While most respiratory viral infections resolve with little harm to the host, severe symptoms arise when infection triggers an aberrant inflammatory response that damages lung tissue. Host regulators of virally induced lung inflammation have not been well defined. Here, we show that enrichment for sialylated, but not asialylated immunoglobulin G (IgG), predicted mild influenza disease in humans and was broadly protective against heterologous influenza viruses in a murine challenge model. Mechanistic studies show that sialylated IgG mediated this protection by inducing the transcription factor repressor element-1 silencing transcription factor (REST), which repressed nuclear factor κB (NF-κB)-driven responses, preventing severe lung inflammation and protecting lung function during influenza infection. Therapeutic administration of a recombinant, sialylated Fc molecule in clinical development similarly activated REST and protected against severe influenza disease, demonstrating that this pathway could be clinically harnessed. Overall, induction of REST through sialylated IgG signaling is a strategy to limit inflammatory disease sequelae in infections caused by antigenically distinct influenza strains.

中文翻译：

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唾液酸化 IgG 在肺泡巨噬细胞中诱导转录因子 REST，以防止肺部炎症和严重的流感疾病


虽然大多数呼吸道病毒感染会消退，对宿主的伤害很小，但当感染引发损害肺组织的异常炎症反应时，会出现严重的症状。病毒诱导的肺部炎症的宿主调节因子尚未明确定义。在这里，我们表明唾液酸化但非亚洲唾液酸化免疫球蛋白 G （IgG） 的富集可预测人类的轻度流感疾病，并且在小鼠攻击模型中对异源流感病毒具有广泛的保护作用。机制研究表明，唾液酸化 IgG 通过诱导转录因子抑制元件 1 沉默转录因子 （REST） 介导这种保护，该转录因子抑制了核因子 κB （NF-κB） 驱动的反应，防止严重的肺部炎症并在流感感染期间保护肺功能。在临床开发中，重组唾液酸化 Fc 分子的治疗性给药同样激活了 REST 并预防了严重的流感疾病，表明该途径可以被临床利用。总体而言，通过唾液酸化 IgG 信号传导诱导 REST 是一种在抗原性不同的流感毒株引起的感染中限制炎症性疾病后遗症的策略。