But fish don’t have lungs…?
Tuberculosis is the world’s oldest and most deadly disease. It’s caused primarily by Mycobacterium tuberculosis, which is commonly known as the tubercle bacillus, or TB. Despite the advent of antibiotics nearly 100 years ago, an estimated two billion people are infected with TB and tuberculosis kills around two million people every year. Drug tolerance in TB, after it has infected humans, appears to be key to its success.
Now it seems we are beginning to understand how this works. In a recent paper published in the journal Cell, Lalita Ramakrishnan and colleagues report that Mycobacterium marinum bacteria infecting zebrafish embryos respond to antibiotic treatment in an exactly the same way as M. tuberculosis bacteria infecting humans. Because M. marinum is 99% identical to TB genetically and infects transparent zebrafish embryos, it is an excellent model for studying tuberculosis. Tracking the M. marinum bacteria during infection and antibiotic therapy of the zebrafish shows that not all of the bacteria are killed by antibiotic treatment; some acquire drug tolerance and hide inside immune cells known as macrophages, then use these immune cells to spread around the body.
These bacteria are not permanently resistant to the drugs but are tolerant for short periods of time. This drug tolerance allows the infection to spread and expand within the immune system. Even stranger, it appears that the immune cells themselves induce drug resistance in the bacteria.
To extend this to humans, it means that our own immune systems not only help TB to spread but also makes them resistant to antibiotic treatment. The drug tolerance persists after the macrophages burst and release the bacteria into the extracellular environment, where they cause disease. The authors finish their remarkable study by showing that the macrophages actually trigger the expression of efflux pumps that actively pump antibiotics out of the bacterial cells.
As well as being excellent science, this study offers the first glimmer of hope for rapid antibiotic treatment of TB. Currently antibiotic therapy takes between six months and two years to clear a TB infection because of these drug-tolerant bacteria. If we can find a way to target and rapidly kill these bacterial cells, the infection could be cleared in a matter of weeks. It seems that understanding our oldest enemy will ultimately be key to winning the battle and reducing the global burden of tuberculosis.
Adams KN, Takaki K, Connolly LE, Wiedenhoft H, Wingkee K, Humbert O, Edelstein PH, Cosma CL and Ramakrishnan L (2011). Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell 145:39-53.
Image credit: This image was published in a Public Library of Science journal; PLoS Biology (2004) 2:e67. Their website states that the content of all PLoS journals is published under the Creative Commons Attribution 2.5 license.
Posted by Matt Hutchings