权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Orchestrating resident memory B cell responses in the lung during secondary infection with influenza virus

流感病毒继发感染期间协调肺部常驻记忆 B 细胞反应

基本信息

批准号：
MR/X000117/1
负责人：
Tal Arnon
金额：
$ 86.24万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FX000117%2F1
关键词：
Orchestrating resident memory cell responses

项目摘要

Respiratory infections present major threat for human health. Among those, influenza virus represents a significant medical challenge, inducing over 3 million cases of severe illness and 500,000 deaths per annum. Moreover, the highly mutable nature of this virus continues to raise concerns of a potential deadly outbreak. Pioneering studies carried out more than 100 years ago demonstrated the enormous potential of pre-existing antibodies for preventing the disease. These early works demonstrated that transfer of antibodies from immunized animals into naïve hosts protects them from lethal doses of influenza strains. Importantly, the most effective results were obtained when the antibodies were administrated directly into the airways of the lungs, where viral replication takes place. These and subsequent studies not only established the potential of antibodies to provide immunity against influenza, but also demonstrated the importance of antibodies being localised to sites of infection as a major factor in achieving optimal results. Better understanding of mechanisms that increase antibody titres locally within the lung may therefore help to guide the development of new and more effective vaccine strategies to prevent the spread of influenza variants.Here we aim to explore a unique subset of memory B cells that has been discovered a few years ago to develop within the lungs of mice and humans following infection with influenza virus. These cells were named resident memory B (BRM) cells because they remain confined to the lung tissue, likely indicating a specialized role in protecting this organ. To study this newly identified memory B cell subset, our lab developed novel mouse models and advanced live imaging approaches that allow us to visualize BRM cell behaviour directly within their natural environment, in live lungs of influenza infected mice. Using these methods, we discovered that upon secondary infection, BRM cells are quickly recruited to sites of infection and subsequently differentiate into antibody producing plasma cells within regions where viral replication takes place. These findings uncover a new mechanism that enables rapid and highly localized secretion of antibodies directly within infected sites in the lung. In this proposal, we aim to identify the molecular mechanisms that regulate this process. We will ask how BRM cells successfully navigate towards infected sites within the lung, how they differentiate into antibody producing cells in these regions and how they contribute to the establishment of short- and long-term humoral immunity against influenza virus. We anticipate that these studies will help to develop new vaccines against influenza and, possibly, other pulmonary pathogens. Moreover, since in some cases antibodies can also cause diseases (e.g., in the case of some autoimmune diseases, allergies or cancer), our findings may help to guide the development of novel therapies aiming to prevent antibody production in the context of immunological disorders.

呼吸道感染是人类健康的主要威胁。其中，流感病毒是一项重大的医疗挑战，每年造成300多万例严重疾病和50万例死亡。此外，这种病毒的高度易变性继续引起人们对可能爆发致命疫情的担忧。100多年前开展的开创性研究表明，预先存在的抗体在预防这种疾病方面具有巨大潜力。这些早期的工作表明，将免疫动物的抗体转移到naïve宿主中可以保护它们免受致命剂量的流感病毒株的侵害。重要的是，最有效的结果是当抗体直接进入肺部气道时获得的，那里发生病毒复制。这些和随后的研究不仅确定了抗体提供抗流感免疫的潜力，而且还证明了抗体定位于感染部位的重要性，这是实现最佳结果的主要因素。因此，更好地了解增加肺内局部抗体滴度的机制可能有助于指导开发新的和更有效的疫苗策略，以防止流感变体的传播。在这里，我们的目标是探索几年前发现的记忆B细胞的一个独特亚群，该亚群在感染流感病毒后在小鼠和人类的肺部发育。这些细胞被命名为常驻记忆B （BRM）细胞，因为它们被限制在肺组织中，可能表明它们在保护这个器官方面起着特殊的作用。为了研究这种新发现的记忆B细胞亚群，我们的实验室开发了新的小鼠模型和先进的实时成像方法，使我们能够在感染流感的小鼠的活肺中直接观察BRM细胞在自然环境中的行为。使用这些方法，我们发现在继发性感染时，BRM细胞迅速被招募到感染部位，随后在病毒复制发生的区域内分化为产生抗体的浆细胞。这些发现揭示了一种新的机制，可以在肺部感染部位直接快速和高度局部地分泌抗体。在本提案中，我们的目标是确定调节这一过程的分子机制。我们将探讨BRM细胞如何成功地导航到肺内的感染部位，它们如何在这些区域分化为产生抗体的细胞，以及它们如何有助于建立针对流感病毒的短期和长期体液免疫。我们预计，这些研究将有助于开发针对流感以及可能的其他肺部病原体的新疫苗。此外，由于在某些情况下抗体也可以引起疾病（例如，在一些自身免疫性疾病，过敏或癌症的情况下），我们的发现可能有助于指导旨在预防免疫疾病背景下抗体产生的新疗法的发展。