Phage therapy: is it safe?

Zombies: are they more common than we thought? ZombieVirus

http://www.gadg.com/2010/11/12/zombie-virus-affects-china/

The topic of Phage Therapy introduced in this blog got me wondering: are we safe from bacteriophages? Bacteriophages are viruses that infect bacteria. I will refer to them as ‘phage’ in this blog. When I first came across ‘phage therapy’ (using phage to combat bacterial infections), I was concerned about safety. Introducing viruses into our bodies to combat disease sounded a little dangerous because it involves employing Nature’s Zombies. Yes, Zombies. Viruses are not necessarily ‘alive’ but they still float around, ‘eating’ bacteria. I have researched the safety of phage therapy and I want to share what I learnt by covering (i) the differences between prokaryotic and eukaryotic cells (ii) the mechanics of infection and (iii) when a virus can cross species barrier. I will then summarise my research and conclude with my opinion on phage therapy.

(i) Prokaryotes vs. eukaryotes
Prokaryotic and eukaryotic cells differ structurally in a number of ways. Prokaryotes have simpler structures, lacking membrane-bound organelles, and with only a single membrane enclosing the whole cell (Figure 1). Prokaryotes are also unicellular. Eukaryotic cells are often multicellular and therefore have different mechanisms of defence (discussed below). Eukaryotic cells are also generally larger than prokaryotic cells (­0.1 – 10 µm vs. 10 – 100 µm).

pro vs eu

Figure 1: http://www.phschool.com/science/biology_place/biocoach/cells/common.html

Humans (eukaryotes) differ from bacteria in a number of ways. For example, humans are multi-cellular and obtain energy by ingesting organic matter and digesting it in specialised organs such as the stomach and intestines. Bacteria (prokaryotes) are unicellular and digest foods by secreting enzymes (extracellular digestion) or absorbing food parcels and digesting within the cell. Humans and bacteria have different optimal environmental conditions. However, bacteria that live symbiotically with us, for example the beneficial gut flora we host, perform optimally at the temperature of our internal organs.

Amongst our structural differences are the specific receptors on the outer membranes’ of cells. These could be likened to name badges used for identification. They also enable our 37.2 × 1012 (37.2 trillion) cells to communicate so that multicellular organisms, such as humans, can function. These receptors are also vital for enabling our immune system to identify and thus destroy potentially dangerous foreigners, such as pathogenic bacteria and viruses. Bacteria do not have highly specialised immune systems like humans. Instead, they rely on ‘(anti)phage defence’ mechanisms.

(ii) Infection resistance
sarahlomas19 has posted about the life-cycle of a phage here: https://phagehuntnz.wordpress.com/2014/05/13/phage-hunt-nz-post-fighting-with-phages/. With this topic sufficiently covered from the perspective of a phage, I will explain phage infection from the bacteria’s perspective.

Once a phage has adsorbed to a bacterial cell, it can ‘decide’ whether or not to go ahead with the infection. Perhaps this is a survival adaptation: if the cell a phage has adsorbed to is damaged or unfit, the phage can ignore this cell and search for a healthier candidate. Once adsorbed to a desired cell, enzymes from the phage are used to create an opening in the cell wall (if present) and the phage’s genome is injected into the host cell… But do not fear for them! Bacteria have four cunning strategies to protect themselves from Zombie Apocalypses (phage infection):

Adsorption inhibition is the inability of viruses to attach to receptors on the cell’s membrane by changing these receptors or shielding them.
DNA injection blocking can be activated by changes in a cell’s permeability, excluding phage from the cell.
Restriction-modification is the prevention of DNA integration into the host genome by methylation at restriction sites. Non-methylated DNA (phage DNA) can then be destroyed by restriction enzymes if it is injected into the cell.
The final strategy, abortive infection, uses the classic “needs of the many outweigh the needs of the few” Star Trek principle to protect the bacterial colony. In this instance, the infected bacterium destroys itself immediately after it is infected to prevent the phage from replicating, thus heroically sacrificing itself for the greater good of the bacterial colony.

So what is the link to humans? Humans are infected by viruses in much the same way, but our bodies have different ways of protecting themselves. We are multicellular and have the advantage of using groups of specialised cells for protection. The first line of defence against viral attack is prevention, for example, mucus secretions that catch, trap and destroy viruses. If a virus manages to slip past this defence, our secondary line of defence will (hopefully) give the virus a warm welcome. For example, white blood cells hunt down and destroy pathogenic foreigners in the body. This is how our bodies defend themselves from virus infection, but the link I want remembered is that each cell, belonging to each organism or species, has its own unique receptors. Viruses use these ‘name badges’ to identify cells for infection. Humans have different receptors to bacteria. This is another preventative line of defence.

(iii) Crossing the species barrier
Phages are not necessarily specific to one bacteria. Most are specific to one host but many have ranges of hosts that they can infect. In eukaryotes, there are examples of viruses with ranges of hosts that cross the species barrier such as rabies, swine flu, bird flu and AIDs (e.g. dogs, pigs, birds, monkeys and humans). So if viruses can adapt and expand their niches to other species, this leads us to the question: why on earth would we consider using viruses from another species to treat illnesses in humans? Aha. In my research, I have not come across any examples of viruses crossing from prokaryotes to eukaryotes. The virus-caused diseases above, that have managed to infect humans, originated from other eukaryotes. The species barrier between prokaryotes and eukaryotes appears too complex for these zombies to overcome.

Concluding remarks:
Prokaryotes and eukaryotes differ structurally in many ways. Prokaryotes are smaller and less complex than eukaryotes. Most importantly they have different receptors/identifiers on the cell membranes which set them apart in the eyes of phages. If phages were somehow able to cross the species barrier from bacteria to humans, I suppose an appropriate name would be required to describe them. ‘Bacteriophage’ (bacteria-eater) would no longer apply. Homophage (homonid-eater)? In conclusion, humans (eukaryotes) and bacteria (prokaryotes) are too different structurally for phage to be able to infect us. Therefore, my final say on this topic is: do not fear a Zombie Apocalypse. But seriously, my conclusion for this post on phage therapy is that it is a safe and fascinating method of treating bacterial infections and I would like to know more about it.

Comment below and share what you know!

 

Sources:

The ecology of prokaryotic viruses: http://en.wikipedia.org/wiki/Swine_influenza

This article describes the limitations to crossing the species barrier and the obstacles a virus must overcome to expand its ecological niche in this way: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1292294/pdf/jrsocmed00146-0011.pdf

Swine flu: http://www.nejm.org/doi/full/10.1056/nejmra0904322

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One Response to Phage therapy: is it safe?

  1. drhhnz says:

    Speaking of Zombies and Phage! Did you know that the original Phage Hunts were conducted in Pittsburgh PA by Prof. Graham Hatfull and his crew there. What is the tie in with Zombies, you ask? WELL! The great classic zombie movies were made by George A. Romero in Pittsburgh PA: http://en.wikipedia.org/wiki/George_A._Romero

    It’s a FACT!

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