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The Tyrosine Kinase Inhibitor Gefitinib Restricts Mycobacterium tuberculosis Growth through Increased Lysosomal Biogenesis and Modulation of Cytokine Signaling
journal contribution
posted on 2017-05-24, 00:00 authored by Kimberly M. Sogi, Katie A. Lien, Jeffrey R. Johnson, Nevan J. Krogan, Sarah A. StanleyHost-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.
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STATEGFRM . tuberculosisgefitinib influences macrophage responsesMycobacterium tuberculosis infection. tuberculosiM . tuberculosis infectiongefitinib treatmentCytokine Signaling Host-directed therapeuticsgefitinib treatment increasesTyrosine Kinase Inhibitor Gefitinib Restricts Mycobacterium tuberculosis Growth
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