the basis of data in the literature, this paper proposes that in any discussion of the pathogenesis of flu and other virus infections it is important to keep in mind that in natural conditions among viruses (as in prokaryotic organisms) microecological processes such as interspecies horizontal gene transfer, microbe/microbe interactions (intracellular virus quorum sensing) and bacteria/virus/host crosstalk may take place. It is suggested that maintenance of the normal host microflora is important for protection against both bacterial and viral infections.
Background
Influenza virus (family Paramyxoviridae, genus Paramyxovirus) is a large multisegmented RNA virus that consists of a single-stranded, segmented genome (eight segments in serological types A and B) that is enclosed within a virus-modified host cell membrane. RNA contained in the genome encodes for at least 11 proteins that are expressed in infected cells. Seven or eight proteins are considered to be structural; the others are non-structural virion proteins found only in infected cells. To date, the exact functions of some flu proteins and polypeptides have not been established. Surface flu virus haemagglutinin is responsible for fixation to cell receptors at the initiation of infection and subsequent penetration of the virus genome into the cell cytoplasm. The relationship between virus and host is a complex process that depends on the virus genome, the intracellular machinery of the host, the presence of specific components (receptors, lectin-like compounds) on the surface of virus and cells, the host immune system and many other factors Citation[1]. Ordinary strains of flu virus circulate in nature, mostly producing asymptomatic or mild flu infections in humans, horses, birds and pigs. Various stresses (chemical, physical, biological or their combination) – nutritional factors may be among the most important Citation[2] – facilitate development of flu infection (local epidemic) outset. The fact that many flu epidemics and pandemics originate in the East may be explained as follows. For example, in China there is a region of the Yellow river with a population of more than 300 million. This region is characterized by an extremely low content of selenium in soil, water and foods. As a result, many Chinese have severe selenium deficiencies and suffer from a number specific diseases (e.g. a specific form of heart disease). Selenium deficiency, zinc deficiency, protein-energy malnutrition and/or perhaps other nutrition disorders in the Chinese population in this region may be responsible for replacement of asymptomatic carriage of flu virus by flu disease. Thus, flu epidemics are preceded by sporadic cases and isolated outbreaks.
According to the modern point of view, highly contagious influenza virus is formed as a result of multiple different mutation and/or recombination event(s) in ordinary flu strains during their multiple passages through virus-sensitive hosts. It is expected that genetic recombination of various serological forms of human or bird flu virus strains with each other or human flu virus with flu virus of another origin (e.g. avian, swine) results in the formation of a pandemic form of flu virus that can produce high morbidity and mortality. It is traditionally also expected that, between epidemic periods, a flu pandemic may be connected with increasing numbers of people who have never previously had contact with the flu virus. Being highly sensitive to flu virus this group of people become very ill with influenza Citation[1], Citation[3].
Ecological and epidemiological processes
During the last decade, microbial ecologists have been actively discussing three novel directions in the biology of prokaryotic and eukaryotic organisms, as follows. (i) Horizontal gene transfer in prokaryotes. The main idea is that a significant proportion of the genes of prokaryotic genomes has been subjected to horizontal exchange of genes between bacteria with both archaean and eukaryotic cells. It is suggested that the fixation and short- or long-term persistence of horizontally transferred genes confers a selective advantage on the recipient organism Citation[4]. (ii) Quorum sensing in bacteria. The main idea is that there is regulation of gene expression in response to fluctuations in cell population density. Bacterial quorum sensing is responsible for producing and releasing chemical signal molecules (autoinducers) that, depending on concentration, can regulate such processes as symbiosis, virulence, competence inside particular populations of prokaryotic cells or interspecies interactions Citation[5]. (iii) Host–bacteria crosstalk. Here the main idea is that during their life cycles bacteria and host cells can produce specific compounds that are able to regulate gene expression of each participant of prokaryotic/eukaryotic symbiotic or parasitic relationships Citation[6], Citation[7].
We consider that all three above-mentioned ecological and epidemiological important processes take place in the conversion of ordinary flu virus into a very contagious pandemic-producing form of flu virus. First of all it means that exchange of separate genes or the whole genomic segments among viruses (similar to prokaryotic organisms) may occur not only among strains of flu viruses of various origins but also among flu viruses and other RNA viruses (belonging to different genera and even families) in natural conditions, if these RNA viruses are able to simultaneously infect humans and other mammals and birds. For instance, combined infection of host respiratory tract cells with ordinary flu virus and such RNA-containing respiratory viruses as parainfluenza virus, respiratory syncytial virus, measles virus, rubella virus, mumps virus, rhinoviruses, human coronavirus and/or others may be accompanied by horizontal gene transfer between them, resulting in the formation of a more contagious and less stable new form of flu virus. Another example: the multiplication of flu viruses in host stem cells may be accompanied by transfer of genetic material from these eukaryotic cells into the genome of flu viruses (or flu virus genome can be enclosed within a new virus-modified host stem cell membrane). Finally, RNA transfer from host cell organelles to mature viruses may take place in infected host cells. Such new forms of flu viruses may become completely immunotolerant and able to infect not only respiratory tract cells but other cells of other tissues (e.g. brain, vessels, nerves), rapidly progressing to a fatal outcome. During passages of new forms of flu virus through sensitive humans additional material acquired may persist for a short time or for longer. On the other hand, passages of modified viruses on artificial medium – hen's embryo, for instance – may result in the loss of acquired genetic or membrane material.
It is impossible to rule out the possibility of the existence of virus quorum sensing system and host–bacteria–virus communication in an infected host. For instance, multiplication of flu virus of Chinese origin in the respiratory tract cells of people belonging to white populations may be accompanied by accumulation of specific signal molecules in the cytoplasm of infected cells. These regulator molecules, depending on concentration, may derepress ‘silent’ islands of pathogenicity in the human flu virus genome, converting ordinary virus into a highly contagious and virulent form of flu virus. According to data from Russian microbiologists, the vast majority of Russian people now have serious disorders in the microflora of their intestinal and respiratory tracts. Imbalance of the normal microflora may create conditions for colonization and penetration of flu viruses into respiratory tract cells. It is known that microecological imbalance in humans and animals is accompanied by sharp increases of a number of opportunistic pathogens producing a large quantity of various types of proteases in intestinal and respiratory tracts. These proteases can actively cleave flu virus surface glycoproteins (e.g. haemagglutinin, controlling viral receptor binding). As a result the flu virus has improved ability to bind, enter and infect the cells of the respiratory tract. In addition, it is known that the respiratory tracts of people suffering from severe influenza usually contain increased numbers of Haemophilus influenzae. This prokaryotic microorganism can produce specific proteases that are able to degrade IgA and possibly interferon. These secretory immunoglobulins are responsible for local antibacterial and antiviral immunity. In the absence of virus-neutralizing IgA the ability of flu viruses to colonize respiratory tract cell receptors, and to infect the cells and overcome or avoid host antiviral immune responses, may be greatly increased. The events described above may be examples of flu viral infectivity promotion through a host–bacteria–virus crosstalk mechanism.
Conclusion
To understand and estimate the biological significance of the microecological mechanisms discussed above in the development of a highly contagious pandemic form of flu viruses in natural conditions will require direct experimental studies. But without doubt, the maintenance and correction of normal host microflora is one of the important measures of control for intervention in the spread of any pathogens and their host–host transmission. In our opinion this approach should be included in the list of measures directed against future flu endemics and pandemics.
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