The Historical/Evolutionary Cause And Possible Treat- Ment Of Pandemic COVID-19 (SARS-CoV-2, 2019-CORONA VIRUS): World-War III: The Blackout Of The Modern World By Neglected Small Infectious Agent

Background: A virus is a small infectious agent that replicates only inside the living cells of an organism. Viruses can infect all types of life forms, from animals and plants to microorganisms, including bacteria and Archaea. In evolution, viruses are an important means of horizontal gene transfer, which increases genetic diversity in a way analogous to sexual reproduction. Influenza (Including (COVID-19), is an infectious disease caused by an influenza virus. Some viruses especially smallpox, throughout history, has killed between 300500 million people in its 12,000-year existence. As modern humans increased in numbers, new infectious diseases emerged, including SARS-CoV-2. We have two groups of virus, RNA and DNA viruses. The most brutal viruses are RNA ones like COVID-19 (Sars-CoV-2). Introduction: Corona viruses are a group of viruses that cause diseases in mammals and birds. In humans, corona viruses cause respiratory tract infections that are typically mild, such as some cases of the common cold (among other possible causes, predominantly rhinoviruses), though rarer forms can be lethal, such as SARS, MERS and COVID-19. Symptoms vary in other species: in chickens, they cause an upper respiratory tract disease, while in cows and pigs they cause diarrhea. Corona viruses constitute the subfamily Orthocoronavirinae, The genome size, corona viruses ranges from approximately 27 to 34 kilo bases, the largest among known RNA viruses. Discussion and Results: We have researched from the first virus in the planet to the last mutated version which is SARS-COV-2. We have collected many informative data in tables and figures to reach the main cause of 2019-Coronavirus and calculated the probability and estimated deaths in the current time. We have discussed about the possible treatment and prevention of the virus and did algebraic calculations on the epidemiology, the size and even the future of this pandemic. The only era which any virus had not been epidemic, were through world war 2, were the German scientists had found the way to fight any viral infections which is very important and can help scientists to reach the main treatment of the new 2019-Coronavirus. We have sorted the deadly and non-deadly corona viruses and explained how this epidemic had begun through Evolutionary Medicine (EM). The result of the article is that 16% of the whole population in the world has been contaminated which is 1248000000 of 7.8 billion people world-wide. SARS-CoV-2 is an RNA virus. Its nucleic acid is single-stranded RNA (ssRNA). The polarity of this virus is positive-sense ((+) ssRNA). Positive-sense viral RNA is similar to mRNA and thus can be immediately translated by the host cell. Recombination in RNA viruses appears to be an adaptation for coping with genome damage. Recombination can occur infrequently between animal viruses of the same species but of divergent lineages. The resulting recombinant viruses may sometimes cause an outbreak of infection in humans. RNA viruses have very high mutation rates this is one reason why it is difficult to make effective vaccines to prevent diseases caused by RNA viruses. The resulting recombinant viruses causes an outbreak of infection in humans. Conclusion: In conclusion, the mutation of the SARS-CoV and influenza viruses through Drift and Reassortment is the main cause of SARS-CoV-2 through natural selection, Lamarckian Evolution and co evolution which caused this RNA virus so powerful, unpredicted and different in the genome size and nations worldwide. The first Pandemic of Influenza was first detected in 1732 and this virus evolved through natural selection till 2019 which caused the worldwide pandemic of SARS-CoV-2. Based on many studies, inhalation of Ozone plus Sulfur Dioxide, increasing the amounts of L-Glutathione (Which is low in children and older adults and this is the main reason why older adults and children die from this disease.) plus Viral Phage Therapy (VPT) which we discussed fully in this article can be the possible prime treatment of SARS-CoV-2 infection. The seasonal temperature cannot be useful in controlling/reducing the pandemic of this virus since the natural selection, Lamarckian Evolution and high mutation of the virus helps its survival. No antiviral drugs will be useful against SARS-CoV-2 because of high rate of mutation and primarily adaptation of the virus to the drugs and even the environmental Temperature.


INTRODUCTION Brief History of Viruses
Prehistory the world, new infectious diseases emerged, including those caused by viruses. [1] Earlier, humans lived in small, isolated communities, and most epidemic diseases did not exist. [2][3] Smallpox, which is the most lethal and devastating viral infection in history, first emerged among agricultural communities in India about 11,000 years ago. [4] The virus, which only infected humans, probably descended from the poxviruses of rodents. [5] Humans probably came into contact with these rodents, and some people became infected by the viruses they carried. When viruses cross this socalled "species barrier", their effects can be severe, [6] and humans may have had little natural resistance. Contemporary humans lived in small communities, and those who succumbed to infection either died or developed immunity. This acquired immunity is only passed down to offspring temporarily, by antibodies in breast milk and other antibodies that cross the placenta from the mother's blood to the unborn child's. Therefore, sporadic outbreaks probably occurred in each generation. In about 9000 BC, when many people began to settle on the fertile flood plains of the River Nile, the population became dense enough for the virus to maintain a constant presence because of the high concentration of susceptible people. [7] Other epidemics of viral diseases that depend on large concentrations of people, such as mumps, rubella and polio, also first occurred at this time. [8] The Neolithic age, which began in the Middle East in about 9500 BC, was a time when humans became farmers. [9] This agricultural revolution embraced the development of monoculture and presented an opportunity for the rapid spread of several species of plant viruses. [10] The divergence and spread of sobemovirusessouthern bean mosaic virusdate from this time. [11] The spread of the potyviruses of potatoes, and other fruits and vegetables, began about 6,600 years ago. [10] About 10,000 years ago the humans who inhabited the lands around the Mediterranean basin began to domesticate wild animals. Pigs, cattle, goats, sheep, horses, camels, cats and dogs were all kept and bred in captivity. [12] These animals would have brought their viruses with them. [13] The transmission of viruses from animals to humans can occur, but such zoonotic infections are rare and subsequent human-to-human transmission of animal viruses is even rarer, although there are notable exceptions such as influenza. Most viruses are species-specific and would have posed no threat to humans. [14] The rare epidemics of viral diseases originating in animals would have been short-lived because the viruses were not fully adapted to humans [15] and the human populations were too small to maintain the chains of infection. [16] Other, more ancient, viruses have been less of a threat. Herpes viruses first infected the ancestors of modern humans over 80 million years ago. [17] Humans have developed a tolerance to these viruses, and most are infected with at least one species. [18] Records of these milder virus infections are rare, but it is likely that early hominids suffered from colds, influenza and diarrhoea caused by viruses just as humans do today. More recently evolved viruses cause epidemics and pandemics. [17] The influenza virus is one that seems to have crossed the species barrier from ducks and water fowl to pigs and from there to humans. It is possible that a fatal plague in the Middle East at the time of the late 18th Dynasty was associated with this transmission at Amarna. [19][20] Influenza Influenza, commonly known as the flu, is an infectious disease caused by an influenza virus. [21] Symptoms can be mild to severe. [25] The most common symptoms include: high fever, runny nose, sore throat, muscle and joint pain, headache, coughing, and feeling tired just like Sars-CoV-2. [21] These symptoms typically begin two days after exposure to the virus and most last less than a week. [21] The cough, however, may last for more than two weeks. [21] In children, there may be diarrhea and vomiting, but these are not common in adults. [26] Diarrhea and vomiting occur more commonly in gastroenteritis, which is an unrelated disease and sometimes inaccurately referred to as stomach flu or the 24-hour flu.. [26] Complications of influenza may include viral pneumonia, secondary bacterial pneumonia, sinus infections, and worsening of previous health problems such as asthma or heart failure. [22][25] Three of the four types of influenza viruses affect humans: Type A, Type B, and Type C. [22][27] Type D has not been known to infect humans, but is believed to have the potential to do so. [27][28] Usually, the virus is spread through the air from coughs or sneezes. [21] This is believed to occur mostly over relatively short distances. [29] It can also be spread by touching surfaces contaminated by the virus and then touching the eyes, nose, or mouth. [25] [29][30] A person may be infectious to others both before and during the time they are showing symptoms. [25] The infection may be confirmed by testing the throat, sputum, or nose for the virus. [22] A number of rapid tests are available; however, people may still have the infection even if the results are negative. [22] A type of polymerase chain reaction that detects the virus's RNA is more accurate. [22] Picture (1) Most sensitive symptoms for diagnosing influenza [1][2][3] Picture (3): Seasonal risk areas for influenza: November-April (blue), April-November (red), and year-round (yellow). [21] List of epidemics of Plagues   [54] Spain 1596-1602 Plague [55] South America 1600-1650 Malaria [56] England 1603 Plague [57] Egypt 1609 Plague Wyandot people 1634 Smallpox [61] Thirteen Colonies 1633 Massachusetts smallpox epidemic Smallpox England 1636 Plague [62] China 1641-1644 Plague [63] Spain 1647-1652 Great Plague of Seville Plague Central America 1648 Yellow fever [64] Death toll (estimate) Location Date Event Disease Ref.

DISCUSSIONS AND RESULTS
By mentioning all the facts, evolution and all the similarities from the viruses, we observe that all kinds of Flu including COVID-19 which have been caused many deaths through epidemic and pandemic of these giant but very small objects, all the viruses from the first one before the rise of the human in evolution, had been existed. Through my deep research, the first virus was or bluegreen algae, pre-date viruses and are one of the oldest forms of life on Earth.
Picture (4): blue-green algae, pre-date viruses and are one of the oldest forms of life on Earth.
The researchers developed algorithms to compare the protein shapes of 3,460 viruses and 1,620 cells. They found that 442 protein folds were shared between cells and viruses, but 66 folds were unique to viruses. To make sense of the data, the team arranged the protein folds into a tree that grew a new 'branch' every time a new type of protein fold evolved. Wherever possible, the team used fossil evidence to put an approximate date on the budding of specific branches. For example, one particular protein fold was first seen in cyanobacteria (blue-green algae), and later appeared in all its descendants. By comparing when cyanobacteria first appeared in the fossil record (2.1 billion years ago) to when its offspring later emerged, they could establish this particular fold appeared around 2 billion years ago. According to Caetano-Anolles's microbial family tree, viruses are ancient, however; they were not the first form of life. In fact, his family tree suggests viruses and bacteria share a common ancestora fully functioning, self-replicating cell that lived around 3.4 billion years ago, shortly after life first emerged on the planet. From this cell, bacteria have evolved in the direction of increasing complexity, while viruses have gradually shed genes they found they didn't need, until they could no longer even reproduce on their own. A key step in the virus evolutionary journey seems to have come about around 1.5 billion years ago and that's the age at which the 66 virus-specific protein folds came on the scene. These changes are to proteins in the virus' outer coatthe machinery viruses use to break into host cells.

Drift
New viruses can also emerge by drift. Drift can refer to genetic drift or antigenic drift. [45] Mutation and selection for the most advantageous variation of the virus takes place during this form of evolution. Natural Selection and Lamarckian Evolution both caused the evolution of several viruses like Coronaviruses fast enough. [45] Antigenic mutants can evolve quickly due to the high mutation rate in viruses. The cause of the antigenic drift lies in the mechanisms of RNA synthesis itself. Mutations arise very easily simply due to the error prone RNA polymerase and its lack of proofreading mechanisms. These mutations lead to subtle changes in the HA and NA genes which completely changes the infectious capabilities of the virus. These changes allow for almost endless possibilities for new viral strains to arise [46] and it is the antigenic drift of the HA and NA genes that allow for the virus to infect humans that receive vaccines for other strains of the virus.

Reassortment
Reassortment, also known as antigenic shift, allows new viruses to evolve under both natural conditions and in artificial cultures. [45] Reassortment occurs in a similar way as chromosome crossover events, as two different viral strains may come in contact and transfer some of their genetic information. This crossing-over event creates a mixture of the two viral strains, which may replicate as one hybrid virus that expresses traits from both original viruses. [46] The mechanism of the evolutionary force of antigenic shift allows influenza viruses to exchange genes with strains that infect different species. Under this mechanism, a human influenza virus could exchange genes with an avian strain, and that is how pandemic strains arise. There have been three occurrences of pandemics caused by antigenic shift since 1900, and it has happened again today as we know as SARS-CoV-2. [47] In fact, the 1957 evolution of the H2N2 virus is thought to be a result of Reassortment. [45] In this case, human H1N1 strains and avian influenza A genes were mixed. [45] Infecting tissue cultures can demonstrate how pathogenic qualities can evolve for a particular species even though the reasserted virus may be nonpathogenic for another species. [45] A prime example of evolution under natural conditions is the Reassortment of two avian influenza strains that were discovered in dead seals back in 1979. [45] Based on research by Fairchild GA. 1977, Inhalation of ozone and sulfur dioxide inhibited influenza virus growth in the nose of mice. Ozone inhalation caused the more pronounced inhibition of influenza virus growth: 0.6 ppm ozone for 3 hours' post-virus exposure almost completely inhibited influenza virus growth in the nose, whereas sulfur dioxide (6 ppm for 7 days) causes only partial inhibition of influenza growth in the nose. Neither gas altered the propagation of influenza virus in the lungs of mice. Vesicular stomatitis virus (VSV) growth was either unaffected by exposure to ozone (0.9 ppm for 3 hours) or, when ozone exposure preceded VSV exposure, the virus may have grown to slightly higher titer. The inhibitory effect of ozone and sulfur dioxide on influenza virus growth in nasal epithelium suggests a competitive interaction between the chemical inhalant, the virus, and host tissues, with net consequences for the pathogenesis of this disease. If the effects of these inhalants are to be properly interpreted, they should be determined for all major regions of virus growth and inhalant deposition. [Fairchild GA., 1977]. Therefore; inhalation of Ozone plus Sulfur Dioxide may inhibit the influenza virus growth in humans as well.

Sulfur and Viruses
Scientists have known about viruses that attack bacteria since the early twentieth century. In 1917, Felix d'Herelle, a French-Canadian microbiologist, and his colleagues successfully isolated phages that kill bacteria like E. coli, salmonella, and dysentery, and doctors used his so-called phage therapies to treat disease. In Taxonomy In the new Coronavirus, Genetic recombination which is the process by a strand of DNA that is broken and then joined to the end of a different DNA molecule. This can occur when viruses infect cells simultaneously and studies of viral evolution have shown that recombination has been rampant in the species studied. [230]. Recombination is common to both RNA and DNA viruses. [231] [108] SARS-CoV-2 has undergone genetic change by several mechanisms. These include a antigenic drift process where individual bases in the RNA mutate to other bases. the mutations of this virus is silent means it does not change the protein that the gene encodes. And confers evolutionary advantages such as resistance to antiviral drugs. [230][231][232][233][234]. Therefore; we cannot mention there would be any possible antiviral drugs to resist this kind of virus even in the future.
SARS-CoV-2 is an RNA Virus. its nucleic acid is single-stranded RNA (ssRNA). The polarity of this virus is positive-sense ((+) ssRNA). Positive-sense viral RNA is similar to mRNA and thus can be immediately translated by the host cell. Recombination in RNA viruses appears to be an adaptation for coping with genome damage. Recombination can occur infrequently between animal viruses of the same species but of divergent lineages. The resulting recombinant viruses may sometimes cause an outbreak of infection in humans. RNA viruses have very high mutation rates. This is one reason why it is difficult to make effective vaccines to prevent diseases caused by RNA viruses. [235] [236]

Mathematical Calculation of SARS-CoV-2 and Future Concerns
The Factorial formula is: The size of SARS-CoV-2 is approximately 0.3 microns [237]. With conversion of Micrometer into nanometer, 0.3 will be 300 nm in size. In page 21, we have described the Antigenic Drift of viruses especially SARS-CoV-2. The mathematical calculation of how many types of this virus exists is: 3x4, since we have 4 types of mild coronavirus and 3 types of deadly with severe symptoms. So the numbers of different coronaviruses will be 3 x 4 = 12. Therefore; based on each type of virus is different from another one, we use Factorial to measure all types of coronavirus which exists on earth till now without the concern of the mutation in vivo of the virus. It is 12! = 479001600. Overall, the number of different SARS-CoV-2 is about 479001600. Each of these kinds of viruses when get inside their hosts also mutates. Therefore; Each of these coronaviruses get inside their host will have different symptoms from mild into severe based on the host's immune system response and other factors. Hence; all these SARS-CoV-2, will mutate and possible severe symptoms will occur based on the Reassortment of the virus which have been described in page 22. The probability of each person in the world who may contaminate with this virus is 7.8 Billion/479001600 equals 16.2838704505. This is the probability from the first time outbreak of the virus means approximately 16% of the population infected by the virus. So the near future of death or infected people from SARS-CoV-2 will be 1248000000. Based on high rates of mutation of 2019-Corovirus, each carrier of this deadly virus may/will contaminate another living human. Therefore; all people will carry this virus in the near future. We do not know the time range of this highly pandemic, but the lesson that we have learnt from the history is that the only way to fight the virus will not produce new vaccines, since the adaptation and the mutation of the virus is higher than any known ones on earth. The only answer to end the pandemic, is the adaptation of human race to SARS-CoV-2 through Lamarckian Evolution. This infectious disease with 7.8 billion people living on earth is like playing with dices and the people contamination is random in mathematical Theorems. Some may adapt to the virus, some will die and the rest will be the carrier, therefore; the graph we predict is like The bean machine, a device invented by Francis Galton shown below: Picture (11): The bean machine, a device invented by Francis Galton, can be called the first generator of normal random variables. This machine consists of a vertical board with interleaved rows of pins. Small balls are dropped from the top and then bounce randomly left or right as they hit the pins. The balls are collected into bins at the bottom and settle down into a pattern resembling the Gaussian curve.
According to the central limit theorem (more specifically, the de Moivre-Laplace theorem), the binomial distribution approximates the normal distribution provided that the number of rows and the number of balls are both large. Varying the rows will result in different standard deviations or widths of the bell-shaped curve or the normal distribution in the bins. [238] [239]

2019-Corovirus Relation to Fibonacci Sequence
The Fibonacci numbers, commonly denoted Fn, is a function called the Fibonacci sequence, means each number is the sum of the two preceding numbers, starting from 0 and 1: And the sequence is: We have collected the infected people with COVID-19. If we suppose each infected individual infects one other individual each day and at the end of day-two recovers fully or dies (we are interested in the number of people who are actively infected and alive). So the time stamps are the beginning of day-one, at the end of day-one and at the end of day-two. According to our model, an infected individual can infect one other person at the end of day-one and at the end of day-two. If we go on through time (days), the table below shows the result of infected people: Picture (12): The right vertical numbers shows the infected people per day.
Picture (13): The number of infected people through time (day) by COVID-19.
Therefore; the formula of infected people per day is: (for n > 2), which is the formula of Fibonacci series.

Viruses Related to COVID-2019
There are some viruses that causes respiratory infection. Enteroviruses, Poliovirus, coxsackie, echovirus and Human orthopneumovirus. Hence; none of them has been related to 2019-Coronavirus. Since their Signs and symptoms, Structure, Genome, Evolution, Taxonomy and Transmission are not similar to the new COVID-2019. The only virus that has been correlated with COVID-2019 is Rhinovirus. The rhinovirus is the most common viral infectious agent in humans and is the predominant cause of the common cold and flu. Rhinovirus infection proliferates in temperatures of 33-35 °C (91-95 °F), the temperatures found in the nose. The three species of rhinovirus (A, B, and C) include around 160 recognized types of human rhinovirus that differ according to their surface proteins (serotypes) They are lytic in nature and are among the smallest viruses, with diameters of about 30 nanometers. By comparison, other viruses, such as smallpox and vaccinia, are around ten times larger at about 300 nanometers (the same diameter as COVID-2019 which is 300 nanometers in size). [240] There are two modes of transmission: via aerosols of respiratory droplets and from fomites (contaminated surfaces), including direct person-toperson contact. Rhinoviruses are spread worldwide and are the primary cause of the common cold. Symptoms include sore throat, runny nose, nasal congestion, sneezing and cough. Those most affected by rhinoviruses are infants, the elderly, and immune compromised people (Most elderly and Children). Human rhinoviruses preferentially grow at 32 °C (89 °F), notably colder than the average human body temperature of 37 °C (98 °F); hence the virus's tendency to infect the upper respiratory tract, where respiratory airflow is in continual contact with the (colder) extrasomatic environment. [241] Rhinoviruses have single-stranded positive sense RNA genomes of between 7200 and 8500 nt in length. At the 5' end of the genome is a virus-encoded protein, and like mammalian mRNA, there is a 3' poly-A tail. Structural proteins are encoded in the 5' region of the genome and nonstructural at the 3' end. This is the same for all picornaviruses. The viral particles themselves are not enveloped and are icosahedral in structure. The viral proteins are translated as a single, long polypeptide, which is cleaved into the structural and nonstructural viral proteins. [242] Human rhinoviruses are composed of a capsid that contains four viral proteins, VP1, VP2, VP3 and VP4.VP1, VP2, and VP3 form the major part of the protein capsid. The much smaller VP4 protein has a more extended structure, and lies at the interface between the capsid and the RNA genome. There are 60 copies of each of these proteins assembled as an icosahedron. Antibodies are a major defense against infection with the epitopes lying on the exterior regions of VP1-VP3. Human rhinovirus is most contagious during the autumn and winter months. The virus can remain activated for up to 3 hours outside of a human host. Once the virus is contracted, a person is most contagious within the first 3 days. Preventive measures such as regular vigorous hand washing with soap and water may aid in avoiding infection. Avoiding touching the mouth, eyes and nose, the most common entry points for rhinovirus, may also aid in prevention. Droplet precautions, which take the form of a surgical mask and gloves, is the method used in major hospitals. [243] [244] [245] As mentioned, through our analysis, the most related virus to COVID-2019, is Rhinovirus which has very similar in Structure, Genome, Size and symptoms of the SARS-CoV-2. There has not been an effective anti-viral vaccination of this virus either. There is a high possibility of mutation in this virus into 2019-Coronavirus. In 2018, a new series of antirhinoviral compounds were reported by researchers at Imperial College London and colleagues at the University of York and the Pirbright Institute. These molecules target human Nmyristoyltransferase, an enzyme in the host cell which picornavirus requires in order to assemble its viral capsid, and thus generate an infectious virion. The lead compound in this series, IMP-1088, very potently inhibited host myristoylation of viral capsid protein and prevented infectious virus formation, rescuing the viability of cells in culture which had been exposed to a variety of rhinovirus serotypes, or to related picornaviruses including poliovirus and foot-and-mouth-disease virus. Because these compounds target a host factor, they are broadly active against all serotypes, and it is thought to be unlikely that they can be overcome by resistance mutations in the virus. [246] [247] [248] The main Cause of COVID-19 Pandemic Through the lines and statements in this article, we hypothesize that the prime cause of SARS-CoV-2 is: [1] The coevolution and Red Queen effect between mammals including humans and viruses. coevolution occurs when two or more species reciprocally affect each other's evolution through the process of natural selection and the Red Queen effect which is an evolutionary hypothesis that proposes organisms must constantly adapt, evolve, and proliferate in order to survive while pitted against ever-evolving opposing organisms in a constantly changing environment, as well as to gain reproductive advantage. Increasing human population, antibiotic resistance, antiviral resistance, malnutrition, immune deficiency (basically nutrition low in sulfur), low adaptation of human in their environment (Lamarckian Evolution) and high adaptation of viruses with human genome. [249][250][251][252] [2] The main cause of SARS-CoV-2 is through natural selection and Lamarckian Evolution Both which caused this RNA virus so powerful and different in the nations worldwide. The first Pandemic of Influenza was detected in 1732 and this virus evolved through natural selection till 2019 through Drift and Reassortment of SARS-CoV-1 and Influenza viruses which caused the worldwide pandemic of SARS-CoV-2. [45] [46] There may be a correlation between Rhinoviruses and COVID-19 which has not been studied yet and should be considered. [240] The Possible Treatment of COVID-19 (SARS-CoV-2) Based on our research/Review of many major researches, there has not been any antiviral vaccines against these viruses and no antiviral drugs will be useful against COVID-19 since the adaptation and high mutation of this virus will not let these drugs be effective. The prime possible treatment Inhalation of ozone and sulfur dioxide, increasing L-Glutathione Plus Viral Phage Therapy (VFT) is the possible prime treatment of this disease. Finding the right Phage Therapy is very hard in any viral infections since this therapy was mainly used against bacterial infections. However; through our research and findings we have concluded that substantial dose-dependent inhibition by T4 phage of adsorption of HAdV to both A549 and HEK293 cell lines in vitro LPS was without effect. Moreover, T4 phage protected A549 cells from an HAdV-induced cytopathic effect (Międzybrodzki et al., 2013;Przybylski et al., 2015). These data suggest that T4 phage could be considered as a potential novel antiviral agent. The capacity of the phage to inhibit HAdV infection at the stage of viral replication suggests that phage could also interfere with viruses using cellular receptors other than those used by HAdV. Notably, the anti-viral effect of phage was measured as the decrease of the end-point HAdV infectious titer. Further in vitro studies were carried out on the effects of T4 and the staphylococcal phage A5/80 on HAdV DNA synthesis (real-time PCR) and the expression of its early and late genes (measured at the level of mRNA synthesis) in an A549 cell culture. Continuous incubation of adenovirus-infected cells with T4 phage significantly reduced the level of adenoviral DNA synthesis (this effect was not observed with the staphylococcal phage). Coincubation with a high titer of T4 phage was required for inhibition of HAdV early gene expression. Late adenoviral gene expression was reduced by preincubation (application of phage prior to HAdV infection) and Coincubation with both phages when a low HAdV titer was used. In contrast, when a high HAdV titer was applied, both incubation and preincubation with T4 phage were inhibitory whilst a staphylococcal phage was inhibitory only when continuous incubation with cells was applied. Those results suggest that the inhibitory effect of phage on HAdV infection may differ and may be partially explained by their influence on the expression of early and late adenoviral genes (Przybylski et al., 2018). When the effect of both phages on the expression of genes involved in antimicrobial immunity by the A549 cell line from human lung was studied, the most striking phenomenon was marked (>10-fold) enhancement of a gene coding for interleukin-2 (Il-2) by a staphylococcal phage (Borysowski et al. . Moreover, NK cells also exhibit activity against a variety of bacteria, e.g., by secretion of the soluble molecules perforin and granulysin. Mice infected with Shigella and lacking B and T cells but with normal NK cells have higher survival rates and lower bacterial titers than mice which lack all three cell types. This suggests that phage-induced Il-2 dependent activation of NKmediated antimicrobial activity may contribute to beneficial effects of PT, especially during prolonged phage administration cumulative median duration of successful phage therapy is 43 days (Międzybrodzki et al., 2012). NK cells could be a promising agent in antimicrobial immunotherapy, as data strongly suggest that these cells are active against not only viral but also bacterial and fungal pathogens (Schmidt et al.

CONCLUSION
In this Research/Review articles, we have gone through all the cases and epidemic of all the fatal diseases from the first time mentioned in history including Flu/Influenza pandemic until 2020. Based on our research, the only period of time when there was no outbreak of influenza, RNA viruses or infectious diseases were during World War 2, where German scientists controlled the epidemic of any virus infections which should be noted by the scientists and researchers. The mutation of the SARS-CoV and Influenza viruses is the main cause of SARS-CoV-2 through natural selection and Lamarckian Evolution Both which caused this RNA virus so powerful and different in the nations worldwide. The first Pandemic of Influenza was first detected in 1732 and this virus evolved through natural selection till 2019 which caused the worldwide pandemic of SARS-CoV-2. Based on many studies, inhalation of Ozone plus Sulfur Dioxide, increasing the amounts of L-Glutathione (Which is low in children and older adults) plus Viral Phage Therapy (VPT) can be the prime treatment of SARS-CoV-2 infection. The seasonal temperature cannot be useful in controlling or reducing the pandemic of this virus since the temperature rises gradually and the natural selection, Lamarckian Evolution and high mutation rate of the virus helps its survival. In our mathematical calculation, the number of infected people is/will be 1248000000 which should not be ignored by the scientists. We also introduced the Fibonacci Model in calculating the infected/will be infected people. Through our research we have found that no antiviral drugs will be useful against SARS-CoV-2 because of high rate of mutation and adaptation of the virus to the drugs and even the environment temperature.