Mycobacterium tuberculosis Sulfolipid-1 Activates Nociceptive Neurons and Induces Cough
2020
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.
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