Biology subjects

Maurer, D. P.

Publications and source records attributed to Maurer, D. P..

8 recordsLinked to original sources

bioRxiv2026

Egyptian rousette bat humoral immunity to H9 influenza hemagglutinin

In mammals, antibodies are central to antiviral defense, but they can also impose selective pressure that drives viral evolution. The interplay between viral antigenic variation and host antibody diversification constitutes a molecular arms race that influences pathogenicity, transmission, and spillover risk. Bats are reservoirs for zoonotic viruses with pandemic potential yet they appear to tolerate infection without overt disease. Although distinctive features of bat innate immunity have been described, the role of adaptive immunity--particularly antibody-mediated responses--remains largely undefined. Moreover, how antibody evolutionary pressure operates in bats is unknown, in part because tools to interrogate bat B cell responses at the monoclonal level are limited. Here, we developed a yeast surface display library of bat antibodies derived from splenic RNA of wild-caught Egyptian rousette bats to interrogate humoral responses to the bat-derived H9 influenza hemagglutinin. We isolated monoclonal antibodies recognizing the hemagglutinin (HA) antigen and defined their gene usage, somatic hypermutation frequency, binding affinities, and breadth. We then used cryo-EM to structurally characterize three bat antibodies in complex with HA engaging distinct antigenic sites. Together, these data enable direct comparison with human anti-influenza antibodies highlighting similarities in humoral immunity across mammals and provides a tool to examine bat antibody responses to other potential zoonotic viruses.

immunology↗

bioRxiv2024

Conserved sites on the influenza H1 and H3 hemagglutinin recognized by human antibodies

Monoclonal antibodies (mAbs) targeting the influenza hemagglutinin (HA) have the potential to be used as prophylactics or templates for next-generation vaccines that provide broad protection. Here, we isolated broad, subtype-neutralizing mAbs from human B cells targeting the H1 or H3 HA head as well as a unique mAb targeting the stem. The H1 mAbs target the previously defined lateral patch epitope on H1 HAs and recognize HAs from 1933 to 2021 in addition to a swine H1N1 virus with pandemic potential. Using directed evolution, we improved the neutralization potency of these H1 mAbs towards a contemporary H1 strain. Using deep mutational scanning of four antigenically distinct H1N1 viruses, we identified potential viral escape pathways. For the H3 mAbs we used cryo-EM to define the targeted epitopes: one mAb recognizes the side of the H3 head, accommodating the N133 glycan and a pocket underneath the receptor binding site. The other H3 mAb recognizes an epitope in the HA stem that overlaps with previously characterized mAbs, but with distinct antibody variable genes and mode of recognition. Collectively, these mAbs identify common sites recognized by broad, subtype-specific mAbs that may be elicited by next-generation vaccines.

immunology↗

bioRxiv2024

Antigenic drift expands viral escape pathways from imprinted host humoral immunity

An initial virus exposure can imprint antibodies such that future responses to antigenically drifted strains are dependent on the identity of the imprinting strain. Subsequent exposure to antigenically distinct strains followed by affinity maturation can guide immune responses toward generation of cross-reactive antibodies. How viruses evolve in turn to escape these imprinted broad antibody responses is unclear. Here, we used clonal antibody lineages from two human donors recognizing conserved influenza virus hemagglutinin (HA) epitopes to assess viral escape potential using deep mutational scanning. We show that even though antibody affinity maturation does restrict the number of potential escape routes in the imprinting strain through repositioning the antibody variable domains, escape is still readily observed in drifted strains and attributed to epistatic networks within HA. These data explain how influenza virus continues to evolve in the human population by escaping even broad antibody responses.

immunology↗

bioRxiv2024

Crimean-Congo Hemorrhagic Fever Survivors Elicit Protective Non-Neutralizing Antibodies that Target 11 Overlapping Regions on Viral Glycoprotein GP38

Crimean-Congo hemorrhagic fever virus can cause lethal disease in humans yet there are no approved medical countermeasures. Viral glycoprotein GP38, unique to Nairoviridae, is a target of protective antibodies, but extensive mapping of the human antibody response to GP38 has not been previously performed. Here, we isolated 188 GP38-specific antibodies from human survivors of infection. Competition experiments showed that these antibodies bind across five distinct antigenic sites, encompassing eleven overlapping regions. Additionally, we reveal structures of GP38 bound with nine of these antibodies targeting different antigenic sites. Although GP38-specific antibodies were non-neutralizing, several antibodies were found to have protection equal to or better than murine antibody 13G8 in two highly stringent rodent models of infection. Together, these data expand our understanding regarding this important viral protein and inform the development of broadly effective CCHFV antibody therapeutics.

immunology↗

bioRxiv2024

Lupus-associated innate receptors drive extrafollicular evolution of autoreactive B cells

In systemic lupus erythematosus, recent findings highlight the extrafollicular (EF) pathway as prominent origin of autoantibody-secreting cells (ASCs). CD21loCD11c+ B cells, associated with aging, infection, and autoimmunity, are contributors to autoreactive EF ASCs but have an obscure developmental trajectory. To study EF kinetics of autoreactive B cell in tissue, we adoptively transferred WT and gene knockout B cell populations into the 564Igi mice - an autoreactive host enriched with autoantigens and T cell help. Time-stamped analyses revealed TLR7 dependence in early escape of peripheral B cell tolerance and establishment of a pre-ASC division program. We propose CD21lo cells as precursors to EF ASCs due to their elevated TLR7 sensitivity and proliferative nature. Blocking receptor function reversed CD21 loss and reduced effector cell generation, portraying CD21 as a differentiation initiator and a possible target for autoreactive B cell suppression. Repertoire analysis further delineated proto-autoreactive B cell selection and receptor evolution toward self-reactivity. This work elucidates receptor and clonal dynamics in EF development of autoreactive B cells, and establishes modular, native systems to probe mechanisms of autoreactivity.

immunology↗

bioRxiv2023

A modular platform to display multiple hemagglutinin subtypes on a single immunogen

Next-generation influenza vaccines aim to elicit cross-reactive humoral responses to multiple influenza subtypes. Such increased breadth would not only improve seasonal vaccines but may afford universal protection against influenza subtypes including those with pandemic potential. Here, we describe a "beads-on-a-string" (BOAS) immunogen, that tandemly links up to eight distinct hemagglutinin (HA) head domains from circulating and non-circulating influenzas. These BOAS are immunogenic in the murine model and elicit comparable serum responses to each individual component. Notably, we also find that BOAS elicit cross-reactive responses to influenza subtypes not included in the immunizing immunogen. Furthermore, BOAS conjugation to protein-based ferritin nanoparticles does not significantly augment serum responses suggesting that our BOAS platform is sufficient for eliciting cross-reactive responses without off-target effects induced by the nanoparticle scaffold. Finally, vaccination with a mixture of the same HA head domains is not sufficient to elicit the same neutralization profile as the BOAS immunogens or nanoparticles. This mix-and-match immunogen design strategy is a robust platform for eliciting responses to multiple influenza subtypes via a single immunogen, and a potential platform for other viral glycoproteins.

immunology↗

bioRxiv2022

Hierarchical sequence-affinity landscapes shape the evolution of breadth in an anti-influenza receptor binding site antibody

Broadly neutralizing antibodies (bnAbs) that neutralize diverse variants of a particular virus are of considerable therapeutic interest1. Recent advances have enabled us to isolate and engineer these antibodies as therapeutics, but eliciting them through vaccination remains challenging, in part due to our limited understanding of how antibodies evolve breadth2. Here, we analyze the landscape by which an anti-influenza receptor binding site (RBS) bnAb, CH65, evolved broad affinity to diverse H1 influenza strains3, 4. We do this by generating an antibody library of all possible evolutionary intermediates between the unmutated common ancestor (UCA) and the affinity-matured CH65 antibody and measure the affinity of each intermediate to three distinct H1 antigens. We find that affinity to each antigen requires a specific set of mutations - distributed across the variable light and heavy chains - that interact non-additively (i.e., epistatically). These sets of mutations form a hierarchical pattern across the antigens, with increasingly divergent antigens requiring additional epistatic mutations beyond those required to bind less divergent antigens. We investigate the underlying biochemical and structural basis for these hierarchical sets of epistatic mutations and find that epistasis between heavy chain mutations and a mutation in the light chain at the VH-VL interface is essential for binding a divergent H1. Collectively, this work is the first to comprehensively characterize epistasis between heavy and light chain mutations and shows that such interactions are both strong and widespread. Together with our previous study analyzing a different class of anti-influenza antibodies5, our results implicate epistasis as a general feature of antibody sequence-affinity landscapes that can potentiate and constrain the evolution of breadth.

evolutionary biology↗

bioRxiv2020

Broad sarbecovirus neutralizing antibodies define a key site of vulnerability on the SARS-CoV-2 spike protein

Broadly protective vaccines against known and pre-emergent coronaviruses are urgently needed. Critical to their development is a deeper understanding of cross-neutralizing antibody responses induced by natural human coronavirus (HCoV) infections. Here, we mined the memory B cell repertoire of a convalescent SARS donor and identified 200 SARS-CoV-2 binding antibodies that target multiple conserved sites on the spike (S) protein. A large proportion of the antibodies display high levels of somatic hypermutation and cross-react with circulating HCoVs, suggesting recall of pre-existing memory B cells (MBCs) elicited by prior HCoV infections. Several antibodies potently cross-neutralize SARS-CoV, SARS-CoV-2, and the bat SARS-like virus WIV1 by blocking receptor attachment and inducing S1 shedding. These antibodies represent promising candidates for therapeutic intervention and reveal a new target for the rational design of pan-sarbecovirus vaccines.

immunology↗