Editors' ChoiceImmunology

Seeing Double to Recognize TB

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Science Translational Medicine  05 Sep 2012:
Vol. 4, Issue 150, pp. 150ec158
DOI: 10.1126/scitranslmed.3004841

One-third of the world is infected with the bacterium Mycobacterium tuberculosis, which causes tuberculosis (TB). However, most infected—yet otherwise healthy—individuals never develop TB disease. Watson and colleagues have now identified an important aspect of a healthy immune system response to M. tuberculosis that keeps the disease at bay.

In mice, the authors showed that double-stranded DNA (dsDNA) from M. tuberculosis present in the host macrophage cytosol elicits an autophagic response. During innate immune cell autophagy, foreign bodies are marked for sequestration and degradation by lysosomes. Previously, the actual signal that triggered autophagy of macrophages harboring M. tuberculosis was unknown, but some evidence pointed toward an immune response to the M. tuberculosis ESX-1 secretion system. Now, Watson et al. show that the pathway is stepwise, leading to death of the pathogen: First, ESX-1 permeablizes the phagosomal membrane; then, this “foreign” M. tuberculosis genomic dsDNA is recognized by the STING-dependent pathway in the macrophage cytosol; next, these bacteria are marked with ubiquitin, which targets these pathogens to autophagy. Mice with monocytes that could not deliver M. tuberculosis to this autophagy pathway could not suppress infection.

This fundamental work by Watson et al. may allow for development of both new vaccines and pharmacological treatments of TB. Future work will be needed to confirm the same immune response with human cells and to determine whether this pathway can be stimulated in immunocompromised individuals. Currently, a major issue is how to treat infections with multidrug-resistant TB strains; few antibiotics exist (if any) that affect these bacteria. Triggering an improved immune response may provide an avenue to more effectively treat even these most problematic TB cases.

R.O. Watson et al., Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 150, 803–815 (2012). [Abstract]

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