Biology subjects

Gibbs, J. S.

Publications and source records attributed to Gibbs, J. S..

6 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↗

bioRxiv2022

NEDD8 activity is important for direct antigen MHC class I antigen presentation

Successful direct MHC class I antigen presentation is dependent on the protein degradation machinery of the cell to generate antigenic peptides which can be loaded onto MHC class I molecules for surveillance by CD8+ T cells of the immune system. Most often this process involves the ubiquitin-proteasome system, however other ubiquitin-like (UBL) proteins have also been implicated in protein degradation and direct antigen presentation. Here, we examine the role of neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) in direct antigen presentation. NEDD8 is the UBL with highest similarity to ubiquitin and fusion of NEDD8 to the amino-terminus of a target protein can lead to the target proteins degradation. We find that appending NEDD8 to the N-terminus of the model antigen ovalbumin resulted in degradation by both the proteasome and autophagy protein degradation pathways, but only proteasomal degradation, involving the proteasomal subunit NEDD8 ultimate buster 1 (NUB1), resulted in peptide presentation. When directly compare to ubiquitin, NEDD8-fusion was less efficient at generating peptides. However, inactivation of the NEDD8-conugation machinery by treating cells with MLN4924, inhibited the presentation of peptides from Defective Ribosomal Products (DRiPs) derived from a model antigen. These results demonstrate that NEDD8 activity in the cell is important for direct antigen presentation, but not by directly targeting proteins for degradation.

immunology↗

bioRxiv2018

Neuraminidase Inhibition Contributes to Influenza A Virus Neutralization by Anti-Hemagglutinin Stem Antibodies

Broadly neutralizing antibodies (Abs) that bind the influenza virus hemagglutinin (HA) stem may enable universal influenza vaccination. Here, we show that anti-stem Abs sterically inhibit viral neuraminidase activity against large substrates, with activity inversely proportional to the length of the fibrous NA stalk that supports the enzymatic domain. By modulating NA stalk length in recombinant IAVs, we show that anti-stem Abs inhibit virus release from infected cells by blocking NA, accounting for their in vitro neutralization activity. NA inhibition contributes to anti-stem Ab protection in influenza infected mice, likely due at least in part to NA-mediated inhibition of Fc{gamma}R dependent activation of innate immune cells by antibody bound to virions. FDA approved NA inhibitors enhance anti-stem based Fc{gamma} dependent immune cell activation, raising the possibility of therapeutic synergy between NA inhibitors and anti-stem mAb treatment in humans.

microbiology↗

bioRxiv2017

Hemagglutinin Glycan Clock Guides Human Influenza A Virus Evolution

Adaptive immunity to influenza A virus is limited by frequent mutations in the immunodominant head of hemagglutinin (HA). Over the last century, the upward trend in HA-head glycosylation indicates glycan addition can increase fitness, but its role in viral evolution remains unclear. Here, we report glycan evolution follows a clock-like rhythm, pacing the timeline, trajectory, and replacement of HA. Following pandemic introduction, glycans are added to HA at 4- to 6-year intervals, until a functional glycan limit is reached, after which, at 9- to 12-year intervals, glycans are either swapped between different sites, or the HA is replaced by a novel pandemic virus. Using this, we predicted the appearance of the newest glycan on pH1N1 HA. Phylogeographic reconstruction suggests these highly fit strains originated in the Middle East, before rapidly replacing all strains globally. Going forward, we can use this simple algorithm to forecast future glycan evolution and identify seasons with higher pandemic potential.

microbiology↗