Introduction to Phage Therapy
Phage therapy is the use of viruses to treat bacterial infections. Application of bacteriophage to a bacterial infection will result in the phage infecting, replicating, and then destroying their bacterial hosts. The newly synthesized phage can then go on to infect other bacteria, resulting in the rapid removal of the infection. The use of phages to treat bacterial infections has received new attention due to the appearance of strains of previously treatable pathogens such as methicillin-resistant Staphylococcus aureus, and multidrug-resistant tuberculosis.
The discovery of a bacterial-killing substance that could pass through extremely small filters was observed independently several times:
|Year||Discoverer, country, microbe sensitive to phage|
|1896||Hankin, British, Vibrio cholerae|
|1898||Gamaleya, Russian, Bacillus subtilis|
|1915||Twort, British, Staphylococcus|
|1917||d'Herelle, French-Canadian, Shigella.|
The first therapeutic usage of phage was in 1919, to treat a child with severe dysentery. In a classic case of old-school science, the lead researchers (which included d'Herelle) drank portions of the bacteriophage preparation the day before treating the child, to check the treatment's safety in humans. The child fully recovered within a few days, and further tests confirmed the result.
In the 1930s and 1940s, bacteriophage preparations were developed and sold by L'Oréal and the Eli Lilly Company. The development and mass production of antibiotics in the late 1940s halted research into phage therapy in the West, due to the superior efficacy and simplicity of antibiotics. Research continued in the Soviet Union. Currently, the only country that has approved phage therapy for human use is Georgia.
Regular use of phage therapy occurs primarily in the Republic of Georgia, due to the presence of the Eliava Institute, which has research phage therapy since the 1920s. However, synthetic biology has enabled entirely new approaches to phage therapy, such as engineering new abilities into the phage. One such ability is the degradation of the extracellular polysaccharides (EPS) produced by bacteria during infections. Production of the EPS results in a biofilm, which protects the bacteria within from external harm, such as antibiotics and bacteriophages, limiting the damage to the cells on the surface. To break through this barrier, researches inserted the gene for DspB, an enzyme that degrades one of the key components of EPS. After bacteria on the surface of the biofilm are infected, they produce DspB along with new phage. After the cells lyse, the DspB can degrade the EPS, which exposes more bacteria to infection.
One concern of phage therapy is the rapid lysing of pathogenic cells which may contain endotoxins. Sudden, masssive releases of toxin can cause dangerous amounts of inflammation. Therefore, phage that kill the targeted pathogen without disrupted the cell's integrity are of interest. This can be accomplished by that by modifying phage to express endonucleases and holins, which are toxic to the cell (chopping DNA and making non-catastrophic disruptions to the cellular membrane). Toxin release was minimized, which decreased inflammation and increased the survival rate of treated mice.
- Chanishvili N. Phage therapy--history from Twort and d'Herelle through Soviet experience to current approaches. Adv Virus Res. 2012;83:3-40. DOI:10.1016/B978-0-12-394438-2.00001-3 |
History of phage research.
- Lu TK and Collins JJ. Dispersing biofilms with engineered enzymatic bacteriophage. Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11197-202. DOI:10.1073/pnas.0704624104 |
Phage that makes infected cells produce Dispersin B, which degrades biofilms.
- Hagens S and Bläsi U. Genetically modified filamentous phage as bactericidal agents: a pilot study. Lett Appl Microbiol. 2003;37(4):318-23.
Describes the engineering of a phage that kills via non-lytic means, i.e. endonucleases and holins.