Calming the Cytokine Storm: Elucidating Mechanisms Contributing to Toxic Inflammatory Responses to Viruses

平息细胞因子风暴：阐明病毒毒性炎症反应的机制

• 批准号: RGPIN-2021-04069
• 负责人: Bridle, Byram
• 金额: $ 2.33万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761921
• 关键词: Calming; Cytokine; Storm; Elucidating; Mechanisms

Viruses induce type I interferons (IFNs) after cells sense viral pathogen-associated molecular patterns. These IFNs are detected by the IFN a/ß receptor (IFNAR), with downstream signaling inducing IFN-stimulated genes that facilitate clearance of viruses through mechanisms that include secretion of pro-inflammatory cytokines. Although this would suggest that a lack of type I IFN signaling might reduce pro-inflammatory cytokines, our results demonstrated the opposite. We developed a murine model of viremia in which hematopoietic cells lacked IFNARs. After these mice received intravenous injections of a highly attenuated, non-pathogenic vesicular stomatitis virus, they succumbed to massive cytokine storms in 18 hours. Out of 26 cytokines that were assessed, 25 reached abnormally high levels. Unexpectedly, and a focus of this application, was that cytokine dysregulation was more exaggerated in females compared to males. This is notable because there is a sex bias towards females in the incidence of many inflammation-mediated diseases. Preliminary results suggested neutrophils may have a predominantly regulatory role in this model, since pro-inflammatory cytokines became more dysregulated when these cells were depleted. Neutrophils can be sub-divided into two major phenotypes after separation in a density gradient. Hypothetically, one of these subsets may have a suppressive role during cytokine responses. Quantitative or qualitative differences in a suppressive subset of male neutrophils may confer resistance to dysregulated cytokine responses to viruses. We also propose a model of cell signaling cascades as a blueprint for testing a second hypothesis: interferon-stimulated response elements in sex-dependent promoters contribute to differential regulation of type I IFN-modulated cytokine responses to viruses. Objectives: 1. Assess quantitative versus qualitative differences in the immunoregulatory potential of subsets of neutrophils from males and females. 2. Identify other leukocytes, beyond neutrophils, that contribute to the virus-induced cytokine storm. 3. Identify mechanisms underlying sex-biased dysregulation of cytokine responses, including intracellular changes in cytokine signaling pathways during viral infection with and without IFNAR-blockade, and the role of host factors that may explain sex differences. Training the next generation of Canadian biomedical scientists in the interdisciplinary field of viral immunology is integral to this research. A need for this expertise has been highlighted by the protracted struggle for scientists to develop solutions for the coronavirus disease (COVID)-19 pandemic. This research should provide a mechanistic understanding of how sex can influence the link between impaired IFNAR-mediated signaling, cytokine overproduction, and the leukocyte subsets that are involved. This has relevance for a spectrum of sex-biased cytokine disorders ranging from life-threatening cytokine storms to excessive inflammation.

细胞感知到病毒病原体相关的分子模式后，病毒会诱导 I 型干扰素 (IFN)。这些 IFN 由 IFN a/ß 受体 (IFNAR) 检测，下游信号传导诱导 IFN 刺激的基因，通过分泌促炎细胞因子等机制促进病毒清除。尽管这表明 I 型干扰素信号传导的缺乏可能会减少促炎细胞因子，但我们的结果证明了相反的情况。我们开发了一种病毒血症小鼠模型，其中造血细胞缺乏 IFNAR。这些小鼠接受静脉注射高度减毒、非致病性水泡性口炎病毒后，18小时内死于大规模细胞因子风暴。在评估的 26 种细胞因子中，有 25 种达到了异常高的水平。出乎意料的是，本申请的重点是，与男性相比，女性的细胞因子失调更为严重。这是值得注意的，因为许多炎症介导的疾病的发病率存在对女性的性别偏见。初步结果表明，中性粒细胞在该模型中可能具有主要的调节作用，因为当这些细胞被耗尽时，促炎细胞因子变得更加失调。在密度梯度中分离后，中性粒细胞可细分为两种主要表型。假设，这些子集之一可能在细胞因子反应过程中具有抑制作用。雄性中性粒细胞抑制性亚群的定量或定性差异可能赋予对病毒的细胞因子反应失调的抵抗力。我们还提出了细胞信号级联模型作为测试第二个假设的蓝图：性别依赖性启动子中干扰素刺激的反应元件有助于 I 型 IFN 调节的细胞因子对病毒反应的差异调节。目标： 1. 评估男性和女性中性粒细胞亚群免疫调节潜力的定量与定性差异。 2. 识别除中性粒细胞之外的其他白细胞，这些白细胞有助于病毒诱导的细胞因子风暴。 3. 确定细胞因子反应的性别偏向失调的潜在机制，包括有和没有IFNAR阻断的病毒感染期间细胞因子信号通路的细胞内变化，以及可能解释性别差异的宿主因素的作用。在病毒免疫学跨学科领域培训下一代加拿大生物医学科学家是这项研究的组成部分。科学家们为开发冠状病毒病 (COVID)-19 大流行的解决方案而进行的长期斗争凸显了对这种专业知识的需求。这项研究应该提供关于性别如何影响受损的 IFNAR 介导的信号传导、细胞因子过量产生以及所涉及的白细胞亚群之间的联系的机制理解。这与一系列性别偏向的细胞因子疾病相关，从危及生命的细胞因子风暴到过度炎症。