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

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 Ca2+ signals in TRPV1+ neurons from both mouse nodose and human dorsal root ganglia (hDRG). These Ca2+ signals were attenuated by the Gαq/11 pathway inhibitor YM254890, even in the absence of extracellular Ca2+, suggesting involvement of intracellular Ca2+ stores. Together, these findings indicate that SL-1 engages Gαq/11-coupled pathways to sensitize nociceptors via intracellular Ca2+ release, providing mechanistic insight into tuberculosis-associated cough and potential targets for therapeutic intervention.