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Explaining the evolutionary persistence of persisters

This week's paper is "Nongenetic individuality in the host-phage interaction"?, published in PLoS Biology by Silvan Pearl and others. This is one of many recent papers on bacterial "persisters" a topic we are also starting to explore in my own lab.

Update: In 2010, we published a paper (discussed here) showing that the bacterial symbionts of alfalfa can form a much greater percentage of persister-like cells than most bacteria. When a starving cell divides, the mother cell keeps most of the resources and then goes dormant. We see this as an example of microbial bet-hedging.

When a large population of bacteria (in an infected person, for example) is exposed to antibiotics, a few of the bacteria may survive. One explanation, which is often true, is that these survivors have genes that make them resistant to the antibiotic. For the purposes of this discussion, it doesn't matter whether they have mutated versions of genes also found in the susceptible bacteria, or an extra gene acquired by horizontal gene transfer from another bacterial cell. Either way, those without the gene (or with the nonmutated version) mostly get killed by the antibiotic. Therefore, subsequent bacterial generations are founded mainly by these surviving resistant mutants. Therefore, the frequency of the resistance gene increases over generations: a classic example of evolution.

Sometimes, however, testing the "evolved"? population for antibiotic resistance shows the same results as in the previous unevolved generation: most of the bacteria die, but a few survive. If there's no change in gene frequency over generations, then the population hasn't evolved. But then why did any of the bacteria survive?

In such cases, the antibiotic-resistant bacteria may have been in a dormant, persister state. They aren't genetically different, just (in effect) asleep. Bacteria in the persister state are resistant to many kinds of stress that would kill them if they were actively growing, including antibiotics for which they have no specific resistance mechanisms. Earlier, I discussed a paper by Andy Gardner and others pointing out that, in addition to surviving stress, "going persister" reduces resource consumption, thereby freeing resources for nearby cells. If the beneficiaries are close relatives, then natural selection may tend to favor genes that trigger persistence more often. On the other hand, cells in the persister state do not grow and reproduce, so there's an opportunity cost to being a persister. These are the aspects of persistence that my grad student, Will Ratcliff, is working on now.

But back to this week's paper. If bacterial persister cells are resistance to antibiotics, are they also resistant to infection by viruses? The authors compared a mutant that forms more persisters than usual with its rare-persister parental strain. The mutants were relatively resistant to being burst by a virus that infects bacteria.

To see more details of this interaction, they used time-lapse photography to track the fate of individual bacterial cells under a microscope. The bacteria were genetically modified so that they glowed when genes key to virus reproduction were active. Viral reproduction was suppressed as long as the bacteria stayed in the persister state, but once they started to grow the viruses could reproduce and burst the bacterial cells.

I've never been quite clear on why it's important to keep taking antibiotics for so long. I recognize that one could start to feel better well after only 95% of the bacteria have been killed, and the remaining 5% could quickly rebound. But why do some of the bacteria take much longer to die than others? There are probably various reasons, but the risks posed by persisters may be one of them. Every day, some fraction of persisters resumes growth, making them once again susceptible to antibiotics. (Or, in the case of this week's paper, susceptible to viruses.) The longer the treatment is continued, the more persisters will come out of hiding and die.

For more on the wonderful world of bacteria, see recent blogs by Carl Zimmer and Olivia Judson. Small Things Considered is usually interesting, too. And The Evilutionary Biologist is an expert on the viruses that attack bacteria.

Comments

I've been reading a lot about the potential of phages (viruses) to replace antiobiotics. Your summary brings up two advantages: first, they should be effective with a single dose since they will reactivate at the same time as the host; and second, they should evolve to counter any resistance that the bacteria manage to evolve. Of course this "arms race" will continue through numerous iterations...

I wonder if there are any clinical trials using phages coming up.

The Evilutionary Biologist has discussed phage therapy a couple of times:
http://evilutionarybiologist.blogspot.com/2008/02/phage-therapy.html
I agree with your proposed potential advantages. I understand that phage therapy is widely used in one Eastern European country and only there. Are they frauds or drug companies covering up a great alternative?

I am leaning towards fraud. If there were more than one country doing it then it would be different. But one sounds more like corruption.

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