Induction and role of type I and III interferons during SARS CoV2 infection

SARS-CoV-2感染是目前对世界的一种威胁，是目前大流行的原因。SARS-CoV-2感染呼吸道并传播到下呼吸道，在那里炎症反应导致新冠肺炎。我们以前已经证明，通过模式识别受体检测呼吸道病毒可以驱动干扰素(干扰素)反应，而干扰素通过抑制病毒复制和驱动抗病毒炎症反应对宿主反应有利。然而，如果I型和III型干扰素反应失调，可能会发生增强的和有害的肺部炎症。SARS-CoV-2感染的结局和炎症程度很可能是在感染过程中很早就确定的，这将在本提案中进行研究。感染早期下呼吸道的反应在人类身上是不可能研究的，因此，这项工作的第一部分将是验证几个小鼠模型。我们将使用人源化的ACE2小鼠和腺病毒将hACE2运送到上皮细胞。这些模型将被转移到转基因和基因敲除小鼠模型中，以确定在SARS-CoV-2感染期间I型和II型IFN的诱导、时机、来源和在炎症反应中的作用。此外，SARS-CoV-2毒株将通过反向遗传学进行改造，该毒株缺乏干扰素拮抗基因，将用于确定病毒如何操纵干扰素反应。这样的工程最终可能有助于弱毒疫苗的战略。综上所述，这项提议将揭示新冠肺炎期间有害炎症是如何启动的。

SARS-CoV-2 infection is a current threat to the world as the cause of the ongoing pandemic. SARS-CoV-2 infects the respiratory tract and spread to the lower airways where an inflammatory response results in the disease COVID-19. We have previously shown that detection of respiratory viruses by pattern recognition receptors drive interferon (IFN) responses that are beneficial for the host response by both inhibiting viral replication and driving an anti-viral inflammatory response. However, if the type I and III IFN response is dyregulated, an enhanced and detrimental lung inflammation can occur. It is very likely that the outcome of SARS-CoV-2 infection, and the magnitude of inflammation, is determined very early during the infection and this will be studied in this proposal. The responses in the lower airways early during infection is impossible to study in humans and therefore, the first part of this work will be to validate several mouse models. We will use humanised ACE2 mice and Adenovirus-delivery of hACE2 to epithelial cells. These models will be transferred to transgenic and knockout mouse models for determination of the induction, timing, source and role of type I and II IFNs in the inflammatory response during SARS-CoV-2 infection. In addition, a SARS-CoV-2 strain will be engineered by reverse genetics, deficient in IFN antagonising genes, that will be used to determine how the virus manipulates the IFN response. Such engineering could eventually contribute to a strategy for attenuated vaccines. In sum, this proposal will unveil a detailed understanding of how the detrimental inflammation during COVID-19 is initiated.