Macrophage NFATC2 mediates angiogenic signaling during mycobacterial infection.
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2022-12
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During mycobacterial infections, pathogenic mycobacteria manipulate both host immune and stromal cells to establish and maintain a productive infection. In humans, non-human primates, and zebrafish models of infection, pathogenic mycobacteria produce and modify the specialized lipid trehalose 6,6'-dimycolate (TDM) in the bacterial cell envelope to drive host angiogenesis toward the site of forming granulomas, leading to enhanced bacterial growth. Here, we use the zebrafish-Mycobacterium marinum infection model to define the signaling basis of the host angiogenic response. Through intravital imaging and cell-restricted peptide-mediated inhibition, we identify macrophage-specific activation of NFAT signaling as essential to TDM-mediated angiogenesis in vivo. Exposure of cultured human cells to Mycobacterium tuberculosis results in robust induction of VEGFA, which is dependent on a signaling pathway downstream of host TDM detection and culminates in NFATC2 activation. As granuloma-associated angiogenesis is known to serve bacterial-beneficial roles, these findings identify potential host targets to improve tuberculosis disease outcomes.
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Brewer, W Jared, Ana María Xet-Mull, Anne Yu, Mollie I Sweeney, Eric M Walton and David M Tobin (2022). Macrophage NFATC2 mediates angiogenic signaling during mycobacterial infection. Cell reports, 41(11). p. 111817. 10.1016/j.celrep.2022.111817 Retrieved from https://hdl.handle.net/10161/28260.
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