Leiden University Scholarly Publications

Persistent URL of this record https://hdl.handle.net/1887/4283607

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Naqvi, K.F.; Warden, L.L.; Dijk, J.H.M. van; Naik, D.K.; Jesus Espinosa-Becerra, F. de; Okolie, I.M.; ... ; Shiloh, M.U. (2025)

Mycobacterial phenolic glycolipid triggers ATP-mediated neuronal P2X3 signaling and cough

Research paper
Cough drives respiratory pathogen transmission, yet how microbes directly engage host sensory neurons to trigger cough is largely unknown. We previously demonstrated that the Mycobacterium tuberculosis (Mtb) glycolipid sulfolipid-1 (SL-1) activates neurons and induces cough. Here, we reveal that phenolic glycolipid (PGL) produced by the hypertransmissible HN878 Mtb strain activates both mouse and human nociceptive neurons in vitro using calcium imaging and electrophysiology and is sufficient to induce cough using plethysmography. Combined with SL-1, PGL potently triggers neuronal activation. By synthesizing various PGL analogs, we show that neuroactivity is proportional to saccharide chain length and structure. Mechanistically, PGL stimulates rapid extracellular ATP release, which engages neuronal P2X3 purinergic receptors-an effect blocked by a P2X3 antagonist. These findings uncover a neuronal activation pathway co-opted by certain Mtb strains to enhance transmission via...Show moreCough drives respiratory pathogen transmission, yet how microbes directly engage host sensory neurons to trigger cough is largely unknown. We previously demonstrated that the Mycobacterium tuberculosis (Mtb) glycolipid sulfolipid-1 (SL-1) activates neurons and induces cough. Here, we reveal that phenolic glycolipid (PGL) produced by the hypertransmissible HN878 Mtb strain activates both mouse and human nociceptive neurons in vitro using calcium imaging and electrophysiology and is sufficient to induce cough using plethysmography. Combined with SL-1, PGL potently triggers neuronal activation. By synthesizing various PGL analogs, we show that neuroactivity is proportional to saccharide chain length and structure. Mechanistically, PGL stimulates rapid extracellular ATP release, which engages neuronal P2X3 purinergic receptors-an effect blocked by a P2X3 antagonist. These findings uncover a neuronal activation pathway co-opted by certain Mtb strains to enhance transmission via cough and suggest inhibition of purinergic signaling as a potential strategy to block airborne spread of Mtb.Show less
All authors
Naqvi, K.F.; Warden, L.L.; Dijk, J.H.M. van; Naik, D.K.; Jesus Espinosa-Becerra, F. de; Okolie, I.M.; Verhoeks, V.F.H.; Rahlwes, K.C.; Xavier, C.P.; Codee, J.D.C.; Price, T.J.; Shiloh, M.U.
Date
2025-05-06
Title of host publication
bioRxiv : the preprint server for biology
Advanced Publication
Yes
DOI
doi:10.1101/2025.05.01.651726
Link
https://www.biorxiv.org/content/10.1101/2025.05.01.651726v1