Defining a Role for Atypical B Cells in RV-Induced Exacerbations of Allergic Asthma

/ABSTRACT Asthma is the second most common chronic respiratory disease worldwide. Nearly 8% of the entire US population has asthma, a significant burden for public health. Most Americans have allergic asthma, which is characterized by an underlying type-2 inflammatory response to allergens. All types of asthma are associated with disease exacerbations; frequent exacerbations link to lung function decline in adulthood, suggesting a chronic inflammatory process driven by these events. The most frequent trigger of asthma exacerbations is respiratory viral infections, and up to 80% of viral exacerbations are caused by rhinoviruses (RV)—the primary cause of the “common cold”. Work from the Woodfolk lab has demonstrated that increased numbers of RV- specific T cells correlate with worse lung function in subjects with allergic asthma, even in the absence of infection. Moreover, RV-specific T cell responses during infection were significantly amplified in subjects with allergic asthma compared to healthy controls. Despite these striking findings relating to T cells, little is known about the nature of RV-specific B cells in subjects with asthma or how B cells might contribute to persistent inflammation in the disease. Our lab has previous investigated the phenotype and temporal dynamics of B cells responding to RV infection in healthy subjects. We demonstrated that the majority of cross-strain B cell memory to RV display an atypical B cell phenotype (T-bet+CXCR5-), are rapidly recruited to the upper airways in response to infection, and rapidly produce IgG. These data led to my core hypothesis that atypical memory B cells are magnified and dysregulated in subjects with allergic asthma due to the influence of the allergic inflammatory milieu, and moreover, that the extent of this dysregulation is linked to disease severity. To address my hypothesis, I propose to 1) define the pro-inflammatory nature of circulating RV-specific atypical B cells in subjects with allergic asthma stratified by the severity of their disease, and 2) investigate how type-2 cytokines influence the expansion and pro-inflammatory functions of RV-responsive atypical B cells in vivo. I will leverage a powerful experimental human RV infection model, novel analytical pipelines, and cutting-edge integrative systems immunology techniques to address these aims. By using human models of investigation and integration with clinical measures we are uniquely poised for translation into clinical practice. Moreover, knowledge generated by these studies will inform the development of therapeutics designed to mitigate post- viral sequalae in allergic asthma. The highly collaborative training environment in the Woodfolk lab and the Division of Allergy is uniquely suited for the pursuit of complex human immunology projects. I am privileged to access the advice and mentorship of an inter-disciplinary team of translational and basic science investigators with expertise in asthma pathophysiology. Completion of this project will further my training and career goals by exposing me to cutting-edge high dimensional analysis and systems immunology techniques with wide applicability. Project Number: 1F31AI188883-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Paul Dell | Institution: UNIVERSITY OF VIRGINIA, CHARLOTTESVILLE, VA | Award Amount: $38,921 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F07B-C (21)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31AI18888301A1