Identification of Nogo-B as a novel regulator of Toll-like receptor activation in virus-induced inflammation

鉴定 Nogo-B 作为病毒诱导炎症中 Toll 样受体激活的新型调节剂

• 批准号: MR/X00922X/1
• 负责人: Ian Humphreys
• 金额: $ 111.99万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX00922X%2F1
• 关键词: Identification; Nogo; novel; regulator; Toll

An effective immune response is critical for host protection against viruses. However, diseases caused by viral infections are caused not only by tissue damage as a direct result of virus replication, but also as a consequence of inflammatory immune responses mounted in response to infection. Thus, the immune response induced by viruses must be carefully balanced to enable efficient control of pathogen replication without inducing over-exuberant immune response that can damage the host it should be protecting. In cases of severe disease, however, this does not occur and substantial and, at times, irreversible damage can occur in vital organs such as the lungs and brain. Understanding what goes wrong in these scenarios and identifying the mechanisms and processes within cells that drive these responses will inform the development of drugs and other therapeutic strategies to treat viral diseases.Cytokines are the hormones of the immune system that are secreted by cells and can induce transmission of signals in other cells. Although certain cytokines help protect from viral infections, they can also participate in tissue damage if expressed at inappropriate levels and/or times. Cytokines are produced by immune cells following stimulation of certain receptors that recognise certain patterns within microbes to be foreign. One such family of receptors is the Toll-like receptors (TLRs). TLRs are critical for induction of cytokines that protect the host from viral infections, but overt activation can also lead to over-production of cytokines and subsequent disease. The mechanisms that regulate the activation of TLRs and thus the balance of 'good' and 'bad' responses to viruses is poorly understood.We identified that a protein called Nogo-B is a potent mediator of virus-induced inflammation and that it functions by modulating the activation of TLRs. Excitingly, when we depleted Nogo-B, we found that the production cytokine responses required to control virus replication were maintained whereas inflammatory responses were greatly reduced. When we deleted Nogo-B from mice, this led to a dramatic reduction in virus-induced disease during infection without affecting the ability of the host to control the virus. These data suggest that 1) understanding the mechanisms that regulate TLR activation through studying the biology of Nogo-B may lead to new ways to target virus-induced inflammation and 2) targeting Nogo-B in its own right may represent an exciting therapeutic strategy for the treatment of virus-induced inflammation. In this proposal, we will study what impact Nogo-B has on TLR activation and identify the mechanisms through which it does this. We will also investigate whether ablation of the function of Nogo-B during different viral infections can influence how the immune system responds to viruses in the body and whether this can reduce inflammation and tissue damage that is triggered by the virus with impacting host control of infection.Overall, these studies will inform the development of strategies to safely treat the inflammatory consequences of current and, potentially, future infectious threats.

有效的免疫反应对于宿主保护病毒至关重要。然而，病毒感染引起的疾病不仅是由病毒复制的直接导致组织损伤引起的，而且是由于响应感染而安装的炎症免疫反应。因此，必须仔细平衡病毒诱导的免疫反应，以有效控制病原体复制，而无需诱导过度过度的免疫反应，从而损害了宿主应保护的宿主。但是，在严重疾病的情况下，这不会发生，并且有时会发生不可逆的损害，例如肺和大脑等重要器官。了解在这些情况下出了什么问题，并确定驱动这些反应的细胞内的机制和过程将为药物的发展和其他治疗病毒疾病的策略提供信息。渐刺是免疫系统的激素，这些激素是由细胞分泌的，并可以诱导其他细胞中信号的传播。尽管某些细胞因子有助于保护病毒感染，但如果以不适当的水平和/或时间表达，它们也可以参与组织损伤。刺激某些受体识别微生物中某些模式的受体后，细胞因子是由免疫细胞产生的。这样的受体家族是收费受体（TLR）。 TLR对于诱导保护宿主免受病毒感染的细胞因子的诱导至关重要，但是明显的激活也会导致细胞因子和随后的疾病的产生过多。不了解调节TLR的激活以及“好”和“不良”反应的平衡的机制，对病毒的反应很差。我们确定一种称为Nogo-B的蛋白质是病毒诱导的炎症的有效介质，并且它通过调节TLR的激活而起作用。令人兴奋的是，当我们耗尽Nogo-B时，我们发现控制病毒复制所需的生产细胞因子反应得以维持，而炎症反应大大减少了。当我们从小鼠中删除Nogo-B时，这导致病毒诱导的感染期间病毒诱发的疾病的降低，而不会影响宿主控制病毒的能力。这些数据表明，1）通过研究Nogo-B的生物学来了解调节TLR激活的机制可能会导致靶向病毒诱发的炎症的新方法； 2）靶向Nogo-B本身可能代表一种令人兴奋的治疗策略，用于治疗病毒诱导的炎症。 在此提案中，我们将研究Nogo-B对TLR激活的影响，并确定这样做的机制。 We will also investigate whether ablation of the function of Nogo-B during different viral infections can influence how the immune system responds to viruses in the body and whether this can reduce inflammation and tissue damage that is triggered by the virus with impacting host control of infection.Overall, these studies will inform the development of strategies to safely treat the inflammatory consequences of current and, potentially, future infectious threats.

项目成果

Mucosal T-cell responses to chronic viral infections: Implications for vaccine design

• DOI: 10.1038/s41423-024-01140-2
• 发表时间: 2024-03-08
• 期刊: CELLULAR & MOLECULAR IMMUNOLOGY
• 影响因子: 24.1
• 作者: Al-Talib，Mohammed;Dimonte，Sandra;Humphreys，Ian R.
• 通讯作者: Humphreys，Ian R.