GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infectionMore about Open Access at the Crick
Authors listEduardo P Amaral Taylor W Foreman Sivaranjani Namasivayam Kerry L Hilligan Keith D Kauffman Caio Cesar Barbosa Bomfim Diego L Costa Beatriz Barreto-Duarte Clarissa Gurgel-Rocha Monique Freire Santana Marcelo Cordeiro-Santos Elsa Du Bruyn Catherine Riou Kate Aberman Robert Wilkinson Daniel L Barber Katrin D Mayer-Barber Bruno B Andrade Alan Sher
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.
Journal Journal of Experimental Medicine
Issue number 11