Mycobacterium tuberculosis Sulfolipid-1 Activates Nociceptive Neurons and Induces Cough

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

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

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. Mycobacterium tuberculosis produces a glycolipid called sulfolipid-1 (SL-1) that triggers cough by activating nociceptive neurons.

Original languageEnglish (US)
Pages (from-to)293-305.e11
JournalCell
Volume181
Issue number2
DOIs
StatePublished - Apr 16 2020

Keywords

  • cough
  • glycolipid
  • host-pathogen
  • mucosal immunology
  • mycobacteria
  • neuro-immune
  • nociceptor
  • sulfolipid
  • tuberculosis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Ruhl, C. R., Pasko, B. L., Khan, H. S., Kindt, L. M., Stamm, C. E., Franco, L. H., Hsia, C. C., Zhou, M., Davis, C. R., Qin, T., Gautron, L., Burton, M. D., Mejia, G. L., Naik, D. K., Dussor, G., Price, T. J., & Shiloh, M. U. (2020). Mycobacterium tuberculosis Sulfolipid-1 Activates Nociceptive Neurons and Induces Cough. Cell, 181(2), 293-305.e11. https://doi.org/10.1016/j.cell.2020.02.026