Polyphosphate Signaling Hints at Potential Therapeutics for Tuberculosis
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Date
2021-05-11
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Abstract
Tuberculosis is one of the leading causes of death by any single infectious agent worldwide. The bacterium that causes tuberculosis, Mycobacterium tuberculosis (Mtb), has evolved mechanisms to bypass host defenses, even when engulfed by macrophages into phagosomes. Phagosomes normally fuse with lysosomes, and this kills ingested bacteria, but Mtb prevents this fusion and proliferates in macrophage phagosomes. Understanding how Mtb prevents phagosome-lysosome fusion and thus the killing of ingested bacteria may enable us to develop therapeutics for tuberculosis.
Dictyostelium discoideum is a eukaryotic microbe that feeds on bacteria by phagocytosis, like macrophages. We found that chains of phosphates called polyphosphate act as an extracellular signal that prevents phagosome-lysosome fusion and causes Dictyostelium cells and human macrophages to retain ingested bacteria alive in the phagosome, analogous to an Mtb infection.
We developed an assay to use the power of Dictyostelium genetics to characterize the proteins involved in the signal transduction pathway used by polyphosphate to prevent killing of ingested bacteria. After allowing Dictyostelium cells to ingest bacteria, the number of live ingested bacteria in the presence or absence of polyphosphate were counted shortly after ingestion, and at 48 hours.
Wild-type Dictyostelium and 20 signal transduction pathway mutants responded to polyphosphate by decreased killing of ingested bacteria. We found three additional mutants that are insensitive to polyphosphate signaling, suggesting that the absent proteins in these mutants are required for Dictyostelium to sense polyphosphate. Pharmacological inhibition of any of the human homologs of these proteins might prevent macrophages from sensing the polyphosphate signal from Mtb, and thus allow them to kill engulfed Mtb. Intriguingly, our findings also led to new biological insights about the chain-length dependence of polyphosphate signaling and allowed us to distinguish differences between polyphosphate and phagocytosis signaling pathways. Due to the conserved biology of polyphosphate across species, future work investigating the fundamental relationships of polyphosphate to other signaling pathways could lead to profound discoveries about the cellular or molecular role of polyphosphate signaling.
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Immunology, Cellular and Molecular Biology, Genetics, Biochemistry