Friday, June 13, 2014

Oh you have bacterial infection? Why don’t you try a virus?


   In previous post, I highlighted that we are moving towards a post antibiotic era. I mentioned of a couple of examples on what the future looks like. One of the most talked about everywhere is the concept of phage therapy. After I published the post, I felt that phage therapy is the most talked about concept and needs a separate blog space. Bacteriophages are viruses of bacteria. For reasons of simplicity, the term phage is used to denote the bacteriophages. It should be noted that a variety of phages have been characterized against fungus, Parasites etc. They too are known as phages and often the term is confusing. In this post, the term phages exclusively refers to bacteriophages.

Table 1:  Examples of phage coding for virulence.
  A phage propagates through one of the modes of a life cycle- Lytic or lysogenic. In lytic life cycle, the phage produces progeny, killing the cell. In contrast, the lysogenic life cycle incorporates the phage genome into host genome and lies dormant, replicating with host. Such incorporation maybe an added advantage for bacteria. Well studied examples of viral genome encoding toxin properties to bacteria which subsequently acts as virulence is shown in table 1. Lysogenised phage can be induced back into lytic cycle by external disturbances. In these situations, a virus may package part of host genome and transfer it into other bacteria. An example of interest is transfer of shiga toxin gene to E coli from Shigella. Such E coli called as EHEC (Enterohemorrhagic Escherichia coli ), is one of the leading concern world over.

   This understanding has important implications. Point is you cannot simply isolate some phage and say "Here's your treatment..." Phage undergoing lysogenic conversion may introduce more problems. So the most important hurdle getting the phage to be only in lytic cycle. How? 

      The decision to undergo lytic or lysogenic cycle is not a random effect as was thought to be. Think of it something like this. If the phage is inside the bacteria, but bacteria is not abundant or in a poor growth medium, the chances that the phage will propagate after lysis is bleak. Because when the new phages will pop out there maynot be enough bacteria in vicinity to infect. In such conditions, the phage will undergo lysogenic conversion and keep quiet. On the other hand if bacteria is abundant. it would be preferable to undergo lytic cycle. This decision is taken by a series of switches called as cI and Cro. The actual genetic circuit consists of more players.

       By a series of complex steps, autoregulation of cI synthesis keeps the cell in a stable state of lysogeny. When the conditions are right, cro is transcribed which negatively regulates cI and enhances its own synthesis. This locks the phage into a lytic cycle. For a step by step look into the process click here. The point is that messing up with the cI production can give you a phage that can only lyse. And that is what exactly we want.

Table 2: Phage therapy, advantages and disadvantages.
  Phage therapy is not a new concept. The concept of use of bacteriophages dates to the work by Felix d’Herelle. Subsequently, multiple studies have been reported in French literature. Many publications have appeared in various journals where phages have been probably used in desperate attempts to save the patient, such as in severe septicemia, surgical site infections etc. Since by definition, phages doesn't infect humans, and studies have shown that they provide a very specific agent of therapy. There were industries and organisations that would produce phages, many of which have dropped the project.

 There are a variety of advantages and disadvantages of phage therapy, listed in Table 2. The greatest advantage of phage therapy is that a small dose of initial inoculum is needed on the site. Since phages will produce new progenies, they will take care of a lot of bacteria. And being very specific, they will not attack any bystander, a feature that has not yet been achieved by any antibiotic designed to date. And source of phages is a huge advantage. It is very easy to find phages in environment with a simple screening procedure. Delete for their potential to become lysogenic and they are ready.

The major disadvantage is we developing antibodies. But considering the huge repertoire of possible phages this is not expected to be a great problem. Even greater is the treatment of bacteria that are inside cells, which phages cannot access. Another difficulty is in administering the dose. The phage has to be put right into the site of infection to be maximally effective. This will require trained personnel which is in sharp contrast to oral antibiotics. A yet another problem is to tell the patient.. "You got severe bacterial infection, Multi drug resistant type. how about trying some virus". Such comments no matter how hard you try will be very difficult for the patient to digest. Of course patient education will help.

    In general, phage therapy is not an interest for pharma giants. The reason for this drawback is that phages are naturally occurring entities, which can be easily replicated and not patentable. And just like antibiotics it is a short course therapy (expectedly still shorter and cheaper for phage therapy). The chances of profit for the company is less. However, companies like Mediphage is devoting a lot of R&D, to developing new phages and phage based therapeutics.

     It should be noted that phage are not the ultimate weapons. As, I have discussed in my previous post on CRISPR (Link), bacteria have strategies to combat back. Bacterial resistance will evolve if we use phages the way we have used antibiotics. But, the argument is we may have too many phages in our arsenal, for the bacteria.

So are we ready for the post antibiotic era???
Oppenheim AB, Kobiler O, Stavans J, Court DL, & Adhya S (2005). Switches in bacteriophage lambda development. Annual review of genetics, 39, 409-29 PMID: 16285866

Abedon, S., Kuhl, S., Blasdel, B., & Kutter, E. (2011). Phage treatment of human infections Bacteriophage, 1 (2), 66-85 DOI: 10.4161/bact.1.2.15845

Chan BK, Abedon ST, & Loc-Carrillo C (2013). Phage cocktails and the future of phage therapy. Future microbiology, 8 (6), 769-83 PMID: 23701332

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