Polyphosphate (green dots) outside cells (Dictyostelium or human macrophages), or secreted by bacteria such as Mycobacterium tuberculosis (red bacteria), binds to polyphosphate receptors (purple) on the cell membrane or on the inside of an endosome, and this activates a signal transduction pathway (red arrows) that blocks the fusion of the bacteria-containing endosome with a lysosome (green). Pharmacologically blocking the red-arrow signal transduction pathway appears to make the cells ignore the polyphosphate signal, and the lysosome fuses with the endosome, killing the bacteria. The pharmacological inhibitors of the red-arrow pathway are thus potential therapeutics for tuberculosis.
Potential additional therapeutics for tuberculosis
Like macrophages, Dictyostelium cells phagocytose and kill bacteria. We noticed that lower concentrations of extracellular polyphosphate cause some Dictyostelium cells to ingest but not kill bacteria, possibly to carry a food supply, much like the farming observed by Debby Brock and Joan Strassman. Mycobacterium tuberculosis (M. tb), the causative bacteria for tuberculosis, is ingested but not killed by macrophages. We found that M. tb also secretes polyphosphate, and that this appears to at least in part cause macrophages to not kill them. Using both Dictyostelium and human macrophages, we are studying how the M. tb polyphosphate signal is sensed by cells, and identifying ways to block this sensing pathway so that macrophages will ignore the polyphosphate ‘don’t kill me’ signal, and kill ingested M. tb. We found that a drug which blocks a polyphosphate signal transduction pathway found in Dictyostelium causes human macrophages to increase their killing of ingested M. tb. Current lab efforts for this project are on expanding understanding of the polyphosphate ‘don’t kill me’ signal transduction pathway to develop more potential therapeutics for tuberculosis.
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