Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection

Murine hepatitis virus strain A59 (MHV-A59) was shown to induce Pyroptosis, Apoptosis, and Necroptosis of infected cells, especially in the murine macrophages. However, whether Ferroptosis, a recently identified form of lytic cell death, was involved in the pathogenicity of MHV-A59 is unknown. We utilized murine macrophages and a C57BL/6 mice intranasal Infection model to address this. In primary macrophages, the Ferroptosis inhibitor inhibited viral propagation, inflammatory cytokines released, and cell syncytia formed after MHV-A59 Infection. In the mouse model, we found that in vivo administration of liproxstatin-1 ameliorated lung inflammation and tissue injuries caused by MHV-A59 Infection. To find how MHV-A59 Infection influenced the expression of ferroptosis-related genes, we performed RNA-seq in primary macrophages and found that MHV-A59 Infection upregulates the expression of the acyl-CoA synthetase long-chain family member 1 (ACSL1), a novel Ferroptosis inducer. Using Ferroptosis inhibitors and a TLR4 Inhibitor, we showed that MHV-A59 resulted in the NF-kB-dependent, TLR4-independent ACSL1 upregulation. Accordingly, ACSL1 inhibitor Triacsin C suppressed MHV-A59-infection-induced syncytia formation and viral propagation in primary macrophages. Collectively, our study indicates that Ferroptosis inhibition protects hosts from MHV-A59 Infection. Targeting Ferroptosis may serve as a potential treatment approach for dealing with hyper-inflammation induced by coronavirus Infection.