You have probably heard about antibiotics to treat bacterial infections, but what do you know about phage therapy?
Phage therapy involves the use of bacteria-specific viruses (bacteriophages or ‘phages’) to combat undesired bacteria associated with infectious disease. A publication in 2011 considered the “pros” and “cons” of phage therapy and compared their use with antibiotics.
An introduction to phage
There are two types of bacteriophage: lytic (virulent) and lysogenic (temperate). Lytic phages force an infected cell to make new phage progeny by taking control of the cellular machinery. Then, when it is time to release the progeny, the infected cell bursts and is destroyed. By contrast, lysogenic phages incorporate their genetic material into host DNA, co-opting host DNA replication machinery to passively maintain and replicate the viral genome. Lysogenic phages do not destroy the host cell. Typically, lytic phage are used for phage therapy. This summary will focus on explaining the advantages and disadvantages of phage therapy through analysis of the lytic cycle, before discussing why lysogenic phage are currently seen as problematic in phage therapy.
Lytic cycle
Attachment: A lytic phage uses its “tail” to attach to a receptor on the bacterium. The “tail” and receptor have very precise shapes making this a specific interaction. This means that the phage can only infect a bacterium that has a receptor matching its “tail”.
Advantages of attachment specificity:
- Phage will not affect normal bacterial flora found in the body. In contrast, many antibiotics target a wide range of bacteria which can disturb healthy flora, possibly leading to infections such as antibiotic-associated Clostridium difficile colitis (see Nottingham iGEM’s wiki to learn about a novel treatment for difficile infection).
- There are fewer types of bacteria that have the potential to develop resistance to a particular phage.
- When discarded as waste, phage will at most only interfere with a few types of environmental bacteria, resulting in a lower impact on the environment compared to many antibiotics.
Potential disadvantage of attachment specificity:
- The type of bacteria causing the infection must be known for phage therapy to be effective. However, since phage can be combined with antibiotic therapy, this greatly broadens the types of bacteria that can be targeted with one dose of therapy. Many phage can also be mixed together to form a cocktail.
Replication: The phage injects its genetic information into the bacterium and uses the protein-producing equipment of the bacterial cell to make many copies of itself.
Advantages of replication:
- Only a single dose of phage needs to be given for treatment to be effective.
Cell lysis: Once the phage have replicated sufficiently in the bacterium, they utilise 2 main mechanisms to exit the cell [1]. One mechanism uses 2 proteins, an endolysin and a holin, to perforate the cell membrane. Another mechanism use alternative single membrane protein species to disrupt the cell envelope (the exact mechanism of which is unknown). The new phage can then go on to infect more bacteria.
Advantages of cell lysis:
- An infected bacterium is always killed; this makes bacterial resistance less likely than compared with some antibiotics where the bacteria remain alive.
- Because phage will replicate only in the target bacteria and increase in number locally, an initial low dose of phage may be sufficient for treatment.
- Since phage kill host bacteria using a different mechanism than antibiotics, phage therapy can be used to kill antibiotic-resistant bacteria.
- Many pathogens form biofilms. This means that bacteria join on a surface and form a protective layer around themselves. Antibiotics struggle to penetrate biofilms but phage have been found to target biofilms more successfully, due to their ability to degrade components of the bacterial biofilm.
Lysogenic cycle
Attachment: Same as for lytic phage
Repression and integration: The genetic material of the phage is incorporated into the genetic information of the bacteria forming what is known as a prophage. A protein called a repressor stops the phage from replicating.
Cellular replication: The bacterium divides as normal to form many daughter cells all containing the prophage.
Induction: These daughter cells can remain in the lysogenic cycle for many generations but can enter the lytic cycle at any time leading to the lysis of that cell and the release of many new phage.
Potential disadvantages of lysogenic phage:
- It is commonly thought that lysogenic phage should be avoided for use in therapy as they are more likely to lead to bacteria becoming phage resistant. Some scientists think that new, effective phage will be continually available indefinitely against most bacteria, mitigating this concern [2].
- It is possible that lysogenic phage could encode for genes that increase the virulence (ability to infect and cause damage) of the bacteria. Therefore, it is important in lysogenic phage therapy to check the genetic information of the phage to ensure that it does not contain genes that increase virulence. (See Nottingham iGEM’s project to find out more about a way lysogenic phage can be used as a therapy).
Phage provide numerous advantages and few disadvantages. Countries such as Russia, Georgia and Poland have relied on phage therapy for close to a century, but not many other countries have followed suit. As stated by Mzia Kutateladze [3], head of the scientific council at the Eliava Institute in Tbilisi “…this [phage] is a virus, and people are afraid of viruses.” With the number of antibiotic-resistant bacteria continuing to rise, surely phage therapy can no longer be ignored.
Summary written by: Ruth Bentley, Nottingham iGEM 2018 team
To read the full article, please click the following link:
Pros and cons of phage therapy
Catherine Loc-Carrillo and Stephen T Abedon
References:
[1] Young, R. (1992). Bacteriophage lysis: mechanism and regulation. Microbiology and Molecular Biology Reviews. 56(3): 430–481.
[2] Örmälä, A.-M., & Jalasvuori, M. (2013). Phage therapy: Should bacterial resistance to phages be a concern, even in the long run? Bacteriophage, 3(1), e24219. http://doi.org/10.4161/bact.24219
[3] Reardon, S. (2014). Phage therapy gets revitalized. Nature News. https://www.nature.com/news/phage-therapy-gets-revitalized-1.1534Figure 1 from the Bacteriophage Wikipedia page.
