Bacteriophages as a Possible weapon for COVID-19

The (COVID-19) pandemic has caused millions of people to die. This study emphasises the possible role of bacteriophages in reducing the mortality rate of patients infected with the virus SARS-CoV-2. Miscommunication between the innate and adaptive immune systems is the indirect cause of mortality in COVID-19, leading to a failure to generate effective antibodies against the virus on time. Despite the urgent need for more research, secondary bacterial infections in the respiratory system may potentially lead to the high mortality rate reported among the elderly due to COVID-19. If bacterial growth is a significant contributing factor to the mortality rate of COVID-19, along with the delayed development of antibodies, then the additional time required for the human body's adaptive immune system to develop specific antibodies could be obtained by reducing the patient's bacterial growth rate in the respiratory system.

The administration of synthetic antibodies against SARS-CoV-2 viruses could theoretically reduce the viral load, regardless of this. The decrease in bacterial growth and the covalent binding of synthetic antibodies to viruses (the indirect cause of death) could further decrease the development of inflammatory fluids in patients' lungs. While antibiotics may theoretically achieve the first objective, I argue that other methods may be more successful, or may be used in combination with antibiotics to reduce bacterial growth rates, and that appropriate clinical trials should be launched.

Bacteriophages can attain both objectives. The aerosol application of natural bacteriophages that feed on the key species of bacteria known to cause respiratory failure could theoretically reduce the bacterial growth rate and should be harmless to the patient. Independently of that, unique antibodies against SARS-CoV-2 could be rapidly generated by synthetically modified bacteriophages. This can be achieved by a "phage show" Nobel Prize awarded technique. If it works, extra time is given to the patient to generate their own particular antibodies against the SARS-CoV-2 virus and to avoid the damage caused by an excessive immunological reaction.

The combined impact of globalisation and the properties of the new virus (SARS-CoV-2) that causes the disease, COVID-19, is the crisis we observe. One of the most dangerous symptoms of COVID-19 is identified by SARS-CoV-2 . While previous alerts have been made of the threat posed by respiratory targeting viruses, the SARS-CoV-2 virus has spread at an alarming pace and is devastating our global health and economy. To solve this problem, we urgently need several approaches.

This brief correspondence aims to highlight the potential for the use of natural bacteriophages to reduce the mortality rate among SARS-CoV-2 virus infected patients. COVID-19 patients can develop SARS, leading to atypical cytokine storm-mediated pneumonia.The respiratory system, where the virus will interrupt its equilibrium, is the most likely entry road of SARS-CoV-2 for humans.

Miscommunication between the innate and adaptive immunological systems may be the indirect cause of death in patients with COVID-19. The adaptive immune response takes much longer to begin effectively combating a new pathogen than the innate immune response. This implies that there is a time where the infection is battled only by the innate immune system and in this period, the reaction of the innate immune system may become too violent when faced with a high load of virus, allowing it to destroy other systems. The growth of the virus allows inflammatory matter (fluid and inflammatory cells) to be secreted into the lungs by the innate immune system. As a result, fluid fills the lungs, reducing the capacity of the body to exchange gases.

Dying and virally infected human respiratory cells' debris may become a substrate for the growth of bacteria, a side effect of infection with the virus. This bacterial growth then allows additional inflammatory material to be secreted into neighbouring alveoli by the innate immune system. A further reaction of the innate immune system appears to be caused by bacterial infections, and they can interfere with virus infections. This mechanism accelerates as the virus begins to invade lung cells, producing more cell debris substrate for the bacteria to feed on. This can result in too much inflammatory fluid being applied to the lungs by the innate immune system, inhibiting gas exchange and resulting in an immediate need for ventilation, and it can cause sepsis and death.

The delay or failure in the manufacture of virus-specific antibodies might explain why SARS-CoV-2 is so dangerous for the elderly. A recent comprehensive immunity analysis in COVID-19 summarises state-of-the-art awareness of the host's immune response to the virus and points out strong discrepancies between younger and older patients in disease progression.

Immunosenescence can delay the development of antibodies (impairment of immune functions) and is typically expected in elderly patients, which may be part of the cause of the high age-dependent mortality observed in patients with COVID-19. Although data for COVID-19 are still scarce, there is evidence that previously contracted influenza predisposes the host to pneumococcal colonization and there is therefore an established mechanism in the human respiratory system for viral infections to trigger bacterial colonisation. For other pathogens, the co-occurrence of viruses and bacteria is also well known.

Although ecologists call this process a "succession," the word "secondary infections" is used by medical doctors. For example, Staphylococcus aureus, Staphylococcus pneumoniae (pneumococcus), Aerococcus viridans, Haemophilius influenza, and Moraxella catarrhalis are usually bacteria found in patients with influenza, as well as other respiratory commensals, which often develop into pathogens that trigger infection.

A recent review indicates that bacterial infections, including Acinetobacter baumanii and Klebsiella pneumoniae, have been identified in patients with COVID-19, especially in the setting of the intensive care unit. Non-survivors were more likely to have sepsis and secondary infection, although no detailed findings of bacteriology were reported. Secondary infections have associated favourably with steroid administration.

The bacterial infection of the respiratory system may be at least part of the high mortality rate attributed to COVID-19, although we still do not have a reliable estimation of the numbers. Due to the overwhelming number of patients seen in clinics and the criteria by which patients are admitted to bacteriology tests, and at what point in the process, there may also be difficulties in providing accurate figures for these numbers. A recent Wuhan study indicates that at least 50% of patients who die developed secondary infections. The median time for the development of these secondary infections is 17 days, although the time range is very wide. It is possible that before acute respiratory distress syndrome is established, bacterial infections begin to colonise.

Bacteria such as Pseudomonas aeruginosa are known to spread rapidly in viral scenarios such as influenza. In addition, the rapid and enormous response of the first-line, innate immune system triggers general inflammation that can modify pulmonary structures (causing fibrosis), further decreasing oxygen absorption and causing permanent respiratory tissue damage. However the degree to which this reaction is triggered by the body's response to the SARS-CoV-2 virus or to which it is caused by its response to infection by bacteria (such as P. aeruginosa) is not yet understood and I postulate that it may vary over the course of the infection.

COVID-19 is also not yet well known for the interplay between the time taken for the human body to produce antiviral antibodies and the role of bacteria in the death of older individuals.

If bacterial growth is a major contributing factor to the mortality rate of COVID-19 along with the delayed development of antibodies, then the additional time required for the human body's adaptive immune system to generate antibodies could be obtained by reducing the patient's bacterial growth rate in the respiratory system. If it is possible to avoid the growth of bacteria in the lungs, therefore the rate of increase in fluid in the lungs should also decrease. However as the growth of the virus is exponential, in order to delay the immunological response, it may be necessary to reduce the viral load at the same time as the bacterial load.

Bacteriophages are viruses that target particular bacterial species selectively and are otherwise harmless to cells in animals including humans. They were discovered by Frederick W. Twort and Félix d'Hérelle 100 years ago and are spread in the habitats of Earth and over a wide variety of bacteria, including bacteria naturally present in humans.

The attack of bacteriophages has been shown to be unique, implying that only one species of bacteriophage attacks a particular species of bacteria (or even a specific strain of one species). This specificity also points to the co-evolutionary process "Red Queen" between these two players. The attack scenario is as follows: The bacteriophage binds itself to a susceptible process between these two players. The bacterium is then killed (lysis) and new copies of bacteriophages are released and invaded exclusively in the surrounding areas by other bacteria of the same genus.

Owing to The Antibiotics Revolution," research into bacteriophages and their future medical applications was mostly abandoned for many years despite this established interplay between bacteriophages and bacteria. Antibiotics were introduced as the primary method of treating bacterial infections primarily due to the fact that they are general purpose, as opposed to bacteriophages that explicitly target a sinus infection. Other benefits include the fact that antibiotics are generally quick-acting, effective, and relatively inexpensive to produce. There are however, many disadvantages to the use of antibiotics as well. One of these is that unlike bacteriophages, in addition to harmful bacteria, antibiotics can kill beneficial bacteria. More specifically, overuse of antibiotics can cause bacteria to develop resistance to them, resulting in superbugs from antibiotic-immune.

Around 70% of hospitalised COVID-19 patients worldwide receive antibiotics as part of their care in the current COVID-19 pandemic. This increases the risk of the emergence of antibiotic-resistant strains of bacteria even higher and creates an even greater need for new methods to combat bacterial infections to be created. Bacteriophage therapies will be much less vulnerable to resistance growth, unlike antibiotics, as the bacteriophage itself can also adapt to overcome any resistance formed by the bacteria.

The existence of bacteriophages has also been suggested to have beneficial effects on human health and patient recovery, suggesting that bacteriophages are to some degree responsible for microbiota homeostasis. For example, a group investigating alternative therapies for Clostridium difficile, a bacterium that can infect the intestine and cause diarrhoea, has described a wide collection of b In addition to numerous bioengineering methods using bacteriophages currently being created, we can find further examples of how bacteriophages are being used for human or animal models.

Despite the fact that the ability of bacteriophages to combat bacterial infections has only recently been rediscovered, they have been used successfully at the molecular level as instruments, leading to Nobel Prize awards.

Bacteriophages have the ability to generate recombinant antibodies rapidly using a technique called phage display. This antibody development technique was developed and successfully applied to MERS-CoV. In phage display, techniques that block ACE2 interaction may be engineered from the serum of immune patients. The Yin-Yang biopanning technique highlights the possibility of using rudimentary antigens via phage display for the isolation of monoclonal antibodies. Artificial antibody development was mainly achieved using animals before this however, this is both slower and less cost-effective than using techniques of bacteriophage display. Another advantage of this technique is that monoclonal antibodies generated by techniques of bacteriophage display can be humanised.

The use of antibody therapy for the control of viral diseases has already been reviewed and some therapies have been licenced for human testing. As an example, by screening a naive human antibody library (LiAb-SFMAXTM, scFv, Fab, IgG) or an immune human antibody library (obtained from the plasma of COVID-19 survivors) by the company ProteoGenix launched accelerated therapeutic antibody development 

There are also two key ways in which bacteriophages may be used to decrease the COVID-19 pandemic mortality rate. They can be used to decrease the bacteria population in the respiratory system of a patient and/or bacteriophage display techniques can be used to generate synthetic antibodies against SARS-CoV-2 effectively.

The aerosol application of bacteriophages that prey on the key species of bacteria known to cause respiratory failure could potentially reduce the bacterial growth rate. Similar to ecological prey-predator control, this may occur in a self-regulatory way. Exponential bacteriophageal population growth (limited primarily by the population of bacteria on which it preys) should allow rapid clearance, especially in cases where the bacterial population has already grown substantially. The relationship may be defined by the population model of Lotka-Volterra or Kill-the-Winner.

In fact, we can already find evidence in the literature that nebulized bacteriophages could cure pneumonia. Prophylactically administered bacteriophages decreased bacterial lung burdens and enhanced antibiotic-resistant S. survival. In the sense of ventilator-associated pneumonia, aureus infected animals If necessary, a group of experts could quickly identify a selection of bacteriophages and optimal target bacteria as the species of bacteria that commonly cause respiratory problems are well known and a bacteriophage that preys on a specific species can be identified quickly by screening methods. If necessary, quantitative microbiome sequencing could potentially be used.