The success of any bacterial pathogen ultimately depends on its ability to multiply and transmit to new hosts. Mycobacterium tuberculosis (Mtb), the causative agent of the human disease tuberculosis and one of the most successful pathogens in human history, likely also employs sophisticated means to spread from one person to the next, including mediating caseation, tissue destruction, and airborne transmission. Yet, despite the toll Mtb has taken on world health, the molecular mechanisms responsible for Mtb transmission remain elusive. A major symptom of active tuberculosis is cough, and cough is a major mechanism of transmission. Although cough is a major route of aerosolization and transmission of Mtb, very little is known about the factors that produce cough during infection. Furthermore, epidemiologic studies have demonstrated that Mtb strains representing specific lineages are more prevalent in humans but whether differences in prevalence are due to differences in bacterial transmissibility and associated factors such as cough induction and aerosolization of bacteria is unknown. Thus, there is an urgent need to better characterize the transmission dynamics of Mtb and the relationship of cough to transmission. Because nociceptive neurons mediate cough, and some bacteria including mycobacteria secrete complex molecules targeting neurons, we hypothesized that Mtb produces molecules to trigger nociceptive neurons to activate the cough response, thereby facilitating transmission. We discovered and characterized the activity of one such molecule, sulfolipid-1, and recently identified a second molecule produced by virulent mycobacteria. In the proposed research we will (1) Identify and study the sulfolid-1 receptor in neurons and experimental animals, (2) Characterize the activity of the second nociceptive molecule in neurons and experimental animals, and determine how its activity combines with that of sulfolipid-1 (3) Develop and use a sophisticated Mtb transmission system to measure transmission, cough and aerosolized particles safely and quantitatively and use the system to compare the transmissibility of a variety of Mtb mutants lacking cough-inducing molecules. The proposed work is expected to identify novel factors associated with nociceptive neuron activation, cough and mycobacterial transmission.
The mechanisms underlying M. tuberculosis (Mtb) transmission are poorly understood. We recently identified a nociceptive-neuron activating, cough-inducing molecule from Mtb called sulfolipid-1 (SL-1). We will discover the signaling mechanism triggered by SL-1 in neurons and in experimental animals. We also identified a second nociceptive molecule and propose to characterize its activity in parallel to studies on SL-1. Finally, we will develop a safe and effective system for measuring Mtb transmission from nave to infected animals that will simultaneously determine other factors associated with transmission including Mtb-induced cough and aerosolized Mtb particle production. We will then use this system to analyze the transmission dynamics of Mtb strains lacking cough inducing molecules to determine relationships between Mtb genes and transmissibility. This approach represents the first systematic analysis of cough-inducing molecules in mycobacterial transmission.
