Investigation of the cell-intrinsic immune response and the antiviral efficacy of interferons against SARS-CoV2

新型冠状病毒SARS-CoV 2是一种正链RNA病毒。RNA病毒感染非常普遍地涉及细胞内在先天免疫系统的分子传感器，所谓的模式识别受体（PRR），最重要的是RIG-I样受体（RLR）家族。RLR触发信号级联，最终导致炎性细胞因子（通过转录因子NFκB）和抗病毒细胞因子（最显著的是I型和III型干扰素（IFN））（通过IRF 3）的转录、产生和分泌。此外，这些抗病毒途径的强烈刺激也会导致细胞死亡的诱导，可能产生危险信号（DAMP），进一步刺激组织中的炎症过程。在SARS-CoV 2感染的特定情况下，我们和其他人已经证明该病毒（及其近亲）强烈抑制IRF 3的激活，从而抑制IFN的产生。相反，它不阻断NFκB的激活和炎症转录程序的诱导。细胞内在防御途径的抗病毒分支的这种选择性阻断导致强烈偏斜的免疫应答，可能有助于观察到的炎症性“细胞因子风暴”的诱导，其与病毒诱导的细胞病的直接组织破坏一起最有可能形成免疫超活化的基础，最终导致过度炎症和免疫病理学特征COVID-19。如果是这样的话，先天免疫反应在COVID-19的发展中发挥了有害作用，但未能遏制病毒的复制和传播。因此，一种前瞻性的治疗方案可能是PRR信号传导的药理学抑制，防止炎性细胞因子的产生，并可能抑制上皮细胞死亡的诱导。将这种抑制与外源性IFN的施用相结合可以提供一种非常有效的双管齐下的治疗选择，既影响病毒复制又影响炎症基础COVID-19。在拟议的项目中，我们将表征参与诱导程序性细胞死亡和激活炎症转录程序的信号通路。我们将进一步研究不同类型的干扰素对SARS-CoV 2的抗病毒效果，包括研究不足的I型干扰素κ。这项为期一年的研究计划的集体结果将为我们提供有关拟议治疗方法的可行性，并为SARS-CoV 2抗病毒免疫的长期深入研究奠定基础。

The novel coronavirus, SARS-CoV2, is a plus-strand RNA virus. RNA virus infection very generally engages molecular sensors of the cell-intrinsic innate immune system, so called pattern recognition receptors (PRRs), most importantly of the RIG-I-like receptor (RLR) family. RLRs trigger a signaling cascade culminating in the transcription, production and secretion of inflammatory cytokines (via the transcription factor NFκB) and antiviral cytokines, most prominently type I and III interferons (IFNs) (via IRF3). Additionally, strong stimulation of those antiviral pathways also leads to the induction of cell death, potentially generating danger signals (DAMPs) that further stimulate inflammatory processes in the tissue. In the specific case of SARS-CoV2 infection, we and others have shown that the virus (and close relatives) strongly inhibits the activation of IRF3 and, hence, the production of IFNs. In contrast, it does not block activation of NFκB and the induction of an inflammatory transcriptional program. This selective blockage of the antiviral branch of cell-intrinsic defense pathways leads to a strongly skewed immune response, likely contributing to the observed induction of an inflammatory “cytokine storm”, which together with direct tissue destruction by virus-induced cytopathy most likely forms the basis of immune hyperactivation, eventually leading to the excessive inflammation and immunopathology characterizing COVID-19. If this is the case, innate immune responses rather play a detrimental role in the development of COVID-19, but fail to contain viral replication and spread. A prospective therapeutic regimen may therefore be the pharmacological inhibition of PRR signaling, preventing the production of inflammatory cytokines and possibly dampening the induction of epithelial cell death. Combining such inhibition with the administration of exogenous IFNs could provide a highly efficacious two-pronged therapeutic option, impacting both, viral replication and the inflammatory basis COVID-19.In the proposed project, we are going to characterize the signaling pathways involved in the induction of programmed cell death and the activation of inflammatory transcriptional programs. We will further investigate the antiviral efficacy of different IFN types against SARS-CoV2, including the understudied type I IFN kappa. The collective results from this one-year research program will then inform us about the feasibility of the proposed therapeutic approach and form the basis for longer-term in-depth studies on antiviral immunity in SARS-CoV2.