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

有效的免疫应答对于保护宿主免受病毒侵害至关重要。然而，由病毒感染引起的疾病不仅由作为病毒复制的直接结果的组织损伤引起，而且还作为响应于感染而产生的炎性免疫应答的结果。因此，必须仔细平衡由病毒诱导的免疫应答，以能够有效控制病原体复制，而不会诱导过度旺盛的免疫应答，过度旺盛的免疫应答可能损害它应该保护的宿主。然而，在严重疾病的情况下，这种情况不会发生，并且在肺和大脑等重要器官中可能发生实质性的，有时是不可逆的损伤。细胞因子是免疫系统的一种激素，由细胞分泌，可以诱导其他细胞的信号传递，是免疫系统的一种重要激素。细胞因子是免疫系统中的一种重要激素，它可以促进免疫系统的免疫反应。虽然某些细胞因子有助于保护免受病毒感染，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。细胞因子是由免疫细胞在刺激某些受体后产生的，这些受体识别微生物中的某些模式是外来的。一个这样的受体家族是Toll样受体（TLR）。TLR对于诱导保护宿主免受病毒感染的细胞因子是至关重要的，但明显的激活也可能导致细胞因子的过度产生和随后的疾病。调节TLR激活的机制以及对病毒的“好”和“坏”反应的平衡知之甚少。我们发现一种名为Nogo-B的蛋白质是病毒诱导炎症的有效介质，它通过调节TLR的激活来发挥作用。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细胞因子反应得以维持，而炎症反应大大减少。当我们从小鼠中删除Nogo-B时，这导致感染期间病毒诱导的疾病急剧减少，而不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导的炎症的新方法，2）靶向Nogo-B本身可能代表治疗病毒诱导的炎症的令人兴奋的治疗策略。 在这项提案中，我们将研究Nogo-B对TLR激活的影响，并确定其机制。我们还将研究在不同病毒感染期间Nogo-B功能的消融是否会影响免疫系统对体内病毒的反应，以及这是否会减少病毒引发的炎症和组织损伤，从而影响宿主对感染的控制。总体而言，这些研究将为安全治疗当前和潜在的炎症后果的策略的发展提供信息，未来的传染病威胁

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.