Mycobacterium tuberculosis Sulfolipid-1 Activates Nociceptive Neurons and Induces Cough

Ruhl, Cody R.; Pasko, Breanna L.; Khan, Haaris S.; Kindt, Lexy M.; Stamm, Chelsea E.; Franco, Luis H.; Hsia, Connie C.; Zhou, Min; Davis, Colton R.; Qin, Tian; Gautron, Laurent; Burton, Michael D.; Mejia, Galo L.; Naik, Dhananjay K.; Dussor, Gregory; Price, Theodore J.; Shiloh, Michael U.

Pulmonary tuberculosis, a disease caused by Mycobacterium tuberculosis (Mtb), manifests with a persistent cough as both a primary symptom and mechanism of transmission. The cough reflex can be triggered by nociceptive neurons innervating the lungs, and some bacteria produce neuron-targeting molecules. However, how pulmonary Mtb infection causes cough remains undefined, and whether Mtb produces a neuron-activating, cough-inducing molecule is unknown. Here, we show that an Mtb organic extract activates nociceptive neurons in vitro and identify the Mtb glycolipid sulfolipid-1 (SL-1) as the nociceptive molecule. Mtb organic extracts from mutants lacking SL-1 synthesis cannot activate neurons in vitro or induce cough in a guinea pig model. Finally, Mtb-infected guinea pigs cough in a manner dependent on SL-1 synthesis. Thus, we demonstrate a heretofore unknown molecular mechanism for cough induction by a virulent human pathogen via its production of a complex lipid.