Study: Cough that spreads tuberculosis has pain-linked trigger

March 06, 2020

Tuberculosis is distinguished primarily by the persistent cough that serves to spread the disease. Stopping whatever triggers that cough could greatly reduce the transmission of the disease, which annually kills more than 1.3 million people worldwide.

Researchers from The University of Texas at Dallas' Center for Advanced Pain Studies worked with colleagues from UT Southwestern Medical Center to pinpoint a molecule that the tuberculosis bacterium manufactures to induce coughing.

Their findings, published online March 5 in the journal Cell, could help reduce the impact of tuberculosis, which remains one of the top 10 causes of death worldwide, according to the World Health Organization.

"Tuberculosis deaths have been greatly reduced in the United States, but it is still a huge issue in many parts of the world, and we would love to have an impact on stopping the spread of the disease," said Dr. Ted Price BS'97, Eugene McDermott Professor of neuroscience in the School of Behavioral and Brain Sciences (BBS) and one of five UT Dallas authors of the Cell paper. "Discovering the mechanism through which TB causes cough affords just such an opportunity, and our collective team has the appropriate expertise to tackle this problem, which we have started to accomplish through this work."

The idea that nociceptors -- the nerve cells that respond to pain stimuli -- cause the coughing associated with TB runs counter to existing suppositions that link the cough to infection-induced lung inflammation or irritation.

"No one had ever shown that TB produces an irritant that acts directly on the sensory innervation of the lungs," Price said. "We have now shown this directly through our collaborative work on this project."

In testing on rodents, researchers sought to identify the components or products of the Mycobacterium tuberculosis that cause coughing or trigger nociceptors. Ultimately, they identified a fatty acid called sulfolipid-1 (SL-1) as a pain-response trigger. They then reproduced that response in isolated human nociceptor cells. Finally, the researchers altered a strain of Mycobacterium tuberculosis to not produce SL-1. Rodents infected with this version developed other tuberculosis symptoms, but not coughing.

If researchers can show that suppressing cough does not worsen the condition of tuberculosis patients, the spread of the disease might be prevented by developing a drug that inhibits SL-1 production, Price said.

"People with active tuberculosis can cough for months and spread disease even when they are receiving appropriate treatment," said corresponding author Dr. Michael Shiloh, associate professor of internal medicine and microbiology at UT Southwestern. "Someday, doctors may give antibiotics in conjunction with a medication that prevents coughing, which in turn could prevent spread."
Additional UT Dallas authors were Dr. Gregory Dussor, associate professor of cognition and neuroscience and Fellow, Eugene McDermott Professor; Dr. Michael Burton, assistant professor in BBS; Dhananjay Naik, a doctoral student in cognition and neuroscience; and Galo Mejia, a graduate student in innovation and entrepreneurship and a research assistant in BBS. Other UT Southwestern authors included Dr. Connie Hsia, professor of internal medicine; Dr. Tian Qin, assistant professor of biochemistry and a Eugene McDermott Scholar in Biomedical Research; Dr. Laurent Gautron, assistant professor of internal medicine; and first author Cody Ruhl, a graduate student and member of Shiloh's lab.

The work of UT Dallas researchers was supported in part by grants from the National Institute of Neurological Disorders and Stroke, a component of the National Institutes of Health (R01NS104200, R01NS065926). The Burroughs Wellcome Fund and The Welch Foundation also supported the study.

University of Texas at Dallas

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