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Persistence of tuberculosis explained

BMJ 2000; 321 doi: https://doi.org/10.1136/bmj.321.7259.469/a (Published 19 August 2000) Cite this as: BMJ 2000;321:469
  1. Abi Berger
  1. BMJ

    A critical biochemical pathway explains how bacteria that cause tuberculosis are able to lie dormant for years before causing active infection. American scientists have identified the secret that allows Mycobacterium tuberculosis to persist subclinically, without causing overt infection. This discovery shows new targets for anti-tuberculosis drug treatment and may dramatically shorten the length of time required for treatment (Nature 2000;406:735-8).

    According to Dr Bill Jacobs, one of the collaborating scientists who is based at the Albert Einstein College of Medicine in New York, more people will die of tuberculosis this year than ever before. Most of these people will have an underlying HIV infection, but their death will be caused by tuberculosis. “Mycobacterium tuberculosis has the amazing ability to persist,” said Dr Jacobs. “T lymphocytes can keep the bacteria in check, but they don't sterilise.”

    To investigate why tuberculosis can persist subclinically in a dormant state despite the availability of treatment and the BCG vaccine, Dr John McKinney and his team acted on an observation made in previous research that M tuberculosis bacteria in persistently infected mice survive by eating lipids. The researchers took tissue from lung tubercles from mice and found that the bacteria isolated from these tubercles had fed well on lipids but not on sugars or amino acids. The metabolic pathway critical for lipid metabolism in bacteria (but one not found in humans) and involves two specific enzymes.

    This suggested to Dr McKinney that these enzymes might be important in the ability of the bacteria to persist. Without the presence of these enzymes to metabolise lipids, bacterial persistence might disappear. To test their hypothesis, the researchers created a knockout (genetically modified) mouse in which production of one of the enzymes, isocitrate lyase, was blocked.

    They then infected mice with the isocitrate lyase mutant and discovered that during the first three weeks (before the immune response kicked in), the bacteria grew unabated. After this time, however, activated macrophages seemed to be able to clear the bacteria completely from the lungs. The team confirmed this with an in vitro model that showed that isocitrate lyase is required for growth of the bacteria in activated macrophages.

    “This makes isocitrate lyase an excellent target for anti-tuberculosis therapy,” said Dr Jacobs.


    Embedded Image

    Chest x ray showing tuberculosis: isocitrate lyase may be a new target in combating the disease

    (Credit: SCIENCE PHOTO LIBRARY)

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