Unjustly Incriminating Bacteria: the Role of Bacteriophages in Bacterial Infections

SUMMARY
Based on human relationship with bacteria, virulence is one of the most important case to us. Some forms of virulence thought to arise only from the actions of bacteria are not actually caused by them but are indirectly influenced by another counterpart in the microbial mix of the ecosystem called bacteriophage; viruses that only infect prokaryotes such as bacteria but not eukaryotes. Bacteriophages preferably attack bacteria due to the lack of specific receptors for phages on eukaryotic cells which are found in bacteria e.g. peptide sequences and polysaccharide moieties in gram positive and gram negative bacteria, bacterial capsules, slime layers, flagella etc. They recognize and bind to bacteria using appropriate receptors, subsequently proceeding to inject their genome called prophage into their host. This review focuses on the most probable outcomes of phage-host interactions via the lytic and lysogenic cycles which are therapeutic effect and pathogenicity/resistance to antibiotics respectively. By lysogenic conversion or transfer of acquired genetic materials via transduction, phages can confer unusual traits such as virulence and antibiotics resistance. Important pathogenic bacteria that cause persistent and critical infections which have their pathogenicity engineered by phages include Pseudomonas aeruginosa, Salmonella enterica, Escherichia coli, Vibrio cholerae, Staphylococcus spp., and Clostridium spp.

The prophages influence their virulence in a variety of ways which include: contribution to the production of phage-encoded toxins, modification of the bacterial envelope, mediation of bacterial infectivity, and control of bacterial cell regulation. The unwavering threat of antimicrobial resistance in global health, extreme difficulty involved in developing novel antibiotics, and the rate at which microorganisms develop resistance to newly introduced antimicrobials have sparked urgency and interest in research for effective methods to eradicate pathogenic bacteria and limit antibiotic resistance. As a result, interest in phage therapy has been reignited because of the high efficiency in detecting and killing pathogenic bacteria by phages.

1. UNIVERSITY OF NIGERIA, NSUKKA FACULTY OF BIOLOGICAL SCIENCE DEPARTMENT OF MICROBIOLOGY A SEMINAR IN MICROBIOLOGY PRESENTATION TOPIC: ROLE OF BACTERIOPHAGE IN BACTERIAL INFECTIONS BY AGBOEZE, CHRISTIAN TOCHUKWU REG. NO: 2017/242712 COURSE: SEMINAR IN MICROBIOLOGY (MCB 481) SUPERVISOR: PROF. (MRS.) I.M EZEONU DATE: JANUARY 10, 2022

2. Introduction In the microbial-dominated world we live in, Bacteria and Archaea dictate various actions seen in the environment but based on human relationship with bacteria, virulence is one of the most important case to us. Some of the diseases thought to arise only from the actions of bacteria are not actually caused by them but are indirectly influenced by another counterpart in the microbial mix which are called bacteriophages. In context, the different life cycles of phages and how they influence change in bacteria lifestyle in terms of pathogenicity and antimicrobial resistance is reviewed. Finally discussed is phage therapy and how the knowledge of phage-host interactions can be used to cure diseases in this era where the increasing crisis of antibiotics resistance threatens to bring down the routine control of diseases using antibiotics.

3. They are viruses that only infect bactria What is a bacterophage? As viruses, they need a host cell (bacteria) to function Inject their genome called ‘prophage’ which is usually DNA into the host cell They recognize and bind to bacteria with receptors and... Figure 1 A bacteriophage Source: https://smart.servier.com/wp-content/uploads/2016/10/bacteriophage_f-414x680.png

4. Why they attack bacteria but not human cells This is due to the presence of specific receptors for phages in bacteria which are not found in eukaryotes (Podlacha et al., 2021). These receptors include: peptide sequences and polysaccharide moieties in gram positive and gram negative bacteria, bacterial capsules, slime layers, flagella etc. (Bertozzi Silva, Storms and Sauvageau, 2016).

5. This is the process by which foreign DNA is introduced into a cell by a virus Part 01 TRANSDUCTION Via transduction, phages can kill bacteria or confer unusual traits such as virulence and antibiotics resistance Phages inject their genome called ‘prophage’ which is usually DNA into the host cell Figure 2 Transduction Source: https://cronodon.com/sitebuilder/images/Phage-injection-1-669x315.jpg

6. LYTIC AND LYSOGENIC CYCLES Lysogeny Lysis The phage genome is transcribed and multiple copies reassemble to kill the host cell by disintegrating its DNA. The cell bursts open. Phages that live this way are called ‘virulent phages’ (Stone et al. , 2019). The phage DNA does not kill the host instantly but is rather integrated into the host chromosome. This is termed ‘lysogenic conversion’ (Dion, Oechslin and Moineau, 2020) Phages that live this way are called ‘temperate phages’ (Schneider, 2021) Figure 3 Lysis ang Lysogeny Source: http://www.virology.ws/wp-content/uploads/2017/01/lysisor.jpg

7. Role of phages in bacterial infecctions Prophage encode their genes, including those acquired from other bacteria into their hosts which go on to express those genes Control of bacterial cell regulation. Modification of the bacterial envelope Contribution to the production of phage-encoded toxins These are the 3 major ways through which phages use to influence virulence (Schroven, Aertsen and Lavigne, 2021).

8. Bacteria Prophage Phage-encoded gene Effect on bacterial virulence Toxin secretion Vibrio cholera CTXϕ Ctx Cholera toxin production Clostridium botulinum CEβ, DEβ C1, D Botulinum toxin production Escherichia coli 933W, H-19B stx1, stx2 Shiga toxin production Staphylococcus aureus 80α Tst Toxic-shock syndrome toxin-1 production Corynebacterium diphtheria β-phage cdtA, cdtB Diphtheria toxin production Clostridium difficile Ancient prophage tcdA, tcdB TcdA and TcdB toxin production PhiSemix9P1 Cdt CDTa and CDTb toxin production Table 1 Overview of phage-mediated pathogenicity (Schroven, Aertsen and Lavigne, 2021)

9. Bacteriophages Vs Antibiotics Resistance Two antibiotics resistant genes ( bla TEM and bla CTX-M ) from phage DNA result in ampicillin resistance when transmitted to susceptible E. coli strains (Colomer-Lluch, Jofre and Muniesa, 2011) High quantities of genes ( bla TEM , bla CTX-M , and bla SHV ) confer resistance to B-lactam antibiotics , Phage genes such as qnrA , qnrB , and qnrS confer lower susceptibility to fluoroquinolones (Marti, Variatza and Balcázar, 2014).

10. Effects of Antimicrobial Resistance Almost all clinically used antimicrobials, have developed resistance at this time and reported cases of resistance usually arise between two to three years of discovery (Fair and Tor, 2014). Phages contribute in the threat posed by antimicrobial resistance to global health According to recent WHO estimates, over 700,000 people die each year from diseases caused by antibiotic-resistant bacteria worldwide (https://www.who.int/). However, this could rise to 10 million deaths per year by 2050 if action is not taken (https://amr-review.org/).

11. Phage Therapy Due to the extreme difficulties encountered in developing novel antibacterial compounds, interest in phage therapy have been reignited because of the high efficiency in detecting and killing pathogenic bacteria by phages (Payne et al., 2007; Wright, 2014; Taylor, 2015; Sarkar et al. 2021). Phages cannot be expected to replace antibiotic agents in our medical arsenal, but can be used where antibiotic agents fail. The selected phages, however, must be obligately virulent, well-characterized, and highly purified before application.(Rohde, Wittmann and Kutter, 2018) Bacteriophage (phage) therapy, is the use of viruses that infect bacteria as antimicrobial agents.

12. 01 The current antibiotic crisis places the need for develop- ment of novel antibacterial strategies front and center. In this regard phage therapy is proving to be a potential solution. 02 The implementation of anti-virulence strategies involving engineered phage or by incorporating safety measurements is essential. CONCLUSION

13. THANKS