Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infection

Abstract

Mycobacterium tuberculosis is the leading worldwide cause of death due to a single infectious agent. Existing anti-tuberculous therapies require long treatments and are complicated by multi-drug-resistant strains. Host-directed therapies have been proposed as an orthogonal approach, but few have moved into clinical trials. Here, we use the zebrafish-Mycobacterium marinum infection model as a whole-animal screening platform to identify FDA-approved, host-directed compounds. We identify multiple compounds that modulate host immunity to limit mycobacterial disease, including the inexpensive, safe, and widely used drug clemastine. We find that clemastine alters macrophage calcium transients through potentiation of the purinergic receptor P2RX7. Host-directed drug activity in zebrafish larvae depends on both P2RX7 and inflammasome signaling. Thus, targeted activation of a P2RX7 axis provides a novel strategy for enhanced control of mycobacterial infections. Using a novel explant model, we find that clemastine is also effective within the complex granulomas that are the hallmark of mycobacterial infection.

Extracellular ATP: A Feasible Target for Cancer Therapy

“…However, a substantial difficulty in devising P2X7R-targeting strategies for cancer therapy is the very steep eATP activation curve of the P2X7R that precludes the controlled activation of this deadly receptor using eATP or pharmacological ATP analogs. Therefore, the use of positive allosteric modulators, compounds that potentiate P2X7R activation in the presence of relatively low eATP concentrations, such as polymyxin B, ginsenosides and clemastine [ 155 , 156 , 157 ], may provide novel strategies to enhance P2X7R-mediated cytotoxicity in cancer. Hyperthermia has also been shown to induce cancer cell death via P2X7R activation, thus suggesting that combining eATP with hyperthermia could be a clinically viable option [ 158 ].…”

Insights into the Structure-Activity Relationship of Glycosides as Positive Allosteric Modulators Acting on P2X7 Receptors

“…However, there has not been an in vivo study to investigate pharmacological targeting of P2X7 with a PAM. This idea has been tested in a zebrafish whole-animal study for Mycobacterium marinum infection using clemastine to potentiate P2X7 ( Matty et al, 2019 ), providing evidence that targeting P2X7 may be beneficial to control mycobacterial infections.…”

Immunogenic Cell Death: A Step Ahead of Autophagy in Cancer Therapy

“…P2X7 receptors on immune cells play a major role in their activation and their response to tumor cells. Positive allosteric modulators like polymyxin-B, clemastine, and ginsenosides can be used to enhance P2X7 mediated cytotoxicity against cancer cells [26][27][28]. Another strategy developed by Igawa and co-workers utilizes the increased extracellular ATP levels in TME to induce immunogenic response by means of anti CD137 antibodies.…”