Hyperinflammation and lymphopenia provoked by SARS-CoV-2-activated macrophages contribute to the high mortality of Coronavirus Disease 2019 (COVID-19) patients. Thus, defining host pathways aberrantly activated in patient macrophages is critical for developing effective therapeutics. We discovered that G9a, a histone methyltransferase that is overexpressed in COVID-19 patients with high viral load, activates translation of specific genes that induce hyperinflammation and impairment of T cell function or lymphopenia. This noncanonical, pro-translation activity of G9a contrasts with its canonical epigenetic function. In endotoxin-tolerant (ET) macrophages that mimic conditions which render patients with pre-existing chronic inflammatory diseases vulnerable to severe symptoms, our chemoproteomic approach with a biotinylated inhibitor of G9a identified multiple G9a-associated translation regulatory pathways that were upregulated by SARS-CoV-2 infection. Further, quantitative translatome analysis of ET macrophages treated progressively with the G9a inhibitor profiled G9a-translated proteins that unite the networks associated with viral replication and the SARS-CoV-2-induced host response in severe patients. Accordingly, inhibition of G9a-associated pathways produced multifaceted, systematic effects, namely, restoration of T cell function, mitigation of hyperinflammation, and suppression of viral replication. Importantly, as a host-directed mechanism, this G9a-targeted, combined therapeutics is refractory to emerging antiviral-resistant mutants of SARS-CoV-2, or any virus, that hijacks host responses.

中文翻译：

---

慢性炎症失调的新型基因特异性翻译机制揭示了有前景的多方面COVID-19治疗剂

SARS-CoV-2活化的巨噬细胞引起的过度炎症和淋巴细胞减少导致2019年冠状病毒病（COVID-19）患者的高死亡率。因此，确定在患者巨噬细胞中异常激活的宿主途径对于开发有效的治疗方法至关重要。我们发现，G9a是一种在高病毒载量的COVID-19患者中过表达的组蛋白甲基转移酶，可激活诱导过度炎症和T细胞功能或淋巴细胞减少的特定基因的翻译。G9a的这种非规范的促翻译活性与其规范的表观遗传功能相反。在模仿内毒素耐受（ET）的巨噬细胞中，这些条件会使先前患有慢性炎性疾病的患者易患严重症状，我们使用生物素化的G9a抑制剂的化学旋转方法确定了SARS-CoV-2感染上调的多个G9a相关翻译调节途径。此外，在严重患者中，用G9a抑制剂逐步治疗的ET巨噬细胞的定量翻译组分析分析了G9a翻译的蛋白，该蛋白将与病毒复制和SARS-CoV-2诱导的宿主反应相关的网络结合在一起。因此，抑制G9a相关途径产生了多方面的系统性作用，即恢复T细胞功能，减轻过度炎症和抑制病毒复制。重要的是，作为一种针对宿主的机制，这种靶向G9a的联合治疗药物对劫持宿主反应的SARS-CoV-2或任何病毒的新兴抗病毒耐药突变体均具有耐药性。