10.1021/acsinfecdis.7b00046.s001 Kimberly M. Sogi Kimberly M. Sogi Katie A. Lien Katie A. Lien Jeffrey R. Johnson Jeffrey R. Johnson Nevan J. Krogan Nevan J. Krogan Sarah A. Stanley Sarah A. Stanley The Tyrosine Kinase Inhibitor Gefitinib Restricts Mycobacterium tuberculosis Growth through Increased Lysosomal Biogenesis and Modulation of Cytokine Signaling American Chemical Society 2017 STAT EGFR M . tuberculosis gefitinib influences macrophage responses Mycobacterium tuberculosis infection . tuberculosi M . tuberculosis infection gefitinib treatment Cytokine Signaling Host-directed therapeutics gefitinib treatment increases Tyrosine Kinase Inhibitor Gefitinib Restricts Mycobacterium tuberculosis Growth 2017-05-24 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/The_Tyrosine_Kinase_Inhibitor_Gefitinib_Restricts_Mycobacterium_tuberculosis_Growth_through_Increased_Lysosomal_Biogenesis_and_Modulation_of_Cytokine_Signaling/5077879 Host-directed therapeutics have the potential to combat the global tuberculosis pandemic. We previously identified gefitinib, an inhibitor of EGFR, as a potential host-targeted therapeutic effective against Mycobacterium tuberculosis infection of macrophages and mice. Here we examine the functional consequences of gefitinib treatment on M. tuberculosis infected macrophages. Using phosphoproteomic and transcriptional profiling, we identify two mechanisms by which gefitinib influences macrophage responses to infection to affect cytokine responses and limit replication of M. tuberculosis in macrophages. First, we find that gefitinib treatment of M. tuberculosis infected macrophages inhibits STAT3, a transcription factor known to repress effective immune responses to M. tuberculosis in vivo. Second, we find that gefitinib treatment of M. tuberculosis infected macrophages leads to increased expression of genes involved in lysosomal biogenesis and function and an increase of functional lysosomes in gefitinib treated cells. Furthermore, we show that gefitinib treatment increases the targeting of bacteria to lysosomes, providing an explanation for the cell intrinsic effects of gefitinib treatment on M. tuberculosis infection. Our data provide novel insights into the effects of gefitinib on mammalian cells and into the possible roles for EGFR signaling in macrophages.