The Role of SPLUNC1/BPIFA1 in the Host Response to Respiratory Virus Infection

PLUNC/BPIF家族是哺乳动物呼吸道中不断产生的快速进化的糖蛋白分子。它们显示出与BPI和LBP的结构相似性，BPI是一种已知的对抗细菌感染的蛋白质，LBP是一种在通过TLR先天防御途径从细菌LPS转导信号中至关重要的分子。这导致假设PLUNC/BPIF蛋白将表现出与BPI和LBP相似的抗菌防御功能。然而，BPIF蛋白的功能尚不清楚，目前还没有令人信服的文献支持其具有显著的抗菌作用，我们自己的数据也未能显示该蛋白在体内和体外具有直接的抗菌/抑菌作用。在这项资助中，我们的重点是SPLUNC1或BPIFA1。BPIFA1是在所有哺乳动物中发现的原型家族成员。它是分泌到呼吸道的主要分泌分子之一。我们已经证明，BPIFA1是在呼吸道内壁细胞中产生的，并且在感染病毒后，其产量增加。通过使用不能产生BPIAF1的转基因小鼠，我们已经证明它参与了对甲型流感病毒的防御。因此，我们认为BPIAF1参与了病毒感染的早期反应。这个项目的目的是：1。发现BPIFA1在MHV-68感染防御机制中的确切作用方式。这将涉及比较缺乏BPIFA1基因的转基因小鼠与正常小鼠的病毒感染进展。我们还将研究BPIFA1是否影响炎症反应、各种类型的免疫反应（抗体和细胞毒性T细胞）以及其他抗病毒反应，如干扰素。使用实验室从bpifa1缺陷小鼠的呼吸道培养的完全分化细胞来观察这种蛋白质如何保护呼吸道免受病毒感染。通过比较感染前后小鼠和缺乏BPIFA1的细胞中基因表达的差异，发现BPIFA1的作用机制。研究结果将大大提高我们对病毒感染防御的基本方面以及呼吸生物学方面的理解。该研究将在利物浦大学和谢菲尔德大学进行，由医学和兽医学院成员组成的多学科团队将使用目前位于这些地点的设备齐全的设施。

The PLUNC/BPIF family are rapidly evolving glycoprotein molecules that are produced continuously in the respiratory tract of mammals. They show structural similarity to BPI, a protein that is known to combat bacterial infections and to LBP, a molecule critically important in transducing signals from bacterial LPS through the TLR innate defence pathway. This led to the hypothesis that PLUNC/BPIF proteins would exhibit similar antimicrobial defence functions to BPI and LBP. However, the function of BPIF proteins is unknown and as yet there is no compelling published support for a significant antimicrobial role, and our own data has failed to show a direct antimicrobial/bacteriostatic role for the proteins, both in vivo and in vitro. In this grant we are focussing on SPLUNC1 or BPIFA1. BPIFA1 is the prototypic family member that is found in all mammals. It is one of the major secretory molecules is secreted into the respiratory tract. We have shown that BPIFA1 is produced in the cells lining the respiratory tract, and that after infection with viruses, its production is increased. Using genetically modified mice that are unable to produce BPIAF1, we have shown that it is involved in the defence against influenza A virus. We therefore believe that BPIAF1 is involved in the early response to virus infection. The aims of this project are to:1. Discover the precise way that BPIFA1 acts in the defence mechanisms to MHV-68 infection. This will involve comparing the progress of viral infection in genetically modified mice deficient in BPIFA1 with normal mice. We will also study whether BPIFA1 influences inflammatory responses, various types of immune responses (antibody and cytotoxic T cell) as well as other anti-viral responses such as interferons.2. Use fully differentiated cells that have been cultured in the laboratory from the respiratory tract of BPIFA1-deficient mice to look at how this protein can protect the respiratory tract from virus infection.3. Discover the mechanisms of action of BPIFA1 by comparing differences in the expression of genes in mice and cells lacking BPIFA1 before and after infection. The results will significantly enhance our understanding of fundamental aspects of defence to virus infection as well as aspects of respiratory biology. The research will be carried out at the Universities of Liverpool and Sheffield by a multi-disciplinary team comprising members of the Medical and Veterinary Faculties using well-equipped facilities currently situated at these sites.