A major role for ferroptosis in Mycobacterium tuberculosis–induced cell death and tissue necrosis

Background:

Necrotic cell death during Mycobacterium tuberculosis (Mtb) infection is considered host-detrimental as it facilitates mycobacterial spread and tissue damage. While apoptosis helps limit Mtb growth, necrosis enhances dissemination. Understanding the specific regulated pathways of necrosis in TB is essential for developing host-directed therapies to control the disease.

Abstract:

Methods: This study utilized murine bone marrow-derived macrophages (BMDMs) and human monocyte-derived macrophages infected with virulent Mtb (H37Rv) to evaluate cell death mechanisms in vitro. In vivo experiments were conducted using C57BL/6 mice infected with Mtb to assess pulmonary necrosis and bacterial load. Hallmarks of ferroptosis, such as glutathione (GSH) levels, glutathione peroxidase-4 (Gpx4) expression, free iron accumulation, and lipid peroxidation, were measured.

Results: Mtb-induced macrophage necrosis was associated with reduced GSH and Gpx4 levels, alongside increased free iron, mitochondrial superoxide, and toxic lipid peroxides. Blockade of this pathway using ferrostatin-1 (Fer-1), a ferroptosis inhibitor, or iron chelation significantly suppressed necrotic cell death in vitro. In mice, Fer-1 treatment reduced pulmonary tissue necrosis and markedly lowered bacterial loads in the lungs and spleen.

Conclusion: Ferroptosis is a major mechanism of necrosis in Mtb infection. These findings identify ferroptosis as a potential target for host-directed therapy to reduce tissue damage and enhance pathogen clearance in tuberculosis.

Keywords: Mycobacterium tuberculosis; Ferroptosis; Necrosis; Host-directed therapy; Lipid peroxidation.

Clique aqui

• Data de Publicação: 20/02/2019
• Autores: Eduardo P. Amaral, Diego L. Costa, Sivaranjani Namasivayam, Nicolas Riteau, Olena Kamenyeva, Lara Mittereder, Katrin D. Mayer-Barber,Bruno B. Andrade and Alan Sher