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

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.