Project 1: Transmission Biology of M. tuberculosis: Genes Required to Survive Stressful Transitions

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Abstract The goal of this project is to identify gene products whose inhibition could offer fresh approaches to reducing to <1 the number of cases generated by the average infected person with tuberculosis (TB) in an uninfected population: the R0. Specifically, using physiologically relevant fluids and environmental conditions, the goal is to conduct a genome-wide survey for genes that Mycobacterium tuberculosis (Mtb) requires to survive the following transitions it encounters in the course of transmission from one host to another: from a necrotic pulmonary lesion to a cavity connected to an airway; from there to expelled micro-droplets that undergo dessication; and from there to rehydration in the pulmonary alveoli of a new host. Inducible CRISPRi libraries of Mtb will be subjected to each of these transitions to identify the genes on which Mtb depends to survive them. Collaboration with the other Projects and Cores in this Program Project will allow us to prioritize individual mutant strains, subject them to realistically-modeled mechanical aerosolization to test their ability to infect mice, and determine if guinea pigs infected with them can transmit disease aerogenically. In parallel, TB drugs and tool compounds will be tested for their impact on Mtb undergoing these transmission-related stresses.