**7. Phages as potential inducers of antiviral immunity**

There are also data suggesting that phages may drive antiviral immunity by inducing antiviral cytokines, for example, IFN-α and IL-12. An experimental study that phage RNA may induce IFN-α in human granulocytes [43]. Recently, *Sweere et al.* demonstrated that Pf phages (and phage RNA) endocytosed by leukocytes trigger TLR3-dependent pattern recognition receptors and inhibit TNF-driving type I IFN production [44]. The phage-dependent virucidal sign in the lungs could be happen in the phage has capable enough to penetrate the body organ through various routes; therefore phage therapy has been applied successfully in respiratory tract. Intriguingly a fine respiratory microbiome including bacteriophages, during the event of viral pathogens even such as Corona virus is also related with quite low percentage of phages. Recent data indicate that Lactobacillus, *E. coli* and *Bacteroides* phages and phage DNA may stimulate IFN-γ production via TLR9 activation. IFN-γ is another potent antiviral cytokine. Although, the increase TNF level might cause significant risk of virus replication. Hence, a therapeutic agent could regulate TNF production to keep the values at normal level for patient could be appreciated. Pre-clinical studies suggest that viral pneumonia may be cured by anti-TNF therapy. As increased levels of TNF are in blood samples and tissue from patients with COVID-19 may be inhibit TNF production through phage, which is confirmed by other author's previous reports that showed phage may down regulate TNF-α level in serum and lungs of mice with experimental acute pneumonia. Interestingly, clinical phage therapy may reduce TNF production when its pre-treatment level is high and increase it in low responders [45, 46].

These informations might be considered as a relevant argument for phages as a potential agent that could help to decrease TNF levels, allowing for appropriate antiviral immune responses in COVID-19 while reducing the risks of excessive immunosuppression. Different Phages may also interact with TLR [47]. TLR2 is involved in antiviral responses as a result of recognition of the repeating protein subunit patterns common to many viral capsids. [*Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsid Is Toll-Like Receptor 2 Dependent*]. Other antiviral effects could be mediated by the A5/80 Staphylococcal phage through its ability to increase the expression of the IL-2 gene. IL-2 drives NK cell activity, which is important in defines against viral infections [47]. Phage can also induce antiviral immunity by up regulating expression of defense in IL-2, and recently shown that the T4 phage may induce a marked up regulation of gene coding for hBD2, a multifunctional peptide expressed mainly in epithelial cells with antiviral activity. Virus replication disrupt by the peptide through the binding of the virus by hBD2, decrease viral replication and modulation of signaling pathway essential for virucidal effects, even do the recruitment of immune cells contributing to antiviral activity leading to down regulation of cytopathic effects in human alveolar and laryngeal epithelial cells [48]. In some experiment studies in mice have revealed a co-relation between beta-defensin expression and pulmonary immunity. Moreover, participation of hBD2 in antiviral defenses in the respiratory tract has been confirmed in human disorders [49].

*Role of Phage Therapy in COVID-19 Infection: Future Prospects DOI: http://dx.doi.org/10.5772/intechopen.96788*

It was advised that phages could be reintroduced for the treatment of not only bacterial, but also other infections such as viral and fungal infections (Adv, *Epstein– Barr virus, Aspergillus fumigatus, Candida albicans*). It showed that there is evidence that proof phage could be comprised in current treatment being studied for repurposing in the therapeutic treatment of COVID-19. According to *Gorskiet et al.* phage in COVID-19 could be in an adjunct antiviral therapy, which is quite similar to the current trend ofcombined phages with antibacterial treatment in bacterial infections. In other way, a standard phage therapy could be considered for the treatment of bacterial complications of COVID-19, which occur in >40% of patients [45, 50]. Phages may act as shield for eukaryotic cells by competing with surface assimilation and viral penetration of cells; virus mediated, programmed cell death as well as viral replica. Phages may also arouse antiviral immunity during contributing to a equal immune response. Moreover, by inhibiting activation of NF-κB and ROS production, phages can down regulate extreme inflammatory reactions relevant in pathology and clinical course of COVID-19. The data presented in this which was judged are often preliminary but suggest that further studies centered on the potential of phage therapy as at least an adjunct treatment of COVID-19 are warranted. Both general and remote safety of phage therapy was corroborating in human viral diseases. Therefore, extensive studies comprising relevant clinical trials are needed to prioritize applicability of phage to help fighting against COVID-19 pandemic [45].

### **8. Production of industrial phage propagation strains**

The development of new page-based resources using traditional methods can be an on-going issue that may require hundreds of species to be treated with plasmids, active prophages, perhaps other mobile genomic elements. However, given the recent breakthroughs in synthetic biology and advances in re-integration with genetic engineering methods, this need not be the case. Even a given phage infects a particular type of bacterium strain from the affected species depending on the bacterial characteristics and the phage [45].

Metabolic compatibility of a bacterium with a phage to support the propagation of the phage in an already existing infection appears to be specific to certain species, but is sometimes extended to more than one species of bacteria of the same or different genera. Definitions of phage acquisition differentiation encoded by a variety of similar species include genes that include phage receptors or their means of integration and restriction-modification systems associated with the phage. In addition, bacteria, encrypt phage defense process but these mechanisms fortify the bacterium itself from infection through certain pathogens or through the propagation of phage, or induce apoptosis to protect people from the spread of the disease [45].

The distinct indicators of phage determinants are reversible between the strains of given species. Bacteria can gain or lose sensitivity to an appropriate phage or the ability to support the phage development by mutation-recombination-, or horizontal genetically modified changes in their phage orientation or phage defense determinants [51]. There are so many genes which are analogous with phage resistance or susceptibility exposure is carried by mobile genetic elements. Key features of Phage that are important of a metabolically-compatible host include the interaction of phage receptor-binding proteins and receptors on the surface of the bacterial cell, alignment of the phage genome with the bacterial restriction-modification mutation system, or the ability to prevent bacterial action by bacterial restriction-modification systems or by encoding efficient anti-restriction mechanisms. In addition, to infect bacteria, phage reproduce effectively, protein-induced phage allows them

to overcome bacterial phage-resistant strains, such as anti-CRISPR proteins and proteins that inhibit the action of Abi systems or toxin-antitoxin (TA) [51, 52].

The structure of each phage and its infectivity for a specific host are determined by the genetic makeup of the phage. The only factors determined by phage handling are considered to be some epigenetic alterations, which are patterns related to host DNA methylation [52]. They have a significant impact on the functioning of new host infections by a phage; play a very important role in horizontal gene transfer through bacteriophages. Therefore, in addition to the species-specific metabolic pathways specific to supporting the efficient propagation of a given phage and which should be equipped with surface receptors for this phage attachment, envelope structures of cell susceptible to the action of the phage lytic protein, and a block-conversion modification system that will allow in this case to infect the desired set of phage in clinics [45, 53].

Removal of such strains of genetic determinants of other phage defense mechanisms (e.g., CRISPR/Cas, Abi, or TA loci), if there is a genetic mutation, can extend the number of phages it can propagate to its cells to phage infecting the strains of the same species and uses the same receptors, but is in capable to overcome the suitable defense. The discovery of sensitivity to several specific phages upon the abolishment of various bacterial phage defense systems has been demonstrated in a number of cases. A good future strategy for finding the therapeutic phage propagation strains of desired properties may be the construction of a bacterial chassis of selected clinically relevant pathogenic species. In synthetic biology, the chassis refers to the microorganism that serves as the basis for genetic engineering and to support them by providing resources for basic tasks, such as replication, transcription, and translation mechanisms [45, 53–55].

The common strains of bacterial chassis that will serve as the basic platforms for construction of industrial phage propagation should have genomes reduce their complexity and unnecessary genetic content by the depletion of most of the transposable element as well as virulence and phage resistance determinants method called as a top-down strategy of the genome reduction process [54]. In addition, they ought to be prepared for the introduction or exchange of genomic modules which enable these strains to function as microbial cells in the use of selected treatment phage. Methods to allow the elimination of mobile genetic elements and other genes are used for genetic reshuffling recombineering, oligo-mediated allelic replacement, or genome editing using CRISPR/Cas-assisted selection of clones for model bacteria, or even on a genomic-wide scale. A repertoire of engineering tools that enhances genomic deceptive ability in bacteria other than *E. coli* uses new and ever-evolving techniques, providing ways to classify genomes belong to particular genera represented by problematic bacterial pathogens, including potential phage propagation strain [45].

The results of studies on micro-organisms that were cured of some or most of the recombinogenic or mobile genetic elements (including prophages) indicate many more benefits. The strain, *Escherichia coli* K-12 with a genomic reduction by approximately 15% by the removal of mobile DNA and cryptic virulence genes. Due to these changes this strain preserved good growth profile and protein production as well as the accurate propagation of recombinant genes and plasmids that could not be stably propagated in other strains [56]. Apart from phage capacity in combating different bacterial infections, emerging evidence suggests role of phages in viral infections as well treatment. Many viral illnesses do not have specific treatment and same antiviral drugs have been used for different viral diseases [57]. Thus, in our opinion, the construction for the propagation of therapeutic phages, of chass is strains equipped with certain phage susceptibility determinants and depleted of phage resistance determinants as well as certain mobiles genetic elements or virulence determinants will not only ensure the safety of therapeutic phage preparations, but will also reduce the cost of phage production substantially [58].

This reduction will be a result of:


In addition, to single fundamental strain establish for a microbial species can serve as a platform for the enrichment of its genome with several gene cassettes required for the propagation of several phages. Further work to remove additional undesired genomic elements from the genomes of these strains is in progress [45, 59].
