Friends and Foes
Bacteriophages are viruses that infect bacteria. They are a major agent of horizontal gene transfer between bacteria–a concept covered in AP® Biology and other biology classes. What students may not be aware of is the role bacteriophages play in human disease.
Bacteriophages play a critical role in some human diseases
You would not expect bacteria viruses to have an effect on human beings, but a closer look reveals that bacteriophages (phages) can play a critical role in human disease. The relationship between phages and human disease is complex. Some of the diseases that have long plagued human beings are indirectly caused by phages. However, phages can also work to our benefit. There is a history of people using bacteriophages to treat human bacterial infections, which with the advent of increasing bacterial antibiotic resistance, is being more widely explored.
Basic phage biology
Understanding the role of phages in human disease requires familiarity with some basic phage biology. The phage particle consists of the phage genome packaged in a capsid. The capsid is a container comprised of phage proteins. Phages have several different types of infectious cycles, two of which are the lytic and the lysogenic life cycles.
During a lytic infection, a phage infects a bacterium and takes over its machinery to replicate itself and produce new phage particles. In the course of replication and release of the new phage particles, the host bacterium is lysed, and thus killed. Phages that can only carry out this type of infection are called lytic, or virulent, phages.
Phages can also carry out a lysogenic infection in which the phage inserts its genome into the bacterial genome. Once inserted, the phage genome then remains in the bacterial genome until it receives an environmental signal, causing it to excise itself from the bacterial genome, replicate, and produce viral particles. Phages that set up a lysogenic infection are referred to as lysogenic, or temperate, phages.
Phages can acquire non-phage genes
During either type of life cycle, phages may acquire genes not originally part of their genome. This process, referred to as transduction, can occur as a result of a lytic or lysogenic infection.
During the lytic life cycle, a piece of bacterial DNA may be packaged into the phage particle in place of the phage genome. The resulting particle is no longer capable of replicating itself, but is capable of infecting a new bacterium. When the phage particle infects a new bacterium, the packaged DNA from the original host bacterium is introduced into the new bacterium. Sometimes that DNA integrates into the new bacterium’s genome.
Transduction can also occur as part of a lysogenic life cycle. When a lysogenic phage genome integrated into a bacterial genome pops back out to replicate, bacterial DNA that is adjacent to the phage genome may also be excised. Such bacterial DNA becomes part of the phage genome and is packaged into the phage particle. When the phage infects a new bacterium, it introduces the original host bacterium’s DNA into the new bacterium.
In this way, phages can introduce a gene that is harmful to humans (e.g., an antibiotic resistance gene or a toxin) from one bacterium to another.
The role of bacteriophages in cholera and diphtheria
Cholera is caused by the bacterium Vibrio cholerae and is estimated to affect millions of people in the undeveloped world every year. At its most severe, cholera is marked by acute vomiting and diarrhea that can fatally dehydrate a person within hours. While good medical care can prevent death, many people still die from the disease. However, V. cholerae does not cause the disease unless it is infected with a lysogenic bacteriophage carrying the gene for cholera toxin. Cholera toxin is what causes the severe diarrhea.
Likewise, Corynebacterium diphtheriae, the bacterium that causes diphtheria, must carry a phage containing the gene for diphtheria toxin to cause the disease. The toxin inhibits protein synthesis. Children in the US are vaccinated against diphtheria, but the disease still kills a significant number of people in the developing world, most of them children. The symptoms of classical diphtheria include a sore throat, low-grade fever, and the formation of a false membrane and sores on the tonsils, pharynx, and/or nasal cavity. The disease can lead to difficulty in breathing, as well as to tissue damage to various parts of the body, including the heart and nerves.
Combatting bacterial infections with bacteriophages
History
Ironically, bacteriophages have also been used to treat bacterial infections. Between 1928 and 1934, lytic bacteriophages that lyse V. cholerae were used in India to combat cholera. The three-year death toll from cholera in the treated areas fell from 30 per 10,000 to 2. However, with the advent of rehydration therapy and antibiotics, interest in the practice of using bacteriophages to treat cholera essentially ended.
Phages have been used with some regularity to treat bacterial infection in several countries, including France, Russia, Georgia, and Poland. However, only in recent times have English-speaking Western countries become more aware of the work done in those countries. This lack of awareness is partly due to the language barrier and partly due to the fact that studies done in Russia were conducted by the military, which did not have an interest in releasing information regarding the work.
In the past, phages were also used by some to treat infections in the United States. However, a limited understanding of phage biology led to less than optimum design of treatments. The resulting mixed results and the introduction of antibiotics dampened any further interest in phage therapy in the country.
Treatment with phage has been carried out in various ways, including (but not limited to):
- By mouth (e.g., for intestinal infections)
- By direct application to skin wounds (e.g., burns), often done through the application of bandages soaked with a solution containing phages
- By injection into the area of infection (e.g., an infected joint)
Advantages
Phages may be useful in killing bacteria that are resistant to antibiotics or in cases where the antibiotic has difficulty in reaching the bacteria, such as when bacteria have formed a biofilm. A biofilm is a population of microorganisms forming a layer on a surface. The cells in a biofilm are embedded in a matrix built of polysaccharides, proteins, nucleic acids, and lipids.
Another advantage is that phages are specific–a specific phage will only kill a few strains of bacteria. Thus, they leave the native bacteria flora intact. This specificity is also viewed as a disadvantage. For example, if the species of infecting pathogenic bacteria has not been identified, it is better to have a drug that will kill a broad range of bacteria.
Barriers to use
The use of phages in treating disease remains controversial in many Western countries in part due to the lack of large, double-blind, placebo-controlled studies demonstrating effectiveness and safety. In those countries, such studies must be done before a medical treatment is licensed for use. The studies are expensive, and many drug companies are reluctant to invest in them unless they are confident that they can recover the expense and produce a profitable product.
The ability to patent phages is questionable, making it hard for any company to control the market on a phage treatment for a significant amount of time. Many drug companies are reluctant to invest the large amount of time and money necessary to bring phage treatments to market unless they can patent them.
The testing required before a phage or phage mixture can be used in agriculture (veterinary use, food growth and processing, etc.) is less rigorous than that required before use in human medicine. Therefore, phages are already used in agriculture. The use of phages in agriculture could help pave the way for their use in human medicine by providing knowledge regarding the existing concerns underlying their use in humans.
Additional concerns regarding the use of phages include the following:
- Treatment with phages may increase the transfer of genes coding for toxins or antibiotic resistance to new bacteria. Sequencing to check the genomes of the phages used for treatment and only using lytic strains would alleviate some of this concern.
- Widespread use of phages could increase the size and nature of the phage population in the environment, disrupting the balance of naturally occurring bacterial populations.
- Rapid lysis of large numbers of bacteria in a patient could lead to the rapid and harmful release of bacterial toxins and LPS (lipopolysaccharides, bacterial molecules that can elicit severe immune reactions). To alleviate the problem, some groups have engineered phages that kill the bacteria without causing the lysis that rapidly releases toxins and LPS.
- As with antibiotics, bacteria can develop resistance to phages. Thus, any use of phages in agriculture and medicine must be done carefully to avoid the development of resistance. One advantage of phages over antibiotics is that phages can, to some extent, evolve to overcome bacterial resistance.
- Using phages to treat a systemic infection can be problematic, since, depending upon the circumstances, the immune system may quickly remove the phage particles from the body.
Use of phage products and genetically engineered phages
Scientists are exploring the use of phages to introduce genes into bacterium that would make it more susceptible to antibiotics or that would specifically restore antibiotic sensitivity. For example, one group changed a bacterium that is resistant to streptomycin, to one sensitive to the drug, by infecting it with a specifically engineered phage.
Scientists are also studying the use of individual phage proteins as drugs. For example, studies with animals have shown that treating the mucosal membranes of animals with lysin (proteins that some phages produce to lyse the bacterial cell wall) can prevent infection by the specific bacteria targeted by the lysin.
Conclusion
There are challenges and concerns regarding the use of phages, some of them economic and regulatory, some of them a result of basic biology. However, given the threat of growing bacterial antibiotic resistance and the potential benefits of including phages in our arsenal of tools for treating infections, work to overcome these barriers may prove extremely valuable. The story of bacteriophages and their role in human disease is also another example of how basic research has inadvertently led to a possible solution to a significant problem facing human beings.
References
Abedon, S.T., S.J. Kuhl, B.G. Blasdel, and E. Martin Kutter. (2011) Phage Treatment of Human Infections. Bacteriophage. Vol. 1:2, 66-85.
Dabrowska, K., K. Switala-Jelen, A. Opolski, B. Weber-Dabrowska, and A. Gorski. (2005) Bacteriophage Penetration in Vertebrates. Journal of Applied Microbiology. Vol. 98, 7-13.
Drulis-Kawa, Z., G. Majkowska-Skrobek, and B. Maciejewska. (2015) Bacteriophages and Phage-Derived Proteins–Application Approaches. Current Medicinal Chemistry. Vol. 22, 1757-1773.
Edgar, R., N. Friedman, S. Molshanski-Mor, and U. Qimron. (2011) Reversing Bacterial Resistance to Antibiotics by Phage-Mediated Delivery of Dominant Sensitive Genes. Applied and Environmental Microbiology. Vol. 78(3) 744-751.
Fischetti, V.A. (2011) Exploiting What Phage Have Evolved to Control Gram-Positive Pathogens. Bacteriophage. Vol. 1(4), 188-194.
Hadfield, T.L., P. McEvoy, Y. Polotsky, V.A. Tzinserling, A.A. Yakovlev. (2000) The Pathology of Diphtheria. The Journal of Infectious Disease. Vol. 181(Suppl 1), S116-120.
Henein, A. (2013) What Are the Limitations on the Wider Therapeutic Use of Phage? Bacteriophage. Vol. 3(2), e24872-1 to e24872-7.
Holmes, R.K. (2000) Biology and Molecular Epidemiology of Diphtheria Toxin and the tox Gene. The Journal of Infectious Disease. Vol. 181(Suppl 1), S156-167.
Lu, T.K., Koeris, M.S. (2011) The Next Generation of Bacteriophage Therapy. Current Opinion in Microbiology. Vol. 14, 524-531.
Meaden, S., B. Koskella. (2013) Exploring the Risks of Phage Application in the Environment. Frontiers in Microbiology. Vol. 4, 1-8.
Nelson, E.J., J.B. Harris, J.G. Morris Jr., S.B. Calderwood, and A. Camilli. (2009) Cholera Transmission: The Host, Pathogen, and Bacteriophage Dynamic. Nature Reviews Microbiology. Vol. 7(10), 693-702.
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