@article{a6d9f3e4bc334671899b3489344c5522,
title = "Mycobacterium tuberculosis Sulfolipid-1 Activates Nociceptive Neurons and Induces Cough",
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.",
keywords = "cough, glycolipid, host-pathogen, mucosal immunology, mycobacteria, neuro-immune, nociceptor, sulfolipid, tuberculosis",
author = "Ruhl, {Cody R.} and Pasko, {Breanna L.} and Khan, {Haaris S.} and Kindt, {Lexy M.} and Stamm, {Chelsea E.} and Franco, {Luis H.} and Hsia, {Connie C.} and Min Zhou and Davis, {Colton R.} and Tian Qin and Laurent Gautron and Burton, {Michael D.} and Mejia, {Galo L.} and Naik, {Dhananjay K.} and Gregory Dussor and Price, {Theodore J.} and Shiloh, {Michael U.}",
note = "Funding Information: We thank B. Levine and members of the Shiloh lab for constructive feedback on the manuscript. We thank G. Dias do Vale and J. McDonald for help with mass spectrometry, C. Bertozzi (Stanford University) for providing Mtb strains, and M. Nassar (University of Sheffield, United Kingdom) for providing MED17.11 cells. We thank BEI Resources, NIAID, NIH, for providing many valuable reagents used in this study as indicated in the STAR Methods. This work is supported by the Burroughs Wellcome Fund (1017894 to M.U.S.), the Welch Foundation (I-1964-20180324 to M.U.S. and I-2010-20190330 to T.Q.), and NIH (R01 NS104200 to G.D.; R01 NS065926 to T.J.P.; U01 AI125939, U19 AI142784, and R21 AI137545 to M.U.S.; 5T32AI005284-40 to H.S.K.; T32AI007520 to C.E.S. and B.L.P.; and T32GM127216 to C.R.D.). T.Q. is supported by the Eugene McDermott Endowed Scholarship, and M.U.S. acknowledges the support of the Disease Oriented Clinical Scholars Program, both at University of Texas Southwestern. Conceptualization, C.R.R. L.M.K. and M.U.S.; Formal Analysis, C.R.R. B.L.P. L.M.K. C.E.S. and M.U.S.; Funding Acquisition, T.Q. G.D. T.J.P. and M.U.S.; Investigation, C.R.R. B.L.P. H.S.K. L.M.K. C.E.S. L.H.F. M.Z. C.R.D. T.Q. L.G. M.D.B. G.L.M. D.K.N. and M.U.S.; Project Administration, C.R.R. and M.U.S.; Resources, C.H. G.D. and T.J.P.; Supervision, T.Q. G.D. T.J.P. and M.U.S.; Visualization, C.R.R. B.L.P. L.K. and M.U.S.; Writing – Original Draft, C.R.R. and M.U.S.; Writing – Review & Editing, all authors. The authors declare no competing interests. Funding Information: We thank B. Levine and members of the Shiloh lab for constructive feedback on the manuscript. We thank G. Dias do Vale and J. McDonald for help with mass spectrometry, C. Bertozzi (Stanford University) for providing Mtb strains, and M. Nassar (University of Sheffield, United Kingdom) for providing MED17.11 cells. We thank BEI Resources, NIAID, NIH, for providing many valuable reagents used in this study as indicated in the STAR Methods . This work is supported by the Burroughs Wellcome Fund ( 1017894 to M.U.S.), the Welch Foundation ( I-1964-20180324 to M.U.S. and I-2010-20190330 to T.Q.), and NIH ( R01 NS104200 to G.D.; R01 NS065926 to T.J.P.; U01 AI125939 , U19 AI142784 , and R21 AI137545 to M.U.S.; 5T32AI005284-40 to H.S.K.; T32AI007520 to C.E.S. and B.L.P.; and T32GM127216 to C.R.D.). T.Q. is supported by the Eugene McDermott Endowed Scholarship , and M.U.S. acknowledges the support of the Disease Oriented Clinical Scholars Program , both at University of Texas Southwestern. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = apr,
day = "16",
doi = "10.1016/j.cell.2020.02.026",
language = "English (US)",
volume = "181",
pages = "293--305.e11",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "2",
}