Competition for polarity influences lymphocyte signaling and function

由病毒和细菌引起的传染病仍然是一个重大的健康问题。CD46是人类细胞表面的一种蛋白质，许多病毒和细菌利用它进入并感染宿主细胞。通过与CD46蛋白结合，病毒和细菌可以诱导免疫细胞（如T淋巴细胞）发生变化，从而影响我们的免疫系统对感染的反应方式。例如，麻疹病毒感染引起的免疫抑制是麻疹相关死亡率和发病率的主要原因，人们对这一现象了解甚少。然而，有证据表明麻疹感染细胞与免疫细胞上的CD46之间的相互作用是观察到的免疫抑制的部分原因。我们的实验室最近发现，CD46（通过抗体或麻疹抗原）在免疫细胞上的结合为细胞提供了改变其极化状态（蛋白质在细胞内分布的方式）的信号，并损害了它们识别和杀死靶细胞的能力，并被激活。这些观察结果表明了一种新的模式，即受体信号的极化竞争决定了信号传导的结果，并为结合CD46的病原体（如麻疹）如何破坏正常的免疫细胞通讯并诱导免疫抑制提供了可能的机制。本研究旨在探讨极化信号对免疫细胞影响的机制，并将CD46和麻疹病毒作为模型。这项研究的结果将定义淋巴细胞生物学的新范式，并剖析支撑CD46如何影响免疫结果的关键途径。

Infectious diseases caused by viruses and bacteria remain a significant health problem. CD46 is a protein on the surface of human cells that is used by a number of viruses and bacteria to enter and infect host cells. Through binding to the CD46 protein, viruses and bacteria can induce changes in immune cells, such as T lymphocytes, that affect the way our immune system responds to infection. For example, immunosuppression induced by infection with measles virus is the primary cause of the mortality and morbidity associated with the disease, and is a phenomenon that is poorly understood. However, there is evidence to suggest that the interaction between measles-infected cells with CD46 on the immune cells is partly responsible for the immunosuppression observed. Our laboratory has recently found that binding of CD46 (by antibody or measles antigen) on immune cells provides a signal to the cell to change its polarisation state (the way proteins are distributed within the cell) and impairs their ability to recognize and kill target cells, and become activated. These observations indicate a new paradigm by which competition of receptor signals for polarization determines signalling outcomes and provides a possible mechanism for how pathogens that bind CD46, such as measles, subvert normal immune cell communication and induce immunosuppression. This proposal aims to investigate the mechanisms behind the effect of polarising signals on immune cells, and will specifically use CD46 and measles virus as a model. The outcomes of this study will define new paradigms in lymphocyte biology and dissect the key pathways that underpin how CD46 influences immune outcome in response to infection.