Biology subjects

yewdell, j.

Publications and source records attributed to yewdell, j..

4 recordsLinked to original sources

bioRxiv2025

Antibodies, Memory B Cells, and Antigen Valency Reshape B Cell Responses to Drifted Influenza Virus Vaccination

Antigenic drift in influenza A virus hemagglutinin (HA) limits humoral protective immunity. Here, we combine cell fate mapping with adoptive transfer of antigenic-site-specific antibodies (Abs) and memory B cells (MBCs) with moderately drifted HA vaccination in mice to better understand how this influences immune escape and protective responses. We demonstrate that drift in vaccine antigens affects MBC reactivation and naive B cell responses in germinal centers (GC). Strikingly, passively transferred monoclonal and polyclonal Abs suppress cognate epitope-specific GC B cell responses only when the vaccine antigen was multivalent while responses to monovalent recombinant trimeric HA remain unaffected. Using MBC and Abs co-transfer we unveil that antigenic site-specific suppression is more potent in blocking MBC rather than naive B cells entry into GC. In addition, we show that MBC hamper naive B cell recruitment to GC even in the absence of antibody transfer through local differentiation and Ab release in the responding lymph node. Altogether, our study reveals that serum Ab feedback depends on vaccine valency, while pre-existing MBC alone without Abs present can reshape immunodominance of naive B cells, with critical practical implications for rational universal influenza vaccine design.

immunology↗

bioRxiv2024

Influenza virus antibodies inhibit antigen-specific de novo B cell responses in mice

Antibody responses to influenza vaccines tend to be focused on epitopes encountered during prior influenza exposures, with little production of de novo responses to novel epitopes. To examine the contribution of circulating antibody to this phenomenon, we passively transferred a hemagglutinin (HA)-specific monoclonal antibody (mAb) into mice before immunizing with whole inactivated virions. The HA mAb inhibited de novo HA-specific antibodies, plasmablasts, germinal center B cells, and memory B cells, while responses to a second antigen in the vaccine, neuraminidase (NA), were uninhibited. The HA mAb potently inhibited de novo antibody responses against epitopes near the HA mAb binding site. The HA mAb also promoted IgG1 class switching, an effect that, unlike the inhibition of HA responses, relied on signaling through Fc-gamma receptors. These studies suggest that circulating antibodies inhibit de novo B cell responses in an antigen-specific manner, which likely contributes to differences in antibody specificities elicited during primary and secondary influenza virus exposures.

immunology↗

bioRxiv2023

C1q Enables Influenza HA Stem Binding Antibodies to Block Viral Attachment and Broadens the Antibody Escape Repertoire

Broadly neutralizing, anti-hemagglutinin stem antibodies (Abs) are a promising universal influenza vaccine target. While anti-stem Abs are not believed to block viral attachment, we show that C1q confers attachment inhibition and boosts fusion and neuraminidase inhibition, greatly enhancing virus neutralization activity in vitro and in mice challenged with influenza virus via the respiratory route. These effects reflect increased steric interference and not increased Ab avidity. Remarkably, C1q greatly expands the anti-stem Ab viral escape repertoire to include residues throughout the hemagglutinin. Some substitutions cause antigenic alterations in the globular region or modulate HA receptor avidity. We also show that C1q enhances the neutralization activity of non-RBD anti-SARS-CoV-2 Spike Abs, an effect dependent on Spike density on the virion surface. Together, our findings show that first, Ab function must be considered in a physiological context and second, inferring the exact selection pressure for Ab-driven viral evolution is risky business, at best.

microbiology↗

bioRxiv2021

Modeling SARS-CoV-2 and Influenza Infections and Antiviral Treatments in Human Lung Epithelial Tissue Equivalents

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the third coronavirus in less than 20 years to spillover from an animal reservoir and cause severe disease in humans. High impact respiratory viruses such as pathogenic beta-coronaviruses and influenza viruses, as well as other emerging respiratory viruses, pose an ongoing global health threat to humans. There is a critical need for physiologically relevant, robust and ready to use, in vitro cellular assay platforms to rapidly model the infectivity of emerging respiratory viruses and discover and develop new antiviral treatments. Here, we validate in vitro human alveolar and tracheobronchial tissue equivalents and assess their usefulness as in vitro assay platforms in the context of live SARS-CoV-2 and influenza A virus infections. We establish the cellular complexity of two distinct tracheobronchial and alveolar epithelial air liquid interface (ALI) tissue models, describe SARS-CoV-2 and influenza virus infectivity rates and patterns in these ALI tissues, the viral-induced cytokine production as it relates to tissue-specific disease, and demonstrate the pharmacologically validity of these lung epithelium models as antiviral drug screening assay platforms.

microbiology↗