@article{Amaral2022,
abstract = {Cellular necrosis during Mycobacterium tuberculosis (Mtb) infection promotes both immunopathology and bacterial dissemination. Glutathione peroxidase-4 (Gpx4) is an enzyme that plays a critical role in preventing iron-dependent lipid peroxidation–mediated cell death (ferroptosis), a process previously implicated in the necrotic pathology seen in Mtb-infected mice. Here, we document altered GPX4 expression, glutathione levels, and lipid peroxidation in patients with active tuberculosis and assess the role of this pathway in mice genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient mice infected with Mtb display substantially increased lung necrosis and bacterial burdens, while transgenic mice overexpressing the enzyme show decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed by the lipid peroxidation inhibitor, ferrostatin-1. These findings provide support for the role of ferroptosis in Mtb-induced necrosis and implicate the Gpx4/GSH axis as a target for host-directed therapy of tuberculosis.},
author = {Amaral, Eduardo P and Foreman, Taylor W and Namasivayam, Sivaranjani and Hilligan, Kerry L and Kauffman, Keith D and {Barbosa Bomfim}, Caio Cesar and Costa, Diego L and Barreto-Duarte, Beatriz and Gurgel-Rocha, Clarissa and Santana, Monique Freire and Cordeiro-Santos, Marcelo and {Du Bruyn}, Elsa and Riou, Catherine and Aberman, Kate and Wilkinson, Robert John and Barber, Daniel L and Mayer-Barber, Katrin D and Andrade, Bruno B and Sher, Alan},
doi = {10.1084/jem.20220504},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Amaral et al. - 2022 - GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infection.pdf:pdf},
issn = {0022-1007},
journal = {Journal of Experimental Medicine},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {sep},
number = {11},
pages = {e20220504},
pmid = {36069923},
title = {{GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infection}},
url = {https://doi.org/10.1084/jem.20220504},
volume = {219},
year = {2022}
}

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Here, we document altered GPX4 expression, glutathione levels, and lipid peroxidation in patients with active tuberculosis and assess the role of this pathway in mice genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient mice infected with Mtb display substantially increased lung necrosis and bacterial burdens, while transgenic mice overexpressing the enzyme show decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed by the lipid peroxidation inhibitor, ferrostatin-1. 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