Critical role of TNF in host-virus interactions and outcome of infection: Involvement of reverse signalling through mTNF

细胞因子是参与免疫反应的细胞产生的分子。它们协调白细胞的活动，并在宿主对病毒感染的反应中发挥重要作用。就其自身而言，病毒已经进化出了试图逃避宿主反应的策略。在病毒感染的背景下分析这些策略将有助于更好地了解免疫系统和宿主与病毒的相互作用。肿瘤坏死因子是一种由特定的白细胞产生的细胞因子，分两个阶段：首先，细胞因子暴露在细胞表面，然后被剪下并以可溶性形式释放。在任何一种形式中，它都可以与其他细胞上的特定受体相互作用，并通过这种方式改变细胞的活动。我们已经发现，肿瘤坏死因子受体与细胞因子的结合，虽然它是以膜的形式存在，但也可以向后向携带肿瘤坏死因子的细胞发送信息。这个过程被称为反向信令，然后改变这个细胞的活动，并构成一条重要的新路径，通过它可以进行信息传输。在这个项目中，我们将描述由特定类型的白细胞中的反向信号引起的生物学变化。我们将研究膜肿瘤坏死因子在两种不同的病毒性疾病模型中的作用。第一种是流感肺炎，它导致了全球范围内的大量发病率和死亡率。第二种是模仿人类天花的痘病毒感染模型(鼠痘)。人痘病毒感染呈上升趋势(例如猴痘)，天花作为生物恐怖主义武器的威胁也在增加。鼠痘是研究全身性病毒感染的一个很好的模型，也是编码专门用于干扰宿主肿瘤坏死因子的蛋白质的病毒的一个很好的例子。我们的研究将集中在这种细胞因子在宿主-病毒相互作用和感染结局中的作用。

Cytokines are molecules produced by cells that take part in the immune response. They coordinate the activities of leukocytes and are important in the host response to virus infections. For their part, viruses have evolved strategies to try and evade the host response. The analysis of these strategies in the context of a viral infection will lead to a better understanding of the immune system and host-virus interactions. Tumour necrosis factor is a cytokine made by specific leukocytes, in two stages: First, the cytokine is exposed on the surface of the cell and then it is clipped off and released as a soluble form. In either form it can interact with specific receptors on other cells and, in this way, change the cells' activities. We have found that binding of tumour necrosis factor receptors to the cytokine, while it is in its membrane form, can also send a message backwards into the cell bearing the tumour necrosis factor. This process, known as reverse signalling, then changes the activity of this cell and constitutes a major new route through which information transfer can occur. In this project we will characterize the biological changes that result from reverse signalling in specific types of leukocytes. We will be looking at the role of membrane tumour necrosis factor in two separate models of viral disease. The first is influenza pneumonia that is responsible for a great deal of morbidity and mortality worldwide. The second is a model of poxvirus infection (mousepox) that mimics the disease smallpox in humans. Human poxvirus infections are on the rise (e.g. monkeypox) and there is an increased threat of smallpox as a weapon of bioterrorism. Mousepox is a good model for the study of generalized viral infections and is also an excellent example of a virus that encodes proteins specifically designed to interfere with host tumour necrosis factor. Our studies will focus on the role of this cytokine in host-virus interactions and the outcome of infection.