Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX; and.
Department of Experimental Pathology, University of Texas Medical Branch, Galveston, TX.
Immunohorizons. 2022 Oct 11;6(10):716-721. doi: 10.4049/immunohorizons.2200065.
Multiple organ damage is common in patients with severe COVID-19, even though the underlying pathogenic mechanisms remain unclear. Acute viral infection typically activates type I IFN (IFN-I) signaling. The antiviral role of IFN-I is well characterized in vitro. However, our understanding of how IFN-I regulates host immune response to SARS-CoV-2 infection in vivo is incomplete. Using a human ACE2-transgenic mouse model, we show in the present study that IFN-I receptor signaling is essential for protection against the acute lethality of SARS-CoV-2 in mice. Interestingly, although IFN-I signaling limits viral replication in the lung, the primary infection site, it is dispensable for efficient viral clearance at the adaptive phase of SARS-CoV-2 infection. Conversely, we found that in the absence of IFN-I receptor signaling, the extreme animal lethality is consistent with heightened infectious virus and prominent pathological manifestations in the brain. Taken together, our results in this study demonstrate that IFN-I receptor signaling is required for restricting virus neuroinvasion, thereby mitigating COVID-19 severity.
多器官损伤在重症 COVID-19 患者中很常见，尽管其潜在的发病机制仍不清楚。急性病毒感染通常会激活 I 型干扰素（IFN-I）信号。IFN-I 的抗病毒作用在体外得到了很好的描述。然而，我们对于 IFN-I 如何调节宿主对 SARS-CoV-2 感染的免疫反应的理解还不完全。本研究使用人 ACE2 转基因小鼠模型表明，IFN-I 受体信号对于保护小鼠免受 SARS-CoV-2 的急性致死性至关重要。有趣的是，尽管 IFN-I 信号限制了肺部（主要感染部位）的病毒复制，但在 SARS-CoV-2 感染的适应性阶段，它对于有效清除病毒是可有可无的。相反，我们发现，在缺乏 IFN-I 受体信号的情况下，极高的动物致死率与脑中病毒载量增加和明显的病理表现一致。总之，我们在这项研究中的结果表明，IFN-I 受体信号对于限制病毒向神经组织的入侵是必需的，从而减轻 COVID-19 的严重程度。
