972. A Mycobacterium tuberculosis Secreted Lipid Triggers Cough Through a Neuronal Cough Receptor
Year: 2019
Type: conference-abstract
Abstract: Background A hallmark symptom of active pulmonary tuberculosis vital for disease transmission is cough. The current paradigm for tuberculosis-related cough is that it results from airway damage or irritation. However, there is limited experimental data to support this theory, and whether Mycobacterium tuberculosis (Mtb) induces cough to facilitate its own transmission has not been explored. The cough reflex is a complex and coordinated event involving both the nervous and musculoskeletal systems initiated by particulate or chemical molecules activating nociceptive neurons, which sense pain or irritation. This activation induces a signaling cascade ultimately resulting in a cough. Respiratory nociceptive neurons innervate the airway of humans and most mammals and thus are poised to respond to noxious molecules to help protect the lung from damage. Because Mtb is a lung pathogen, cough is a primary mechanism of Mtb transmission, and respiratory nociceptive neurons activate cough, we hypothesized that Mtb produces molecules that stimulate cough thereby facilitating its spread from infected to uninfected individuals. We previously identified a cough molecule produced by Mtb, and in this work characterize its neuronal receptor using genetics, biochemistry, and pharmacology. Methods We used an in vitro neuronal activation bioassay to study Mtb cough-inducing molecules. We also used a biochemical assay to identify the cough receptor. Finally, we used gene silencing, biochemistry, and pharmacologic inhibition to validate and characterize the activity of the newly discovered cough receptor. Results We isolated a complex lipid produced by Mtb that activates nociceptive neurons. Both an organic Mtb extract and the purified molecule alone were sufficient to induce cough in a conscious guinea pig cough model and guinea pigs infected with wild-type Mtb cough much more frequently than guinea pigs infected with Mtb strains unable to produce nociceptive molecules. Using genetics, biochemistry, and pharmacology techniques, we identified and validated a cough receptor for the Mtb lipid expressed on nociceptive neurons. Conclusion We conclude that Mtb produces a molecule that activates nociceptive neurons and induces cough through a specific neuronal receptor. These findings have significant implications for our understanding of Mtb transmission. Disclosures All Authors: No reported Disclosures.
Source: Open Forum Infectious Diseases
Authors: Paxton Cruz, Cody Ruhl, Michael Shiloh
Institution: The University of Texas Southwestern Medical Center
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,053
OpenAlex ID: W2981732440