GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infection

Tissue necrosis is a major pathophysiological hallmark of disease progression in tuberculosis. In this study, Amaral et al. show that GPX4, an antioxidant selenoenzyme, is an essential regulator of both lipid peroxidation-mediated cellular necrosis and host resistance in Mycobacterium tuberculosis infection. 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.

Automated summary

In this study, the researchers found that GPX4, an antioxidant selenoenzyme, acts as an essential regulator of cellular necrosis and host resistance in tuberculosis caused by Mycobacterium tuberculosis (Mtb) infection. The study shows that Gpx4-deficient mice display increased lung necrosis and bacterial burdens, while mice overexpressing the enzyme have decreased bacterial loads and necrosis. The findings suggest that targeting the Gpx4/GSH axis could be a potential host-directed therapy for tuberculosis.