Department of Systems Biomedicine, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Viruses. 2021 Nov 28;13(12):2383. doi: 10.3390/v13122383.
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.
鼠肝炎病毒 A 株（MHV-A59）已被证明可诱导感染细胞发生细胞焦亡、凋亡和坏死性凋亡，尤其是在鼠巨噬细胞中。然而，铁死亡——一种新发现的溶细胞死亡形式，是否参与了 MHV-A59 的致病性尚不清楚。我们利用鼠巨噬细胞和 C57BL/6 小鼠鼻腔感染模型来解决这个问题。在原代巨噬细胞中，铁死亡抑制剂抑制了 MHV-A59 感染后病毒的增殖、炎症细胞因子的释放和细胞合胞体的形成。在小鼠模型中，我们发现体内给予 liproxstatin-1 可改善 MHV-A59 感染引起的肺部炎症和组织损伤。为了研究 MHV-A59 感染如何影响铁死亡相关基因的表达，我们在原代巨噬细胞中进行了 RNA-seq 分析，发现 MHV-A59 感染上调了长链酰基辅酶 A 合成酶家族成员 1（ACSL1）的表达，ACSL1 是一种新的铁死亡诱导剂。通过使用铁死亡抑制剂和 TLR4 抑制剂，我们表明 MHV-A59 导致了 NF-κB 依赖性、TLR4 非依赖性的 ACSL1 上调。相应地，ACSL1 抑制剂 Triacsin C 抑制了 MHV-A59 感染诱导的原代巨噬细胞合胞体形成和病毒增殖。总之，我们的研究表明铁死亡抑制可保护宿主免受 MHV-A59 感染。靶向铁死亡可能成为应对冠状病毒感染引起的过度炎症的潜在治疗方法。
