New insight into tuberculosis infection
Michiel van der Vaart with a team from Leiden University and the LUMC, led by IBL-researcher Annemarie Meijer, discovered that DRAM1 is a protein that regulates anti-bacterial autophagy, a defense mechanism against infections such as tuberculosis.
Autophagy (literally self-eating) has long been known as a cellular mechanism to degrade and recycle damaged components. Recently, it has become clear that autophagy also plays an important role in defense against intracellular pathogens, such as Mycobacterium tuberculosis. However, it is still unknown how pathogen recognition and autophagy are connected.
Central role in innate immunity
DRAM1 (DNA damage-regulated autophagy modulator 1) has previously drawn attention because of its role in cellular stress and cancer. All earlier studies have described DRAM1 as a target of tumor suppressor p53. In contrast, van der Vaart et al. found that DRAM1 is induced by p53-independent signaling during infection and now place this regulator of autophagy in the Toll-like receptor pathway central to innate immunity.
Zebrafish as model species
Exploiting the advantages of the zebrafish in vivo model for tuberculosis, van der Vaart et al. show that this novel pathway provides protection against pathogenic mycobacteria. They found that DRAM1 cooperates with the selective autophagy receptor p62 and that it promotes the fusion of autophagosomes with lysosomes where mycobacteria are killed.
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Figure 1: Infected zebrafish larva: the red signal indicates the presence of mycobacteria
Broader implications for infectious diseases
The role of DRAM1 as an inducer of anti-mycobacterial autophagy makes this pathway a highly interesting therapeutic target for tuberculosis. The authors expect that their findings also have broader implications for infectious diseases caused by other intracellular pathogens. Michiel van der Vaart and coworkers published their recent findings in the journal Cell Host & Microbe.