PROJECT 1: IDENTIFICATION OF HOST AND BACTERIAL PATHWAYS THAT CONTROL TB PATHOGENESIS IN HUMANS SUMMARY Phagocytes of the mammalian innate immune system, in particular macrophages, form the first line of defense upon bacterial infection and are armed with powerful mechanisms to limit bacterial growth and eradicate invaders. In addition to having direct antimicrobial activity, macrophages also initiate and shape powerful inflammatory responses that dramatically influence disease. Bacterial pathogens, however, have evolved mechanisms to thwart these killing mechanisms of phagocytes, and to persist in human tissues. Indeed, the inflammatory pathways robustly elicited by Mycobacterium tuberculosis (Mtb) – the etiological agent of the devastating human disease tuberculosis (TB) and the focus of Project 1 – work to promote bacterial growth and TB disease. However, the host genes and cellular pathways that dictate the outcome of infection are not entirely clear. There is growing evidence that the earliest interactions of Mtb with two very different subsets of lung macrophages, alveolar and “recruited” macrophages, are critical for TB control, but our understanding of the response of alveolar macrophages to Mtb has been limited due to the difficulty in studying these tissue resident lung macrophages. In Project 1, we will use new cellular models of alveolar macrophages coupled with unbiased, systematic approaches to identify the specific molecular networks that underly infection of these different macrophage types. In collaboration with the Technology Core, we will use this information to make predictions about bacterial infectivity that will be tested in human samples and mouse models of infection in an iterative fashion to model host response during infection. These results, and those from Project 2, will be integrated by the Data Management and Bioinformatics and Modeling Cores with existing -omics and human GWAS datasets to identify host and bacterial signatures that correlate significantly with clinical pathogenesis. Importantly, we will focus our functional testing on pathways that are shared between bacterial and viral responses (with Project 2) to understand the mechanisms that lead to synergies during bacterial-viral co-infection.