BPIFA1: from anti-viral peptide to immunomodulator

BPIFA1：从抗病毒肽到免疫调节剂

• 批准号: 1961573
• 金额: --
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1961573
• 关键词: BPIFA1; anti; viral; peptide; immunomodulator

Seasonal influenza is a major cause of respiratory infection resulting in substantial morbidity, mortality and economic burden worldwide. Pandemic influenza emerges sporadically and are a substantial global health concern. There are vaccines and antiviral drugs to combat influenza. However, due to rapid virus evolution, vaccines need to be re-formulated and re-administered annually with associated economic cost. For instance, the UK spent £1.24 billion preparing for and responding to the 2009 pandemic. It is therefore important to understand how host mechanisms modulate influenza virus infection and how these may be used to develop novel therapeutic interventions. This is particularly important in the elderly, where a decreased response means annual influenza vaccination is less effective in this age-group The airway epithelium has a fundamental role in the defense against pathogens and secretes proteins/peptides that function in innate and adaptive immunity. BPIFA1 is a protein that is secreted into the airways. The supervisory team (virologist, respiratory biologist and immunologist) in collaboration has shown that BPIFA1 is an anti-viral peptide, restricting influenza A virus infection of cells (Mucosal Immunology, Published online in advance of print. DOI:10.1038/mi.2017.45). Also, BPIFA1 promotes the antibody response to influenza infection and therefore protection from re-infection. Vaccination against influenza relies upon the generation of high titre antibodies. Combining in vitro and in vivo approaches we will determine whether BPIFA1 can enhance (act as an adjuvant to) the antibody response to influenza vaccination and so improve protection to transmission and severe clinical disease. There are 3 specific aims: 1. Can BPIFA1 increase the antibody response to influenza A virus? Recombinant BPIFA1 will be used with influenza vaccines in mice to measure increases in anti-influenza antibody and T cell responses and increased protection against infection/transmission. With our industrial partner, BPIFA1 and/or vaccine will be combined with ProSilic drug delivery technology to see if controlled release enhances the efficacy. Multiple strains of influenza virus will be used to assess protection against heterologous virus strains. We will also perform pathological analyses to see whether administration of BPIFA1 has any consequences in terms of adverse pathology on the mice before and after challenge. 2. Does the effect of BPIFA1 alter with ageing or predispose to disease. To address this, we will use human nasopharyngeal aspirate samples, stratified by age to determine if the level of BPIFA1 decreases with age and whether it correlates with susceptibility to disease. This will be replicated in young and aged mice. We will also determine if BPIFA1 can positively enhance vaccine responses to influenza A in aged mice as in aim 1 above. 3. Does BPIFA1 alter the uptake by antigen-presenting cells To understand mechanism, we will model the human airway using in vitro 3D air-liquid interface cultures. We will add dendritic cells to these, infect with influenza and look at the uptake of virus before and after the knockdown of BPIFA1 and with or without the use of ProSilic. We will also examine the phenotype of dendritic cells that take up virus, and whether BPIFA1 can enhance presentation of influenza proteins to CD4 and CD8 T cells The results will significantly enhance our understanding of anti-viral defence, the inflammatory response during IAV infection and inform the generation of novel vaccines.

季节性流感是呼吸道感染的主要原因，在世界范围内导致大量的发病率、死亡率和经济负担。大流行性流感偶尔出现，是一个重大的全球健康问题。有疫苗和抗病毒药物来对抗流感。然而，由于病毒的快速进化，疫苗需要每年重新配制和重新施用，这带来了相关的经济成本。例如，英国花费了12.4亿英镑准备和应对2009年的大流行。因此，重要的是要了解宿主机制如何调节流感病毒感染，以及如何利用这些机制来开发新的治疗干预措施。这在老年人中尤其重要，其中反应降低意味着每年的流感疫苗接种在该年龄组中效果较差。气道上皮在防御病原体方面起着重要作用，并分泌在先天性和适应性免疫中起作用的蛋白质/肽。BPIFA 1是一种分泌到气道中的蛋白质。监督团队（病毒学家、呼吸生物学家和免疫学家）合作表明，BPFA 1是一种抗病毒肽，可以限制甲型流感病毒对细胞的感染（Mucosal Immunology，在印刷前在线发布。DOI：10.1038/mi.2017.45）。此外，BPIFA 1促进对流感感染的抗体应答，从而防止再次感染。针对流感的疫苗接种依赖于高滴度抗体的产生。结合体外和体内方法，我们将确定BPIFA 1是否可以增强（作为佐剂）对流感疫苗接种的抗体应答，从而提高对传播和严重临床疾病的保护。有三个具体目标：1。BPIFA 1能增加对甲型流感病毒的抗体反应吗？重组BPIFA 1将与小鼠流感疫苗一起使用，以测量抗流感抗体和T细胞应答的增加以及对感染/传播的保护增加。与我们的工业合作伙伴一起，BPIFA 1和/或疫苗将与ProSilic药物递送技术相结合，以观察控释是否会提高疗效。将使用多种流感病毒株评估对异源病毒株的保护作用。我们还将进行病理学分析，以观察在攻击前后施用BPIFA 1是否对小鼠具有任何不良病理学方面的后果。2. BPFA 1的作用是否会随着年龄的增长或疾病的易感性而改变？为了解决这个问题，我们将使用人鼻咽抽吸物样本，按年龄分层，以确定BPIFA 1水平是否随年龄下降，以及它是否与疾病易感性相关。这将在年轻和老年小鼠中复制。我们还将确定BPIFA 1是否可以积极增强老年小鼠对甲型流感的疫苗应答，如上述目的1所述。3. BPIFA 1是否改变抗原呈递细胞的摄取为了理解机制，我们将使用体外3D气液界面培养来模拟人类气道。我们将在这些细胞中加入树突状细胞，感染流感病毒，并观察BPIFA 1敲除前后以及使用或不使用ProSilic的病毒摄取情况。我们还将研究树突状细胞的表型，采取的病毒，以及BPIFA 1是否可以增强流感蛋白的呈递给CD 4和CD 8 T细胞的结果将显着提高我们的抗病毒防御的理解，在IAV感染的炎症反应，并告知新疫苗的产生。