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

呼吸道感染是人类健康的主要威胁。其中，流感病毒是一个重大的医学挑战，每年导致300多万例严重疾病和50万例死亡。此外，这种病毒的高度变异性继续引起人们对潜在致命疫情的担忧。100多年前进行的开创性研究证明了预先存在的抗体在预防疾病方面的巨大潜力。这些早期的工作表明，抗体从免疫动物转移到幼稚宿主保护他们免受致命剂量的流感病毒株。重要的是，最有效的结果是当抗体被直接施用到肺部的气道时，病毒复制发生在那里。这些和随后的研究不仅确定了抗体提供抗流感免疫力的潜力，而且还证明了抗体定位于感染部位作为实现最佳结果的主要因素的重要性。因此，更好地了解肺内局部增加抗体滴度的机制可能有助于指导新的和更有效的疫苗策略的开发，以防止流感变种的传播。在这里，我们的目标是探索一个独特的记忆B细胞亚群，几年前已被发现在小鼠和人类感染流感病毒后的肺内发育。这些细胞被命名为常驻记忆B（BRM）细胞，因为它们仍然局限于肺组织，可能表明在保护这个器官的专门作用。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活体成像方法，使我们能够直接在流感感染小鼠的活肺中观察BRM细胞在其自然环境中的行为。使用这些方法，我们发现在二次感染时，BRM细胞被迅速募集到感染部位，随后在病毒复制发生的区域内分化成产生抗体的浆细胞。这些发现揭示了一种新的机制，能够使抗体直接在肺部感染部位快速和高度定位分泌。 在这项提案中，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抗体产生细胞，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和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，在某些自身免疫性疾病、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性疾病背景下抗体产生的新疗法的开发。

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.