結核菌由来のスルホリピド-1はGαq/11共役経路を活性化し、感覚ニューロンの興奮性を増加させる

Cough is a hallmark sign of tuberculosis and a 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 act on 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. 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). We observed that YM254890 (a Gαq/11 inhibitor) could attenuate these Ca²⁺ signaling events, even in the absence of extracellular Ca²⁺, suggesting a G protein-coupled receptor (GPCR)-mediated mechanism driven by Gαq/11 signaling to intracellular Ca²⁺ stores. Mtb extract treatment also enhanced action potential (AP) generation in mouse nodose nociceptors via an SL-1-dependent mechanism. Mtb extract increased the number and half-width of evoked APs, indicating direct modulation of voltage-gated ion channel activity. The Mtb extract-induced change in mouse nodose neuron excitability and in the AP half-width was blocked by YM254890 treatment. Taken together, these findings link TB pathogen-derived lipids to GPCR signaling that directly increases the excitability of sensory neurons.