Why Fighting Disease With Disease Doesn’t Always Work

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A new study finds the technique, though potentially effective against a dreadful stomach infection, could backfire in other diseases.

By Nathan Collins


Clostridium difficile.

(Photo: Stanford University)

Last year, microbiologists reported on an odd new way to fight a nasty stomach bug called Clostridium difficile: Infect people with with a less-nasty strain of the same bacteria. To the surprise of many, it seemed to work, and along with a number of studies in the last decade, the idea of deliberate infection with less-virulent strains looked like a promising new way to fight some diseases. Too bad, then, that it will likely backfire in others.

To be fair, there was good reason to believe the strategy could work, and, to see why, it helps to understand how Clostridium difficile works. Typically, people get C. diff infections, as they’re often called, after taking antibiotics, and the reason for that has to do with what’s called competitive exclusion. Bacteria inside us are constantly fighting over space to live and food to eat, and, ordinarily, C. diff loses out. But C. diff does fare very well against most antibiotics, so when a person takes an antibiotic that kills most bacteria, our bodies become C. diff’s playground.

The trick, then, is to introduce something that resists the same antibiotics, doesn’t cause patients any harm, and crowds out C. diff—namely, a strain of C. diff that doesn’t produce the dangerous toxins it’s nastier sibling does.

Odd though it might sound, competitive exclusion works, and not just on C. diff. It’s effective for certain infections in plants and animals and might even yield a new way to treat cancer. But does competitive exclusion always work, “or is there a risk that such interventions might have unforeseen consequences?” Richard J. Lindsay, Ivana Gudelj, and their colleagues at the University of Exeter ask in the journal eLife.

To find out, the researchers looked at rice blast (Magnaporthe oryzae), a fungus that attacks rice and works in part through cooperation. Essentially, a small number of invading cells excrete a substance called invertase that breaks down rice’s complex sugars into more-digestible forms—in other words, food to supply an expanded invasion.

The researchers’ idea was that a less-virulent rice blast strain that doesn’t produce invertase could piggy-back on the more-virulent strain’s work. Because it would steal food and cause less harm to plants, the milder strain could crowd out the virulent strain in a manner roughly similar to C. diff.

“Strikingly, we observed the opposite result,” the researchers write. Infections with two different rice-blast strains—one common in the wild and another created in the lab to be less virulent and produce no invertase—did more damage than the virulent strain alone.

The team argues it’s a sort of tragedy of the commons. When only the virulent, invertase-producing strain is around, a small infection produces a lot of food, which, in turn, rapidly grows the infection—except that M. oryzae doesn’t use its food efficiently, and the infection ends up starving. With the weaker strain present, there’s less food to go around, and both types use their food more efficiently. In that case, the strains manage not just to survive, but to grow and spread.

Although the study concerns just one type of disease in one plant, the implications may be much broader. Approaches aimed at taming disease through competitive exclusion could backfire, Lindsay, Gudelj, and their team write, especially when it comes to cancer. Like rice blast, cancerous tumors are more efficient in times of scarcity, in which case a competitive-exclusion treatment could, paradoxically, help cancers grow faster rather than beat them back.