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

I 型和 III 型干扰素在 SARS CoV2 感染过程中的诱导和作用

• 批准号: BB/V013831/1
• 负责人: Cecilia Johansson
• 金额: $ 38.76万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV013831%2F1
• 关键词: Induction; role; type; III; interferons

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.

SARS-CoV-2感染是目前对世界的威胁，是持续大流行的原因。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疾病COVID-19。我们之前已经证明，通过模式识别受体检测呼吸道病毒会驱动干扰素（IFN）反应，这通过抑制病毒复制和驱动抗病毒炎症反应而有利于宿主反应。然而，如果I型和III型IFN应答失调，则可能发生增强的和有害的肺部炎症。SARS-CoV-2感染的结果和炎症的严重程度很可能在感染过程中很早就被确定，本提案将对此进行研究。感染早期下呼吸道的反应不可能在人类中研究，因此，这项工作的第一部分将是验证几种小鼠模型。我们将使用人源化ACE 2小鼠和腺病毒将hACE 2递送至上皮细胞。这些模型将被转移到转基因和基因敲除小鼠模型，以确定在SARS-CoV-2感染期间I型和II型IFN在炎症反应中的诱导、时机、来源和作用。此外，SARS-CoV-2毒株将通过反向遗传学进行工程改造，缺乏IFN拮抗基因，这将用于确定病毒如何操纵IFN反应。这种工程改造最终可能有助于减毒疫苗的策略。总之，该提案将揭示对COVID-19期间有害炎症如何启动的详细了解。

项目成果

Type I interferon receptor signalling deficiency results in dysregulated innate immune responses to SARS-CoV-2 in mice.

I 型干扰素受体信号传导缺陷导致小鼠对 SARS-CoV-2 的先天免疫反应失调。

• DOI: 10.1002/eji.202249913
• 发表时间: 2022
• 期刊: European journal of immunology
• 影响因子: 5.4
• 作者: Ogger PP

Formulation, inflammation, and RNA sensing impact the immunogenicity of self-amplifying RNA vaccines.

• DOI: 10.1016/j.omtn.2022.11.024
• 发表时间: 2023-03-14
• 期刊: MOLECULAR THERAPY NUCLEIC ACIDS
• 作者: Tregoning, John S.;Stirling, David C.;Wang, Ziyin;Flight, Katie E.;Brown, Jonathan C.;Blakney, Anna K.;McKay, Paul F.;Cunliffe, Robert F.;Murugaiah, Valarmathy;Fox, Christopher B.;Beattie, Mitchell;Tam, Ying K.;Johansson, Cecilia;Shattock, Robin J.
• 通讯作者: Shattock, Robin J.