Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection

Area of Science:

• Virology
• Immunology
• Cell Biology

Background:

• Murine hepatitis virus strain A59 (MHV-A59) causes cell death, including pyroptosis, apoptosis, and necroptosis.
• The role of ferroptosis, a distinct form of lytic cell death, in MHV-A59 pathogenicity remained unexplored.

Purpose of the Study:

• To investigate the involvement of ferroptosis in MHV-A59 infection.
• To explore ferroptosis-related gene expression changes during MHV-A59 infection.
• To evaluate the therapeutic potential of targeting ferroptosis against MHV-A59.

Main Methods:

• Utilized primary murine macrophages and a C57BL/6 mice intranasal infection model.
• Administered ferroptosis inhibitors (e.g., liproxstatin-1, Triacsin C) and performed RNA-sequencing.
• Investigated the role of Toll-like receptor 4 (TLR4) and NF-kB signaling pathways.

Main Results:

• Ferroptosis inhibition reduced viral propagation, inflammatory cytokine release, and syncytia formation in vitro.
• In vivo liproxstatin-1 administration ameliorated lung inflammation and tissue injury in infected mice.
• MHV-A59 infection upregulated acyl-CoA synthetase long-chain family member 1 (ACSL1), a ferroptosis inducer, in a NF-kB-dependent, TLR4-independent manner.
• ACSL1 inhibition suppressed MHV-A59-induced syncytia formation and viral propagation.

Conclusions:

• Ferroptosis plays a significant role in MHV-A59 pathogenesis.
• Inhibition of ferroptosis offers a protective effect against MHV-A59 infection and associated hyper-inflammation.
• Targeting ferroptosis, particularly ACSL1, presents a promising therapeutic strategy for coronavirus infections.