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

SPLUNC1/BPIFA1 在宿主对呼吸道病毒感染反应中的作用

• 批准号: BB/K009664/1
• 负责人: James Stewart
• 金额: $ 53.69万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK009664%2F1
• 关键词: Role; SPLUNC1; BPIFA1; Host; Response

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.

PLUNC/BPIF家族是一种快速进化的糖蛋白分子，在哺乳动物的呼吸道中持续产生。它们在结构上与BPI和LBP相似，BPI是一种已知用于对抗细菌感染的蛋白质，LBP是通过TLR天然防御途径传递细菌内毒素信号的关键分子。这导致了一种假设，即PLUNC/BPIF蛋白将表现出与BPI和LBP类似的抗微生物防御功能。然而，BPIF蛋白的功能尚不清楚，到目前为止还没有令人信服的文献支持其具有重要的抗菌作用，我们自己的数据也没有显示出蛋白质在体内和体外的直接抗菌/抑菌作用。在这笔赠款中，我们的重点是SPLunc1或BPIFA1。BPIFA1是在所有哺乳动物中发现的典型家族成员。它是分泌到呼吸道的主要分子之一。我们已经证明，BPIFA1是在呼吸道衬里的细胞中产生的，而且在感染病毒后，它的产生会增加。使用不能产生BPIAF1的转基因小鼠，我们已经证明它参与了对A型流感病毒的防御。因此，我们认为BPIAF1参与了对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BPIFA1基因缺陷小鼠和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。使用实验室培养的来自BPIFA1缺陷小鼠呼吸道的完全分化的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。这一结果将大大增强我们对病毒感染防御的基本方面以及呼吸道生物学方面的理解。这项研究将在利物浦大学和谢菲尔德大学由一个由医学和兽医学院成员组成的多学科团队进行，该团队使用目前位于这些地点的设备齐全的设施。

项目成果

Gammaherpesvirus infection modulates the temporal and spatial expression of SCGB1A1 (CCSP) and BPIFA1 (SPLUNC1) in the respiratory tract

伽马疱疹病毒感染调节呼吸道中 SCGB1A1 (CCSP) 和 BPIFA1 (SPLUNC1) 的时空表达

• DOI: 10.5167/uzh-108056
• 发表时间: 2015
• 作者: Leeming, G H

An innate defense peptide BPIFA1/SPLUNC1 restricts influenza A virus infection.

先天的防御肽BPIFA1/SPLUNC1限制了流感病毒感染。

• DOI: 10.1038/mi.2017.109
• 发表时间: 2018-05
• 期刊: Mucosal immunology
• 影响因子: 8
• 作者: Akram KM;Moyo NA;Leeming GH;Bingle L;Jasim S;Hussain S;Schorlemmer A;Kipar A;Digard P;Tripp RA;Shohet RV;Bingle CD;Stewart JP
• 通讯作者: Stewart JP

An in vitro model of murine middle ear epithelium.

• DOI: 10.1242/dmm.026658
• 发表时间: 2016-11-01
• 期刊: Disease models & mechanisms
• 影响因子: 4.3
• 作者: Mulay A;Akram KM;Williams D;Armes H;Russell C;Hood D;Armstrong S;Stewart JP;Brown SD;Bingle L;Bingle CD
• 通讯作者: Bingle CD

Constitutive TRIM22 Expression in the Respiratory Tract Confers a Pre-Existing Defence Against Influenza A Virus Infection.

• DOI: 10.3389/fcimb.2021.689707
• 发表时间: 2021
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Charman M;McFarlane S;Wojtus JK;Sloan E;Dewar R;Leeming G;Al-Saadi M;Hunter L;Carroll MW;Stewart JP;Digard P;Hutchinson E;Boutell C
• 通讯作者: Boutell C

Influenza A Virus Challenge Models in Cynomolgus Macaques Using the Authentic Inhaled Aerosol and Intra-Nasal Routes of Infection.

• DOI: 10.1371/journal.pone.0157887
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Marriott AC;Dennis M;Kane JA;Gooch KE;Hatch G;Sharpe S;Prevosto C;Leeming G;Zekeng EG;Staples KJ;Hall G;Ryan KA;Bate S;Moyo N;Whittaker CJ;Hallis B;Silman NJ;Lalvani A;Wilkinson TM;Hiscox JA;Stewart JP;Carroll MW
• 通讯作者: Carroll MW