**1. Introduction**

Phages are infections caused by bacterial viruses and they are the most bountiful elements on the Earth [1], due to the introduction of antibiotics their application in clinical practice was immediately overcome in Western countries [2]. Patients with antibiotic-resistant infections are traveling from different spots to Georgia and Poland for phage treatments [3]. Despite all the success cases of patients, phage therapy is still faces significant obstacles, particularly administrative issues. In European countries and United States several on-going efforts are being led for the acceptance of phage therapy [4]. In this chapter, we will first discuss the early and current state of phage therapy, address the major challenges faced by phage therapy treatment in Covid-19 infection and the future prospects in this field [5].

### **1.1 Early studies of phage therapy (PT)**

The efficacy of the phage treatment was confirmed when three patients having the same infection dysentery treated with one dose of the anti dysentery phages and recovered within 24 hours of treatment but his study was not published [1]. However, treatment of infectious diseases of humans reported in 1921 by Richard Bruynoghe and Joseph Maisin, who used bacteriophages to treat staphylococcal skin disease [6]. In addition, d'Herelle used various phage preparations in India to treat thousands of peoples suffering with cholera and bubonic plague [7].

Phages mediate immune regulatory and immunotherapeutic trials that are significant in balancing the immunological homeostasis in human [8]. It was suggested that the viability of PT in autoimmune diseases and it can also be used to for the treatment of infection caused by SARS-CoV-2virus [9]. To determine the infection in mass population, a single sewage test is enough to examine the whole population has been infected or not because RNA of SARS-CoV-2 remains stable with the capsid [10]. However, it has been found from accessible information that although the concentration of the virus in sewage water is high but the transmission risk via this route is very low. This information can play a major role in managing COVID-19 [11].

Phage display technique of producing antibodies was developed for MERS-CoV and effectively applied in light of the fact that bacteriophages have the potential to produce recombinant antibodies (Ab) rapidly [12]. Another Yin-Yang biopanning technique features the chance of utilizing crude antigens for the isolation of monoclonal Ab by phage display method [13]. Before using these expensive techniques, production of artificial Ab was primarily done by using animals but it is a slow process and less cost effective than using bacteriophage display techniques [14]. Bacteriophage could be used to decrease the mortality rate due to Covid-19 pandemic, and for the production of artificial Ab against SARS-CoV-2 in the early stages of infection [15, 16].

## **2. Interactions between phages and the immune system**

It is well known that the immune system plays an important role in phage clearance from animal and human bodies [17]. Components of the mono nuclear phagocyte system (MPS) in the spleen and liver are major sites of phage accumulation. The MPS has been credited for the quick expulsion of administered wild-type phage λ from the human circulatory system [18]. In addition, these phages can directly interact with immune cells by either interacting with cell surface molecules or receptors or through phage transcytosis [19]. Besides the take-up of phages, by Ag presenting cells (APC; e.g., dendritic cells) prompts the activation of B-cells and the exhibition of specific Ab against the phage as shown in **Figure 1** [20].

### **3. Mode of action**

In spite of the huge number of publications on phage therapy, there are only few reports in which the pharmacokinetics of therapeutic phage preparations is depicted [21]. Phages get into the circulatory system of experimental animals (after giving a single dose orally) within 2 to 4 h and they reached into the internal organs within 10 hours and can remains in the human body up to several days [22]. In any case extra exploration is required in order to obtain rigorous

**Figure 1.** *Interaction of bacteriophage with mammalian immune cells (Belleghem et al. [20]).*

pharmacological information concerning lytic phages, including full-scale toxicological research [23]. However, after few years studies reveal that not all phages replicate correspondingly and that there are significant differences in the replication cycles of lytic and lysogenic phages as shown in **Figure 2** [11]. Moreover, it is possible that numerous therapeutic phages act through a common path; however, it may also possible that some therapeutic phages have some distinctive unidentified genes or some unknown mechanisms responsible for lysis of their target bacteria [24]. In a study conducted by *Sulakvelidze et al*. More interpretation of these and common mechanisms is likely to produce

**Figure 2.** *Mechanism of phage action in bacterial cell (Mishra et al. [11]).*

information useful for genetically engineering which was helpful in effective therapeutic phage preparations for the treatment of Coronavirus [7].

### **3.1 How can ms2 bacteriophage help to fight against coronavirus?**

MS2 Bacteriophage is contemplating as a control to study molecular biology processes. It includes viral RNA replication, translation method, and physiology of infected cells. MS2 RNA coding for viral polypeptides includes protein A, coat protein, and RNA replicase complex. The structure of the MS2 virus comprises of Protein A and coat protein makeup.MS2 Bacteriophage can be used as an internal control in RT-PCR testing for COVID-19 to prevent false negative results and to verify the efficacy of the sample preparation and absence of inhibitors in the PCR reaction [25].
