Publication: The Mycobacterium marinum-zebrafish model to study host-pathogen interactions in tuberculosis
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Roca Soler, Francisco José
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Abstract
While Tumor Necrosis Factor (TNF) is host protective in mycobacterial infections, its excess is pathogenic. TNF excess triggers production of mitochondrial reactive oxygen species (ROS) that cause programmed necrosis (necroptosis) of infected macrophages through the participation of the mitochondrial protein cyclophilin D, a regulator of mitochondrial permeability transition. Here we show that mitochondrial ROS mediate necrosis through a signaling pathway that traverses the lysosome, cytosol, and endoplasmic reticulum (ER) before returning to the mitochondrion to execute cell death. We have identified the specific proteins, including Ca2+ channels, which orchestrate this pathway, which we will present. In summary, we find that mitochondrial Ca2+ overload is the ultimate feature in the pathway responsible for TNF-mediated programmed necrosis in infected macrophages. We identify currently used calcium channel blockers as well as drugs that specifically inhibit ER calcium release as pharmacological interventions that prevent pathogenic necrosis in tuberculosis.
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