Mycobacterium tuberculosis sulfolipid-1 (Sl-1) increases the excitability of mouse and human TRPV1-positive sensory neurons in a YM254890-reversible fashion

Naik, D. K.; Espinosa, F.; Okolie, I. M.; Naqvi, K. F.; Nguyen, G.; Ruhl, C. R.; Kroener, S.; Dussor, G.; Shiloh, M. U.; Price, T. J.

doi:10.1101/2025.06.28.662105

bioRxiv · 10.1101/2025.06.28.662105

Mycobacterium tuberculosis sulfolipid-1 (Sl-1) increases the excitability of mouse and human TRPV1-positive sensory neurons in a YM254890-reversible fashion

Naik, D. K.·Espinosa, F.·Okolie, I. M.·Naqvi, K. F.·Nguyen, G.·Ruhl, C. R.·Kroener, S.·Dussor, G.·Shiloh, M. U.·Price, T. J.

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Abstract

Cough is a hallmark sign of tuberculosis and key driver of transmission. While traditionally attributed to host-driven inflammation, we previously demonstrated that Mycobacterium tuberculosis lipid extract (Mtb extract) and its component sulfolipid-1 (SL-1) directly activate nociceptive neurons to induce cough in guinea pigs. However, the cellular mechanisms by which Mtb extract and SL-1 modulate nociceptive sensory neurons remain incompletely understood. Here, we show that Mtb extract enhances action potential (AP) generation in mouse nodose nociceptors via an SL-1-dependent mechanism. Using calcium imaging, we found that Mtb extract and SL-1 increased intracellular Ca{superscript 2} signals in TRPV1 neurons from both mouse nodose and human dorsal root ganglia (hDRG). These Ca{superscript 2} signals were attenuated by the Gq/11 pathway inhibitor YM254890, even in the absence of extracellular Ca{superscript 2}, suggesting involvement of intracellular Ca{superscript 2} stores. Together, these findings indicate that SL-1 engages Gq/11-coupled pathways to sensitize nociceptors via intracellular Ca2+ release, providing mechanistic insight into tuberculosis-associated cough and potential targets for therapeutic intervention.

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Naik, D. K., Espinosa, F., Okolie, I. M., Naqvi, K. F., Nguyen, G., Ruhl, C. R., Kroener, S., Dussor, G., Shiloh, M. U., Price, T. J.. 2025-06-29. Mycobacterium tuberculosis sulfolipid-1 (Sl-1) increases the excitability of mouse and human TRPV1-positive sensory neurons in a YM254890-reversible fashion. https://doi.org/10.1101/2025.06.28.662105

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