Phage Therapy
Contents
Introduction
As pathogenic microorganisms are developing resistance to many antibiotics, phage therapy is receiving more attention. This treatment uses bacteriophages to target specific pathogens. Although phage therapy was introduced almost one hundred years ago, it is still not widely accepted through most the world. [1] Yet some countries, especially Russia, have succeeded in integrating phage therapy into many treatment plans. [2] Phage have also shown to be useful in the control of bacteria in food and agriculture. [3]
History
Felix d’Herelle and Frederick Twort were very important in the beginnings of phage therapy. [4]. In 1910, d’Herelle traveled to Mexico to examine an infestation of locusts that were dying from a bacterial intestinal condition. From the locusts’ fecal matter, he was able to isolate Coccobaccilus aeridiorum – the bacterium that was causing the infection. Soon after, d’Herelle noticed a clear zone in the culture plates. [5]. However, it was not until a 1915, when he read an article from Twort describing the same phenomenon in plates of Staphylococcus, that he really began to study bacteriophage. [5] Later that year, d’Herelle was asked to research an outbreak of dysentery from French troops. He inoculated Shigella strains from the patients, with fecal samples of the diseased. Again, he found clear areas in the bacterial lawn, leading him to the conclusion that viruses were capable of killing bacteria. [6].
The first trial of bacteriophage as a treatment option occurred in 1919. After ingesting phage himself to assess the safety, d’Herelle administered phage to a young patient with a very serious case of dysentery. The patient quickly recovered after one dose. [7]. Further experiments reinforced this success. For example, when d’Herelle and his colleagues traveled to India to treat a cholera outbreak, they found that patients treated with phage had almost a 90 percent reduction of mortality compared to those treated with traditional medicines. [8].
Despite the success of phage therapy, its use declined in much of the Western world as a result of the introduction of antibiotics. However, as a result of being isolated from much of the modern world, the former Soviet Union continued studying bacteriophage, especially in the treatment of soldiers. Much of this continued research was conducted at the Eliava Institute of Bacteriophage, which was founded by young scientist, George Eliava, who had met d’Herelle in 1921, and became very fascinated in the study of bacteriophage. [4] This institute remained very influential in the retained focus on phage therapy in the USSR.
Eliava Institute of Bacteriophage
Unfortunately, Eliava established the institute in Tbilisi, Georgia during the height of Stalin’s power. Just a few years after its opening, Eliava and his family were executed and d’Herelle was forced to flee.[9] Despite this tragedy, the institute was extremely successful and hugely influencial throughout the Soviet Union. It was not long before over one thousand employees were involved in receiving pathogenic bacteria and testing different phage for their ability to eliminate the pathogen. Phage therapy was used extensively in the treatment of dysentery and wounds of the Soviet Military in the early years of the institute. [10] The institute remains a leader in phage therapy research, treating patients from all over the world who have had antibiotics fail them. [4]
Possible Applications
Phage therapy has more uses than just fighting infections in the body. It has also exhibited success in eliminating food pathogens. For example, a recent study has shown phage to be very successful in exterminating hydrogen sulfide-producing bacteria, known to cause meat to spoil, in animal products. [11]
Phage therapy offers even more advantages when its applied before slaughter. For example, cattle often carry an infectious E. coli strain in their intestinal tract. This has been known to contaminate the meat, causing severe gastrointestinal problems for the consumer. [12] If the pathogen could be reduced before slaughter, the threat of contamination would decrease.[13]
Bacteriophage have been specifically employed in fighting Salmonella contamination. Salmonella has been known to contaminate meat and vegetables, contributing to over one million illnesses in the United States every year. Furthermore, it is credited as the leading cause of foodborne hospitalizations and deaths. [14] Because of this huge threat Salmonella poses, researchers have been searching for effective ways to contain Salmonella infections. A recent study demonstrated the effectiveness of phage by purposefully contaminating different commonly consumed meats and vegetables with S. Typhimurium and S. Enteritidis (both Salmonella carrying bacteria).[15] Such contaminated sources were then treated with a bacteriophage cocktail. Treated pig skin, poultry meats, eggs and lettuce showed a significant reduction of bacterial growth suggesting bacteriophage is effective at different stages of food production. Its effectiveness against the pig skin is important as many pre-slaughter animals face skin infections that can contaminate the food. Its effectiveness in ready to eat products like eggs is also of particular interest as eggs account for almost half of salmonella related illnesses. [15]
Phage therapy is also used in agriculture. Bacteria can pose a severe threat to a high crop yield. The benefit of phage over other treatments is that it is safe for both the environment and other living organisms that are good for the crops. [3]
There has also been an increasing interest in Phage and Cancer.Phage have been shown to induce a stronger immune response against tumor related cells. They also are used as a platform to display powerful drugs to specific targets. [16]
Treatment Process
The first step in treating a pathogen with phage is isolating the correct phage. It is critical the appropriate phage is isolated for an effective treatment. The phage is usually found by taking samples from locations where the pathogenic bacterium can be found, often including sewage sources, water, soil or fecal matter. [17] The samples are plated with the bacteria and examined for evidence of phage activity. Sometimes these phage are isolated as a single phage, but often they are combined into a phage cocktail. A cocktail is advantageous in preventing problems arising from bacterial resistance. [18]
Once the desired phage or phage cocktail has been determined, they must be multiplied. Phages, like all viruses, are obligate intracellular parasites and therefore must be prepared using live bacteria. After they have been allowed to multiply, they are purified from the bacteria before application. Once purified, phage can be administered by a number of ways including orally, topically or even through inhalation. Oral application is often supplemented with an antacid in order to keep the stomach acidity from destroying the phage. [19]
Manipulation
Genetic manipulation can play an important role in phage therapy. Phage can be genetically modified to control lysis. [3] Virulent phage are generally used as opposed to temperate phage because of the possible adverse affects a phage can have if allowed to replicate in the host. For example, a lysogenic phage might alter the host cell phenotype, release exotoxins, and can protect its host from being affected by other phage. However, many virulent phage can cause the release of endotoxins when the bacterial host lyses. Researchers can take out the gene responsible for cell lysis to prevent the release of endotoxins. The bacteria will still die, but instead of bursting, it will remain whole until it is phagocytized. [20] Genetic modification can also be used for altering the range of bacterial hosts which a phage can infect using methods such as induced recombination. Furthermore, phage can be modified to help it escape from the patient’s immune response. Some phage will be recognized and destroyed by the immune system before they have a chance to infect the pathogen. With genetic manipulation, phage can evade the immune response and successfully reach its target. [18]
Advantages Over Antibiotics
The decline in effectiveness of antibiotics makes bacteriophage therapy very appealing for several reasons. They are particularly important for bacteria that have already built up immunity against antibiotics. Bacteria will not be able to resist phage as well as antibiotics because phage are able to mutate along with the bacteria. Phages are also much greater in number and can multiply in the body as long as an infection is present. Once the pathogenic bacteria dies, the phage will die as well. [21] Furthermore, phage are specific so they can fight a pathogen while allowing beneficial bacteria to live, eliminating many adverse effects antibiotics can cause. [22]
Disadvantages
Despite the appeal, phage therapy has its disadvantages. Phage exert their effect by causing the pathogenic bacteria to lyse. This can result in the pathogen releasing endotoxins, potentially causing serious health concerns for the patient. [21] Another problem is that the host immune response has been known to eliminate phage before they have a chance to infect the pathogen. Passing through the acidic stomach also can reduce the function of the phage. [23] The specificity of phage that attributes to much of its appeal, also contributes to much of its disadvantages. Because it is only successful in killing a certain species of bacteria, the exact pathogenic bacterium must be known and the correct phage matched to it. This takes much more time than administering antibiotics.[24] Furthermore, temperate phage can play a role in genetic recombination between bacteria, allowing for increasing resistance and virulence of bacteria. [25]
References
- ↑ d'Herelle, F (1931) Bacteriophage as a Treatment in Acute Medical and Surgical Infections. Bull N Y Acad Med 7 329-48 PubMed
- ↑ McCallin, S et al. (2013) Safety analysis of a Russian phage cocktail: from metagenomic analysis to oral application in healthy human subjects. Virology 443 187-96 PubMed
- ↑ 3.0 3.1 3.2 Eyer, L et al. (2007) [New perspectives of the phage therapy]. Klin. Mikrobiol. Infekc. Lek. 13 231-5 PubMed
- ↑ 4.0 4.1 4.2 Chanishvili, N (2012) Phage therapy--history from Twort and d'Herelle through Soviet experience to current approaches. Adv. Virus Res. 83 3-40 PubMed
- ↑ 5.0 5.1 Summers, WC (2001) Bacteriophage therapy. Annu. Rev. Microbiol. 55 437-51 PubMed
- ↑ D'Herelle, F (2007) On an invisible microbe antagonistic toward dysenteric bacilli: brief note by Mr. F. D'Herelle, presented by Mr. Roux. 1917. Res. Microbiol. 158 553-4 PubMed
- ↑ Keen, EC (2012) Felix d'Herelle and our microbial future. Future Microbiol 7 1337-9 PubMed
- ↑ Jensen, MA et al. (2006) Modeling the role of bacteriophage in the control of cholera outbreaks. Proc. Natl. Acad. Sci. U.S.A. 103 4652-7 PubMed
- ↑ Parfitt, T () Georgia: an unlikely stronghold for bacteriophage therapy. Lancet 365 2166-7 PubMed
- ↑ Abedon, ST et al. (2011) Phage treatment of human infections. Bacteriophage 1 66-85 PubMed
- ↑ Gong, C et al. (2014) Application of bacteriophages specific to hydrogen sulfide-producing bacteria in raw poultry by-products. Poult. Sci. 93 702-10 PubMed
- ↑ Rasmussen, MA & Casey, TA (2001) Environmental and food safety aspects of Escherichia coli O157:H7 infections in cattle. Crit. Rev. Microbiol. 27 57-73 PubMed
- ↑ García, P et al. (2008) Bacteriophages and their application in food safety. Lett. Appl. Microbiol. 47 479-85 PubMed
- ↑ Scallan, E et al. (2011) Foodborne illness acquired in the United States--major pathogens. Emerging Infect. Dis. 17 7-15 PubMed
- ↑ 15.0 15.1 Spricigo, DA et al. (2013) Use of a bacteriophage cocktail to control Salmonella in food and the food industry. Int. J. Food Microbiol. 165 169-74 PubMed
- ↑ van Kan-Davelaar, HE et al. (2014) Using viruses as nanomedicines. Br. J. Pharmacol. 171 4001-9 PubMed
- ↑ Gill, JJ & Hyman, P (2010) Phage choice, isolation, and preparation for phage therapy. Curr Pharm Biotechnol 11 2-14 PubMed
- ↑ 18.0 18.1 Goodridge, LD (2010) Designing phage therapeutics. Curr Pharm Biotechnol 11 15-27 PubMed
- ↑ Ryan, EM et al. (2011) Recent advances in bacteriophage therapy: how delivery routes, formulation, concentration and timing influence the success of phage therapy. J. Pharm. Pharmacol. 63 1253-64 PubMed
- ↑ Stone, R (2002) Bacteriophage therapy. Stalin's forgotten cure. Science 298 728-31 PubMed
- ↑ 21.0 21.1 Burrowes, B et al. (2011) Bacteriophage therapy: potential uses in the control of antibiotic-resistant pathogens. Expert Rev Anti Infect Ther 9 775-85 PubMed
- ↑ Pirisi, A (2000) Phage therapy--advantages over antibiotics? Lancet 356 1418 PubMed
- ↑ Merril, CR et al. (1996) Long-circulating bacteriophage as antibacterial agents. Proc. Natl. Acad. Sci. U.S.A. 93 3188-92 PubMed
- ↑ Kutter, E et al. (2010) Phage therapy in clinical practice: treatment of human infections. Curr Pharm Biotechnol 11 69-86 PubMed
- ↑ Jensen, EC et al. (1998) Prevalence of broad-host-range lytic bacteriophages of Sphaerotilus natans, Escherichia coli, and Pseudomonas aeruginosa. Appl. Environ. Microbiol. 64 575-80 PubMed
