Severity of COVID-19 is affected by multiple factors; however, it is not understood how the inflammatory milieu of the lung at the time of SARS-CoV-2 exposure affects the control of viral replication. Here, we demonstrate that immune events in the mouse lung closely preceding SARS-CoV-2 infection affect viral control and identify innate immune pathways that limit viral replication. Pulmonary inflammatory stimuli including resolved, antecedent respiratory infections with Staphylococcus aureus or influenza, ongoing pulmonary Mycobacterium tuberculosis infection, ovalbumin/alum-induced asthma, or airway administration of TLR ligands and recombinant cytokines all establish an antiviral state in the lung that restricts SARS-CoV-2 replication. In addition to antiviral type I interferons, TNFα and IL-1 potently precondition the lung for enhanced viral control. Our work shows that SARS-CoV-2 may benefit from an immunologically quiescent lung microenvironment and suggests that heterogeneity in pulmonary inflammation preceding SARS-CoV-2 exposure may contribute to variability in disease outcomes.

中文翻译：

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感染时肺部的炎症微环境控制着 SARS-CoV-2 复制的先天控制


COVID-19 的严重程度受多种因素影响;然而，尚不清楚 SARS-CoV-2 暴露时肺部的炎症环境如何影响病毒复制的控制。在这里，我们证明 SARS-CoV-2 感染之前小鼠肺中的免疫事件会影响病毒控制，并确定限制病毒复制的先天免疫途径。肺部炎症刺激，包括已解决的、先前的金黄色葡萄球菌或流感呼吸道感染、持续的肺结核分枝杆菌感染、卵清蛋白/明矾诱导的哮喘，或 TLR 配体和重组细胞因子的气道给药，都在肺部建立一种抗病毒状态，限制 SARS-CoV-2 复制。除了抗病毒的 I 型干扰素外，TNFα 和 IL-1 还能有效地调节肺部以增强病毒控制。我们的研究表明，SARS-CoV-2 可能受益于免疫静止的肺部微环境，并表明 SARS-CoV-2 暴露前肺部炎症的异质性可能导致疾病结果的变异性。