What leads to the mutation of avian influenza viruses?
Qu Yuan Qu Lai Qu Shaozhong
Qinhuangdao Haigang Hepatitis B Research Institute of Traditional Chinese Medicine （066000）
Abstract
The cause that leads to the mutation of avian influenza viruses is the lack of selenium proteins and the cause of serious lack of selenium in poultrys body is the deficiency of selenium in the fodder plus large consumption of selenium in egg production. The lack of selenium in the fodder is mainly due to the deficiency of selenium in the land. Study shows the outbreak of high causative bird flu in 2005 is closely related with selenium deficiency areas and the deficiency of selenium has something to do with the mutation of avian influenza. The mutation and epidemic (Keshan disease) of another kind of RNA viruses - Coxsackies viruses similar to avian influenza viruses have been controlled with supplementation of selenium, creating a miracle in the history of nutriology, the research method of which can be referred to in the study on avian influenza viruses.
What leads to the mutation of avian influenza viruses? Investigation shows that it is because of the comprehensive nutritional factors including the lack of selenium in the environment, the consumption of selenium in egg production and the scarcity of selenium in viral replication, and the error occurred in viral replication due to the lack of selenium protein has brought about the mutation of low causative avian influenza viruses to high causative ones.
1. Environment factor
Studies indicate that the variation of avian influenza viruses is related with selenium deficiency regions. More than 40 countries and regions in the world are deficient in selenium, mainly in Europe, America, Asia and Southeast Asia and among which, China is seriously deficient in selenium.
In China, there are 45 selenium deficiency bands extending from the Northeast to the Southwest. In addition, parts of Jiangsu, Anhui, Shandong, Ningxia, Gansu and Xinjiang are also short of selenium. There is only 1/3 of the territory of the country that can reach the normal critical value of 100μg /kg as published internationally in terms of selenium contents and the rest 2/3 belongs to selenium deficiency area, among which, the area, seriously short of selenium, with selenium contents ≤20μg /kg accounts for 29%. These figures are based on the statistics conducted in 1980 and since then, our country has witnessed a high speed development and the serious industrial pollution and the discharge of large amount sulfur dioxide have make the selenium in soil synthesized into compound that can not be absorbed by plants It is just in these areas that avian influenza has broken out repeatedly, and each time, it can be confirmed on the selenium distribution map of China. (See Fig. 1)
As seen from the history of avian influenza, the disease was first broken out in Italy, a selenium deficiency country in Europe, followed by Spain, Russia and Holland, which are also short of selenium. In the world, avian influenza disease has broken out for 5 times and most of them happened in selenium deficiency areas, and the areas where avian influenza happened in 2004-2005 are also short of selenium (See Fig 2).
The United States and Canada have also conducted a survey on the selenium contents of their soil, and it can be seen from the selenium distribution map of North America that the epidemic situation of avian influenza in 2005 is also corresponded to the areas of selenium deficiency (see Fig.3)
As the fodder of poultry is inexpensive and most is taken from adjacent resources, the intake of selenium of poultry is dependent on the selenium contents of the local feed chain. The lack of selenium together with the poultry being compelled to produce a large amount of eggs will make the body of the poultry lose its balance, leading to the variation of low causative avian influenza viruses into high causative viruses.
2. Physiological factor
Selenium plays a fundamental role in the generation of human being and animals and is an important substance to increase the fecundity and productivity of animals. As for the poultry, they are reproduced by egg production and hatching, which also need selenium to increase their production and hatching rate. The highest content of selenium is in the semen and ovum of animals (each semen contains selenium and each time of sexual interchange, hundred million of semen is discharged in the period of peak sexual activity in the age between 20 to 40 for human being and in the period of peak egg production for poultry. In this period, the consumption of selenium is the highest, leading to serious shortage of selenium in the body and possibility to be attacked by viruses). This is designed in the breeding instruction of gene. As the main task of gene is to reproduce, the gene keeps most selenium in a spermatic (fallopian) tube to be used for reproduction. Likewise, the poultry also store selenium in their eggs according to gene instruction to meet requirement for reproduction. This is why the content of selenium in eggs is the highest, with goose egg containing 336μg/kg and duck egg 307μg /kg, both reaching the selenium rich standard (280g/kg). The selenium content of hens egg is 223μg /kg, also approaching selenium rich standard. It can be said that poultry are providing high selenium nurture to human being. The study shows that the health of poultry can be guaranteed only if the daily fodder is added with selenium 200μg /kg-400μg /kg in growing period, 500μg /kg in production period and 800μg /kg in anti-infection period (calculated as the actual contents of selenium). But in some countries and regions deficient in selenium, it is difficult to reach the level (because the selenium in soil is provided to animals through plant, and if soil is short of selenium, the fodder is of cause short of selenium.). The excessive extortion to let the poultry produce a large quantity of eggs (up to dozens of method, such as scientific hastening delivery by increasing illumination time) under the condition of lack of selenium to increase egg production 3.4 times from 7.95 million tons in 1990 to 27 million tons in 2004 in our country) has made the body of poultry lose its balance and the extreme shortage of selenium has resulted in the error of avian influenza viruses in their replication due to the lack of selenium proteins and their mutation into high causative viruses in the low selenium body of the poultry [1].
3. Nutrition factor
Studies in recent years have demonstrated that selenium has a direct and indirect relation with viruses, and selenium proteins are certainly present in poxviruses, HIV, hepatitis C viruses and Coxsackies viruses as well as Zaire Ebola viruses, hepatitis B viruses and some human herpes viruses. There are a lot of evidences, demonstrating that selenium plays a key role on the fatality of Coxsackie viruses; selenium deficiency is a dangerous factor in the development and death of AIDS patients; and selenium compound can restrain the pathologic changes of cells induced by HIV and the activation of HIV brought about under oxidized adversity. It is also demonstrated that selenium can, as expected, restrain HIV through the selenium protein mechanism of viruses [2]. Therefore, some people think that selenium is the only nutritious element that has direct relation with viruses [3]. It can be seen that selenium is needed by the organism, also by viruses, but with different quantity. Relatively speaking, the quantity needed by the organism is much larger than that needed by viruses and the organism has priority to use. Therefore, when the organism has enough selenium, viruses will not make mistakes in their replication due to shortage of selenium proteins, but when the selenium in the organism is low and not enough to meet the requirements of viruses to replicate, the viruses will duplicate variants short of selenium, a kind of high causative avian influenza viruses. The following are two cases, which can help us understand the cause of mutation.
3.1 Coxsackie virus, like avian influenza virus, is also a kind of RHA virus. It can mutate and cause the Chinese keshan disease (a typical selenium deficiency disease) and myocarditis, which have been controlled through supplement of selenium. This has always been considered as a miracle [4].
In the United States, over 2 million people are infected with Coxsackie viruses each year, leading to various diseases from cold to carditis. As Coxsackie viruses are most benign, only about 10000 people among the infected suffer from illness. The people deficient in selenium are apt to have carditis, the so called keshan disease. Just as Beck has pointed out, Coxsackie viruses have been found in the patients suffering from this disease.
Beck study group thinks that Coxsackie viruses may mutate into causative viruses in the infected population who are deficient in selenium, and this may help explain why new types of influenza virus continuously appear in China because vast areas of China are short of selenium [5].
It has been proved that Coxsackie virus, especially Coxsackie virus B (CVB), is the major causative agent of human carditis. Beck et al [6-12] have found that selenium deficiency in the host will have influence not only on the immune function but also on the virulence of Coxsackie viruses. Non-causative viruses may quickly mutate in the body of selenium deficiency host and have pathogenicity, and once mutation has happened, host with normal selenium is also apt to be infected by the mutilated strain. Studies have been conducted on selenium deficiency mice, and the result shows that non-causative strain (CVB3/20) can have genetic mutation in the body of selenium deficiency mice and become causative strain (CVB3/20), and if the mutant strain is separated out and inoculated into normal mice with sufficient selenium, is can also cause damage to cardiac muscle of normal mice. This means the mutation can not be reversed. Selenium deficiency can increase the virulence of the strain in the body of mice and intensify the damage to the cardiac muscle. The damage caused to the cardiac muscle by CVB1 and Echo virus (EV9) is significantly higher for the mice taking low selenium food than that for the normal group. Mice deficient in selenium are likely to be infected with CVB and even common viruses.
Beck et al [13] have found that mice deprived of (knocked off) GPX-1 (a kind of selenium protein) gene and infected with non-causative viruses (CVB3/0) will contract myocarditis after the viruses have mutated while the mice with normal GPX-1 genes will not. Genetic mutation has been detected in the sequence measurement of the viruses in the body of GPX-1 gene deprived mice. And in the original viruses taken out of the heart of selenium deficiency mice and in the RNA sequence of CVB3 that causes cardiopathy there are 6 places where mutation has happened. The viruses, once having invaded into the body of mice deficient in selenium, will quickly mutate as the immune system of the mice has been weakened. What is not clear at present is whether the variation from benign viruses to causative viruses needs mutation at all the 6 places or one or two places. However, as can be seen from the fact that no change of viral gene sequence has been found in the body of mice with normal GPX-1 genes, it can be said GPX-1 can prevent non-causative viruses in the body from mutation. However, when the body is deficient in selenium, the activity of GPX-1 will be lowered, non-causative viruses will mutate into causative ones, leading to the damage to the cardiac muscle or myocarditis of the host. GPX-1, therefore, is the key factor between low selenium and viral mutation.
Coxsackie virus is a kind of RNA virus with each nucleotide may be copied 10-3～10-5. This means its genetic mutation rate is 10 times higher than that of leucocyte DNA. The biological foundation of the variation is due to the lack of revision mechanism (RNA revision of replicative enzyme) enjoyed by DNA viruses to identify and correct the replication error. It may further accelerate the evolution rate of viral RNA gene group, which is already very high under the condition of lacking antioxidant (selenium or V it E), and generate much more genetic error.
Recent study shows that Coxsackies B3 virus also has a coded selenium protein promoter, and under the condition of normal selenium contents, the Coxsackies B3 viruses can express its selenium proteins, which has an effect on the replication of the virus itself. But under low selenium condition, the Coxsackies B3 virus can not express its selenium proteins and the restrain on its replication will disappear, allowing the virus duplicate in large numbers, which in turn will provide much more opportunities for mutation [14].
The Chinese Academy of Preventive Medicine also has conducted studies on the relation between low selenium contents and the virulent mutation of Coxsackies virus CVB3/0 and thinks that the Coxsackies virus CVB3/0, after being generated 20 times in umbilical vein endothelial cells cultivated in low selenium sell culture fluid, has a pathological effect on cells, and the mutated strain, after being inoculated in a BALB/c mouse, can cause damage to the cardiac muscle tissue of the mouse. It also believes that the CVB3/0 non-causative strain can not only mutate into causative strain in mice with low selenium contents, the mutation can also appear in human cells in the umbilical vein cultivated in vitro in the culture fluid of low selenium added with H2O2. It is through strengthening the immune system that Selenium is effective in protecting the human body from being attacked by and reducing the mutation of viruses [15].
3.2 A study on influenza virus A conducted in 2001 by another group of scientists in the United States also indicated that the virulence of viral strain inoculated in the mice deficient in selenium will significantly increase.
During the outbreak of SARS viruses, Chen Junshi, a nutritionist of our country advanced a theory that selenium deficiency may strengthen the virulence of mutated SARS viruses [1].
The above theory on the mutation caused by selenium deficiency has aroused wide spread attention, but the study on the mutation caused by avian influenza viruses has just started. As avian influenza viruses, SARS viruses and Coxsackies viruses all belong to RNA viruses and there is great consistency between the studies of them, the study on avian influenza will have a sound foundation. We think that the mechanism that low selenium may cause viral mutation most probably lies in the serious lack of selenium, which makes viruses mutate due to the lack of selenium proteins during their replication (assuming that extraction type egg production will make the body of poultry have not sufficient selenium even for the mutation of viruses), and the lack of selenium proteins at the 6 nucleotide points (234, 788, 2271, 2438, 3324, and 7334) where replication error occurs is the major causative factor. Why the viruses deficient in selenium may have their virulence strengthened? The answer should be that in order to perfect and repair itself, a selenium deficiency gene will not satisfy itself with the selenium supplied by the host (feeding selenium) and destroy much more histiocytes to grab selenium and thus mutate into high causative virus. This is just like a thief in the family who will rob with knife in hand when he (she) is unable to live continuously by stealing and thus cause great trouble to others.
To sum up, the viruses now the people face are mutating at a speed much faster than the development of new vaccines, and this makes the people feel passive. How to change from passive to active? It needs rethinking and studying how viruses may mutate and how to make them stable, and only then can we have our preventive work well done. Otherwise, the vaccines developed by us will always lag behind the mutation of viruses. As the saying in medical terms goes: a good physician only treats persons not yet suffering from diseases instead of those already in illness, the organism is not disturbed by harmful environmental agents when vital energy is sufficiently strong and where can diseases come from when internal genuine vital energy is preserved?, here the vital energy and genuine vital energy also include selenium, which is the only trace element that has direct relation with viruses. After Keshan disease being controlled with selenium supplementation, we should once again make use of scientific selenium supplement to overcome avian influenza, avail ourselves of this opportunity to bring along a series of studies on the mutation laws of RNA viruses inclusive of HIV and HCV, etc. and make contribution to the health of mankind.
　　
References:
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