Disrupting Tuberculosis Transmission: Bacterial and Host Drivers of Mycobacterium Tuberculosis Aerosolization

Project Abstract The global tuberculosis (TB) epidemic is fueled by the airborne transmission of Mycobacterium tuberculosis (Mtb), yet the mechanisms underlying cough-mediated aerosolization and the impact of antibiotic treatment and drug resistance on transmission remain poorly understood. We propose to address these gaps using ex vivo cultured nociceptive neurons and a guinea pig model of human cough to investigate the role of host and bacterial factors in TB transmission and evaluate strategies to disrupt this process. Preliminary data show that Mtb glycolipids, sulfolipid-1 (SL-1) and phenolic glycolipid (PGL), activate nociceptive neurons and drive the cough reflex, a critical driver of Mtb aerosolization and person-to-person transmission. Leveraging our innovative nociceptive neuron activation model and Mtb cough measurement and particle capture systems we developed specifically to study Mtb aerobiology, this project will uncover the drivers of Mtb transmission and explore interventions to mitigate it. In the first aim, we will analyze how biological sex, antibiotic treatment, and drug resistance influence Mtb-induced cough and Mtb aerosol production. By comparing male and female guinea pigs, we will determine the impact of host sex on cough frequency and Mtb aerosol generation. We will also evaluate how standard (rifampin-isoniazide-pyrazinamide; RIP) and newer (bedaquiline-pretomanid-linezolid; BPaL) antibiotic regimens reduce cough and Mtb aerosol production and test whether drug-resistant Mtb strains alter these processes, potentially enhancing transmissibility. The second aim will focus on cough suppression as a host-directed intervention. Using inhibitors of nociceptive neuron pathways, we will evaluate their ability to reduce Mtb-induced neuronal activation, cough and infectious particle production. These studies will test whether blocking the cough reflex has potential to mitigate Mtb transmission.