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

有效的免疫反应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是由病毒复制直接导致的组织损伤引起的，而且也是因感染而产生的炎症免疫反应的结果。因此，病毒诱导的免疫反应必须谨慎平衡，以有效控制病原体的复制，而不诱导可能损害其应保护的宿主的过度免疫反应。然而，在病情严重的情况下，这种情况不会发生，肺和脑等重要器官有时会受到严重的、不可逆转的损害。了解在这些情况下出了什么问题，并确定细胞内驱动这些反应的机制和过程，将为治疗病毒性疾病的药物和其他治疗策略的开发提供信息。细胞因子是免疫系统的激素，由细胞分泌，可以诱导信号在其他细胞中传递。虽然某些细胞因子有助于防止病毒感染，但如果表达水平和/或时间不合适，它们也会参与组织损伤。细胞因子是由免疫细胞在某些受体的刺激下产生的，这些受体识别出微生物内部的某些模式是外来的。其中一类受体是toll样受体（TLRs）。tlr对于诱导保护宿主免受病毒感染的细胞因子至关重要，但明显的激活也会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，从而平衡对病毒的“好”和“坏”反应的机制，人们知之甚少。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，而炎症反应却大大降低。当我们从小鼠中删除Nogo-B时，在不影响宿主控制病毒的能力的情况下，这导致感染期间病毒诱导疾病的急剧减少。这些数据表明，1)通过研究Nogo-B的生物学来了解TLR激活的调节机制可能会为靶向病毒诱导的炎症提供新的途径；2)靶向Nogo-B本身可能是治疗病毒诱导炎症的一种令人兴奋的治疗策略。在本提案中，我们将研究Nogo-B对TLR激活的影响，并确定其作用机制。我们还将研究在不同的病毒感染期间消融Nogo-B的功能是否会影响免疫系统对体内病毒的反应，以及这是否可以减少由病毒引发的炎症和组织损伤，从而影响宿主对感染的控制。总的来说，这些研究将为制定安全治疗当前和潜在的未来感染威胁的炎症后果的策略提供信息。

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.