Bacteriophages: basic science and applications

How bacteriophage kills bacteria (SITN, Harvard University)

“We urgently need an alternative method to fight bacterial infection. One promising method for killing bacteria is to use bacteriophages: viruses that infect and kill bacteria … As a type of virus, phages cannot live and reproduce alone. Viruses need to invade a host cell, consume the host’s nutrients to make more copies of themselves, and lastly get out of the host cell – often by killing the host in the process … Phages could have several advantages over antibioticsPhages are able to kill antibiotic-resistant bacteria.”

*Srisuknimit, V. (2018, February 1). Fighting Fire with Fire: Killing bacteria with virus. Blog: SITN, Science in the News, Harvard University.

Viruses that infect bacteria (bacteriophages; also known as phages) were discovered 100 years ago. Since then, phage research has transformed fundamental and translational biosciences. For example, phages were crucial in establishing the central dogma of molecular biology — information is sequentially passed from DNA to RNA to proteins — and they have been shown to have major roles in ecosystems, and help drive bacterial evolution and virulence. Furthermore, phage research has provided many techniques and reagents that underpin modern biology — from sequencing and genome engineering to the recent discovery and exploitation of CRISPR–Cas phage resistance systems. In this Timeline, we discuss a century of phage research and its impact on basic and applied biology.”

*Salmond, G. P. C., & Fineran, P. C. (2015). A century of the phage: Past, present and future. Nature Reviews. Microbiology, 13(12), 777-786. [PDF] [Cited by]

Featured articles (these articles have been added to the Science Primary Literature database):

*Łusiak-Szelachowska, M., Weber-Dąbrowska, B., Żaczek, M., Borysowski, J., & Górski, A. (2020). The presence of bacteriophages in the human body: Good, bad or neutral? Microorganisms, 8(12), 2012. [PDF]

The presence of bacteriophages (phages) in the human body may impact bacterial microbiota and modulate immunity. The role of phages in human microbiome studies and diseases is poorly understood. However, the correlation between a greater abundance of phages in the gut in ulcerative colitis and diabetes has been suggested. Furthermore, most phages found at different sites in the human body are temperate, so their therapeutic effects and their potential beneficial effects remain unclear. Hence, far, no correlation has been observed between the presence of widespread crAssphage in the human population and human health and diseases. Here, we emphasize the beneficial effects of phage transfer in fecal microbiota transplantation (FMT) in Clostridioides difficile infection. The safety of phage use in gastrointestinal disorders has been demonstrated in clinical studies. The significance of phages in the FMT as well as in gastrointestinal disorders remains to be established. An explanation of the multifaceted role of endogenous phages for the development of phage therapy is required.”

*Nikolich, M. P., & Filippov, A. A. (2020). Bacteriophage therapy: Developments and directions. Antibiotics, 9(3), 135. [PDF] [Cited by]

In an era of proliferating multidrug resistant bacterial infections that are exhausting the capacity of existing chemical antibiotics and in which the development of new antibiotics is significantly rarer, Western medicine must seek additional therapeutic options that can be employed to treat these infections. Among the potential antibacterial solutions are bacteriophage therapeutics, which possess very different properties from broad spectrum antibiotics that are currently the standard of care, and which can be used in combination with them and often provide synergies. In this review we summarize the state of the development of bacteriophage therapeutics and discuss potential paths to the implementation of phage therapies in contemporary medicine, focused on fixed phage cocktail therapeutics since these are likely to be the first bacteriophage products licensed for broad use in Western countries.”

*Rasmussen, T. S., Koefoed, A. K., Jakobsen, R. R., Deng, L., Castro-Mejía, J.,L., Brunse, A., . . . Nielsen, D. S. (2020). Bacteriophage-mediated manipulation of the gut microbiome – promises and present limitations. FEMS Microbiology Reviews, 44(4), 507-521. [Cited by]

Gut microbiome (GM) composition and function are linked to human health and disease, and routes for manipulating the GM have become an area of intense research. Due to its high treatment efficacy, the use of fecal microbiota transplantation (FMT) is generally accepted as a promising experimental treatment for patients suffering from GM imbalances (dysbiosis), e.g. caused by recurrent Clostridioides difficile infections (rCDI). Mounting evidence suggests that bacteriophages (phages) play a key role in successful FMT treatment by restoring the dysbiotic bacterial GM. As a refinement to FMT, removing the bacterial component of donor feces by sterile filtration, also referred to as fecal virome transplantation (FVT), decreases the risk of invasive infections caused by bacteria. However, eukaryotic viruses and prophage-encoded virulence factors remain a safety issue. Recent in vivo studies show how cascading effects are initiated when phage communities are transferred to the gut by e.g. FVT, which leads to changes in the GM composition, host metabolome, and improve host health such as alleviating symptoms of obesity and type-2-diabetes (T2D). In this review, we discuss the promises and limitations of FVT along with the perspectives of using FVT to treat various diseases associated with GM dysbiosis.”

*Sieiro, C., Areal-Hermida, L., Pichardo-Gallardo, Á., Almuiña-González, R., Trinidad, d. M., Sánchez, S., . . . Villa, T. G. (2020). A hundred years of bacteriophages: Can phages replace antibiotics in agriculture and aquaculture? Antibiotics, 9(8), 493. [PDF] [Cited by]

“Agriculture, together with aquaculture, supplies most of the foodstuffs required by the world human population to survive. Hence, bacterial diseases affecting either agricultural crops, fish, or shellfish not only cause large economic losses to producers but can even create food shortages, resulting in malnutrition, or even famine, in vulnerable populations. Years of antibiotic use in the prevention and the treatment of these infections have greatly contributed to the emergence and the proliferation of multidrug-resistant bacteria. This review addresses the urgent need for alternative strategies for the use of antibiotics, focusing on the use of bacteriophages (phages) as biocontrol agents. Phages are viruses that specifically infect bacteria; they are highly host-specific and represent an environmentally-friendly alternative to antibiotics to control and kill pathogenic bacteria. The information evaluated here highlights the effectiveness of phages in the control of numerous major pathogens that affect both agriculture and aquaculture, with special emphasis on scientific and technological aspects still requiring further development to establish phagotherapy as a real universal alternative to antibiotic treatment.”

*Yang, X., Wisuthiphaet, N., Young, G. M., & Nitin, N. (2020). Rapid detection of escherichia coli using bacteriophage-induced lysis and image analysis. PloS One, 15(6), e0233853. [PDF] [Cited by]

Rapid detection of bacterial pathogens is a critical unmet need for both food and environmental samples such as irrigation water. As a part of the Food Safety Modernization Act (FSMA), the Produce Safety rule has established several requirements for testing for the presence of generic Escherichia coli in water, but the current method available for testing (EPA M1603) demands specified multiple colony verification and highly trained personnel to perform these tests. The purpose of the study was to assess a phage induced bacterial lysis using quantitative image analysis to achieve rapid detection of Ecoli at low concentrations within 8 hours. This study aimed to develop a simple yet highly sensitive and specific approach to detect target bacteria in complex matrices. In the study, Ecoli cells were first enriched in tryptic soy broth (TSB), followed by T7 phage induced lysis, concentration, staining and fluorescent imaging. Image analysis was conducted including image pre-processing, image segmentation and quantitatively analysis of cellular morphological features (area, eccentricity and full width at half maximum). Challenge experiments using realistic matrices, including simulated fresh produce wash water, coconut water and spinach wash water, demonstrated the method can be applied for use in situations that occur in food processing facilities. The results indicated Ecoli cells that are lysed by T7 phages demonstrated significantly (P < 0.05) higher extracellular DNA release, altered cellular shape (from rod to circular) and diffused fluorescent signal intensity. Using this biosensing strategy, a sensitivity to detect Escherichia coli at 10 CFU/ml within 8 hours was achieved, both in laboratory medium and in complex matrices. The proposed phage based biosensing strategy enables rapid detection of bacteria and is applicable to analysis of food systems. Furthermore, the steps involved in this assay can be automated to enable detection of target bacteria in food facilities without extensive resources.”

*Żbikowska, K., Michalczuk, M., & Dolka, B. (2020). The use of bacteriophages in the poultry industry. Animals, 10(5), 872. [PDF] [Cited by]

“The emergence of multidrug-resistant infections and antibiotic failures have raised concerns over human and veterinary medicine worldwide. Poultry production has had to confront the problems of an alarming increase in bacterial resistance, including zoonotic pathogens. According to the European Food Safety Authority (EFSA), campylobacteriosis and salmonellosis have been the most frequently reported human foodborne diseases linked to poultry. This situation has strongly stimulated a renewal of scientists’ interest in bacteriophages (phages) since the beginning of the 21st century. Bacteriophages are the viruses of bacteria. They are abundant in nature, and accompany bacteria in each environment they colonize, including human microbiota. In this review, we focused on the use of bacteriophages as therapeutic agents to treat infections and reduce counts of pathogenic bacteria in poultry, as biocontrol agents to eliminate foodborne pathogens on/in food, and also as disinfectants to reduce contamination on food-contact surfaces or poultry carcasses in industrial conditions. Most of the phage-based products are targeted against the main foodborne pathogens, such as Campylobacter jejuniSalmonella spp., Escherichia coliListeria monocytogenesStaphylococcus aureus, and Clostridium perfringens. Phages are currently addressed at all stages of the poultry production “from farm to fork”, however, their implementation into live birds and food products still provokes discussions especially in the context of the current legal framework, limitations, as well as public health and safety.”

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