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Bacterial pathogens have evolved a diverse range of strategies to infect, survive, and replicate within a host. Dissecting the interactions between bacteria and their hosts can help us understand how pathogens cause disease and facilitate the developments of novel diagnostics and therapeutics to treat human disease. My laboratory studies bacterial host-pathogen interactions using a combination of two powerful tools – large scale genetic screens designed to identify novel bacterial virulence factors, and three-dimensional air-liquid interface tissue cultures that allow us to characterize the mechanisms through which these candidates interact with the human lung epithelium. In this seminar I will discuss the applications of these tools towards a better understanding of respiratory pathogens including Mycobacterium tuberculosis and the neglected tropical pathogen Burkholderia pseudomallei.