Biology subjects

Davidson, E.

Publications and source records attributed to Davidson, E..

At least 19 recordsLinked to original sources

bioRxiv2026

Convergent IGHV3-53/3-66 antibodies elicited by Omicron BA.1 infection broadly neutralize emerging SARS-CoV-2 variants

Natural SARS-CoV-2 infections or vaccinations induce neutralizing antibodies (nAbs) offer protection from severe disease. The shared use of IGHV3-53/3-66 genes makes this class of monoclonal antibodies (mAbs) a public clonotype and is well established, but the evolution and structural basis of how these public antibodies maintain broad binding and acquire potent neutralizing activity is not completely understood. To understand how these features are facilitated by the IGHV3-53/3-66 germline segments and enhanced by somatic mutations, we investigated the biology of a panel of 242 human mAbs isolated from an individual infected with SARS-CoV-2 BA.1 strain and recovered. Interestingly, a mAb designated COV2-3731 encoded by IGHV3-53/IGKV1-33 retained potent neutralizing activity against SARS-CoV-2 variants BA.2.86, JN.1, KP.2, BA.3.2, and, to some extent, KP.3. Studies using deep mutational scanning with a BA.2 lentiviral library and determination of the structural complex of the BA.2 S protein and COV2-3731 Fab fragments using cryo-EM revealed key contact residues. Further, germline revertant analysis of the COV2-3731 mAb provided additional insights into how this COV2-3731 and other IGHV3-53/3-66-encoded public antibodies evolve to gain breadth against antigenically distinct SARS-CoV-2 variants such as BA.2.86, JN.1, KP.2, and BA.3.2.

immunology↗

bioRxiv2026

Thalamocortical orchestration of human theory of mind

Reasoning about others thoughts or beliefs is central to human social behavior. This ability, known as theory of mind (ToM), has been primarily attributed to cortical regions of the default network (DN). However, whether and how subcortical structures, particularly the thalamus, contribute to this high-level computation remains unknown. Here, we investigated human thalamocortical dynamics during a naturalistic ToM movie watching condition, taking a rare dual-modality approach by combining high-field 7T fMRI and intracranial stereoelectroencephalography (sEEG). Across both modalities, ToM events reliably activated the DN, whereas the thalamus lacked canonical local activation. Despite this absence of local activation, the thalamus shared ToM-related representational structure and exhibited enhanced bidirectional interactions with the DN during mentalizing across methods. Crucially, sEEG revealed that the thalamus coordinated DN activity via cross-frequency phase-amplitude coupling (PAC), whereby thalamic low-frequency phase unidirectionally modulated DN high-frequency activity. Furthermore, the strength of thalamic-DN PAC predicted both the activity magnitude and the representational quality of ToM-related information within the dorsomedial DN subsystem. Together, these findings identify the human thalamus as a regulatory hub that gates DN computations during ToM without exhibiting observable localized activity, revealing a previously unrecognized mechanism by which thalamic dynamics coordinate high-level social cognition in humans.

neuroscience↗

bioRxiv2026

Estradiol modulates neuronal network hyperexcitability in select NDD risk genes

Sex hormone signaling during neurodevelopment may act as a modulator of risk for neurodevelopmental disorders (NDDs), including autism spectrum disorders (ASDs). By conducting a systematic and multi-modal evaluation of estradiol effects across loss-of-function deletions in 36 functionally diverse, large-effect ASD/NDD genes in human induced pluripotent stem cell-derived neurons and larval zebrafish, we uncover convergent and divergent gene-by-estradiol interactions at the transcriptomic, circuit, and behavioral levels. Whereas estradiol partially ameliorates dysregulated expression signatures across all ASD/NDD gene knockouts examined, it selectively and rapidly dampens network hyperexcitability phenotypes in only a subset of ASD/NDD gene knockouts. Two genes, ASH1L and SCN2A, are particularly responsive to estradiol treatment, with dramatic rescue of molecular and cellular effects in human knockout neurons, coupled with behavioral phenotypes in larval zebrafish mutants. The seven most estradiol responsive genes show enhanced protein-protein interaction network connectivity, strong co-expression in specific postnatal time periods, and enrichment in upper-layer mature excitatory neurons. Altogether, we describe distinct estradiol rescue in different modalities, elucidating shared transcriptomic effects as well as gene-specific cellular and behavioral rescue in the context of loss of function mutations of select ASD/NDD genes.

genomics↗

bioRxiv2024

Dynamic convergence of autism disorder risk genes across neurodevelopment

Over three hundred and seventy-three risk genes, broadly enriched for roles in neuronal communication and gene expression regulation, underlie risk for autism spectrum disorder (ASD) and developmental delay (DD). Functional genomic studies of subsets of these genes consistently indicate a convergent role in neurogenesis, but how these diverse risk genes converge on a smaller number of biological pathways in mature neurons is unclear. To uncover shared downstream impacts between neurodevelopmental disorder (NDD) risk genes, here we apply a pooled CRISPR approach to contrast the transcriptomic impacts of targeting 29 NDD loss-of-function genes across human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells, glutamatergic neurons, and GABAergic neurons. Points of convergence vary between the cell types of the brain and are greatest in mature glutamatergic neurons, where they broadly target not just synaptic and epigenetic, but unexpectedly, mitochondrial biology. The strongest convergent networks occur between NDD genes with common co-expression patterns in the post-mortem brain, biological annotations, and clinical associations, suggesting that convergence may one-day inform patient stratification and treatment. Towards this, ten out of eleven drugs tested that were predicted to reverse convergent signatures in human cells and/or arousal and sensory processing behaviors in zebrafish ameliorated at least one behavioral phenotype in vivo. Altogether, robust convergence in post-mitotic neurons represents a clinically actionable therapeutic window.

genetics↗

bioRxiv2023

Single B cell transcriptomics identifies multiple isotypes of broadly neutralizing antibodies against flaviviruses

Sequential dengue virus (DENV) infections often generate neutralizing antibodies against all four DENV serotypes and sometimes, Zika virus. Characterizing cross-flavivirus broadly neutralizing antibody (bnAb) responses can inform countermeasure strategies that avoid infection enhancement associated with non-neutralizing antibodies. Here, we used single cell transcriptomics to mine the bnAb repertoire following secondary DENV infection. We identified several new bnAbs with comparable or superior breadth and potency to known bnAbs, and with distinct recognition determinants. Unlike all known flavivirus bnAbs, which are IgG1, one newly identified cross-flavivirus bnAb (F25.S02) was derived from IgA1. Both IgG1 and IgA1 versions of F25.S02 and known bnAbs displayed neutralizing activity, but only IgG1 enhanced infection in monocytes expressing IgG and IgA Fc receptors. Moreover, IgG-mediated enhancement of infection was inhibited by IgA1 versions of bnAbs. We demonstrate a role for IgA in flavivirus infection and immunity with implications for vaccine and therapeutic strategies.

microbiology↗

bioRxiv2023

Multi-Omic Signatures of Sarcoidosis and Progression in Bronchoalveolar Lavage Cells

IntroductionSarcoidosis is a heterogeneous, granulomatous disease that can prove difficult to diagnose, with no accurate biomarkers of disease progression. Therefore, we profiled and integrated the DNA methylome, mRNAs, and microRNAs to identify molecular changes associated with sarcoidosis and disease progression that might illuminate underlying mechanisms of disease and potential genomic biomarkers. MethodsBronchoalveolar lavage cells from 64 sarcoidosis subjects and 16 healthy controls were used. DNA methylation was profiled on Illumina HumanMethylationEPIC arrays, mRNA by RNA-sequencing, and miRNAs by small RNA-sequencing. Linear models were fit to test for effect of diagnosis and phenotype, adjusting for age, sex, and smoking. We built a supervised multi-omics model using a subset of features from each dataset. ResultsWe identified 46,812 CpGs, 1,842 mRNAs, and 5 miRNAs associated with sarcoidosis versus controls and 1 mRNA, SEPP1 - a protein that supplies selenium to cells, associated with disease progression. Our integrated model emphasized the prominence of the PI3K/AKT1 pathway in sarcoidosis, which is important in T cell and mTOR function. Novel immune related genes and miRNAs including LYST, RGS14, SLFN12L, and hsa-miR-199b-5p, distinguished sarcoidosis from controls. Our integrated model also demonstrated differential expression/methylation of IL20RB, ABCC11, SFSWAP, AGBL4, miR-146a-3p, and miR-378b between non-progressive and progressive sarcoidosis. ConclusionsLeveraging the DNA methylome, transcriptome, and miRNA-sequencing in sarcoidosis BAL cells, we detected widespread molecular changes associated with disease, many which are involved in immune response. These molecules may serve as diagnostic/prognostic biomarkers and/or drug targets, although future testing will be required for confirmation.

genomics↗

bioRxiv2022

Broadly neutralizing antibodies target the coronavirus fusion peptide

The potential for future coronavirus outbreaks highlights the need to develop strategies and tools to broadly target this group of pathogens. Here, using an epitope-agnostic approach, we identified six monoclonal antibodies that bound to spike proteins from all seven human-infecting coronaviruses. Epitope mapping revealed that all six antibodies target the conserved fusion peptide region adjacent to the S2 cleavage site. Two antibodies, COV44-62 and COV44-79, broadly neutralize a range of alpha and beta coronaviruses, including SARS-CoV-2 Omicron subvariants BA.1 and BA.2, albeit with lower potency than RBD-specific antibodies. In crystal structures of Fabs COV44-62 and COV44-79 with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine at the S2 cleavage site. Importantly, COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings identify the fusion peptide as the target of the broadest neutralizing antibodies in an epitope-agnostic screen, highlighting this site as a candidate for next-generation coronavirus vaccine development. One-Sentence SummaryRare monoclonal antibodies from COVID-19 convalescent individuals broadly neutralize coronaviruses by targeting the fusion peptide.

immunology↗

bioRxiv2022

Systematic analysis of human antibody response to ebolavirus glycoprotein reveals high prevalence of neutralizing public clonotypes

Understanding the human antibody response to emerging viral pathogens is key to epidemic preparedness. As the size of the B cell response to a pathogenic virus protective antigen is undefined, we performed deep paired heavy and light chain sequencing in EBOV-GP specific memory B cells, allowing analysis of the ebolavirus-specific antibody repertoire both genetically and functionally. This approach facilitated investigation of the molecular and genetic basis for evolution of cross-reactive antibodies by elucidating germline-encoded properties of antibodies to EBOV and identification of the overlap between antibodies in the memory B-cell and serum repertoire. We identified 73 public clonotypes to EBOV, 20% of which encoded antibodies with neutralization activity and capacity to protect in vivo. This comprehensive analysis of the public and private antibody repertoire provides insight into the molecular basis of the humoral immune response to EBOV-GP, which informs vaccine design of new vaccines and improved therapeutics.

immunology↗

bioRxiv2022

An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer

The protective human antibody response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus focuses on the spike (S) protein which decorates the virion surface and mediates cell binding and entry. Most SARS-CoV-2 protective antibodies target the receptor- binding domain or a single dominant epitope ( supersite) on the N terminal domain (NTD). Here, using the single B cell technology LIBRA-seq, we isolated a large panel of NTD-reactive and SARS-CoV-2 neutralizing antibodies from an individual who had recovered from COVID-19. We found that neutralizing antibodies to the NTD supersite commonly are encoded by the IGHV1-24 gene, forming a genetic cluster that represents a public B cell clonotype. However, we also discovered a rare human antibody, COV2-3434, that recognizes a site of vulnerability on the SARS-CoV-2 S protein in the trimer interface and possesses a distinct class of functional activity. COV2-3434 disrupted the integrity of S protein trimers, inhibited cell-to-cell spread of virus in culture, and conferred protection in human ACE2 transgenic mice against SARS-CoV-2 challenge. This study provides insight about antibody targeting of the S protein trimer interface region, suggesting this region may be a site of virus vulnerability.

immunology↗

bioRxiv2021

Potent neutralization of SARS-CoV-2 variants of concern by an antibody with a unique genetic signature and structural mode of spike recognition

The emergence of novel SARS-CoV-2 lineages that are more transmissible and resistant to currently approved antibody therapies poses a considerable challenge to the clinical treatment of COVID-19. Therefore, the need for ongoing discovery efforts to identify broadly reactive monoclonal antibodies to SARS-CoV-2 is of utmost importance. Here, we report a panel of SARS-CoV-2 antibodies isolated using the LIBRA-seq technology from an individual who recovered from COVID-19. Of these antibodies, 54042-4 showed potent neutralization against authentic SARS-CoV-2 viruses, including variants of concern (VOCs). A cryo-EM structure of 54042-4 in complex with the SARS-CoV-2 spike revealed an epitope composed of residues that are highly conserved in currently circulating SARS-CoV-2 lineages. Further, 54042-4 possesses unique genetic and structural characteristics that distinguish it from other potently neutralizing SARS-CoV-2 antibodies. Together, these findings motivate 54042-4 as a lead candidate for clinical development to counteract current and future SARS-CoV-2 VOCs.

immunology↗

bioRxiv2021

Convergent antibody responses to the SARS-CoV-2 spike protein in convalescent and vaccinated individuals

Unrelated individuals can produce genetically similar clones of antibodies, known as public clonotypes, which have been seen in responses to different infectious diseases as well as healthy individuals. Here we identify 37 public clonotypes in memory B cells from convalescent survivors of SARS-CoV-2 infection or in plasmablasts from an individual after vaccination with mRNA-encoded spike protein. We identified 29 public clonotypes, including clones recognizing the receptor-binding domain (RBD) in the spike protein S1 subunit (including a neutralizing, ACE2-blocking clone that protects in vivo), and others recognizing non-RBD epitopes that bound the heptad repeat 1 region of the S2 domain. Germline-revertant forms of some public clonotypes bound efficiently to spike protein, suggesting these common germline-encoded antibodies are preconfigured for avid recognition. Identification of large numbers of public clonotypes provides insight into the molecular basis of efficacy of SARS-CoV-2 vaccines and sheds light on the immune pressures driving the selection of common viral escape mutants.

immunology↗

bioRxiv2021

Neutralizing and protective human monoclonal antibodies recognizing the N-terminaldomain of the SARS-CoV-2 spike protein

Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes.

immunology↗

bioRxiv2020

A novel antigenic site spanning domains I and III of the Zika virus envelope glycoprotein is the target of strongly neutralizing human monoclonal antibodies

Zika virus (ZIKV), a mosquito-transmitted flavivirus, caused a large epidemic in Latin America between 2015 and 2017. Effective ZIKV vaccines and treatments are urgently needed to prevent future epidemics and severe disease sequelae. People infected with ZIKV develop strongly neutralizing antibodies linked to viral clearance and durable protective immunity. To understand mechanisms of protective immunity and to support the development of ZIKV vaccines, here we characterize the properties of a strongly neutralizing antibody, B11F, isolated from a recovered ZIKV patient. Our results indicate that B11F targets a complex epitope on the virus that spans domains I and III of the envelope glycoprotein. While previous studies point to quaternary epitopes centered on domain II of ZIKV E glycoprotein as targets of strongly neutralizing and protective human antibodies, we uncover a new site spanning domain I and III as a target of strongly neutralizing human antibodies. ImportancePeople infected with Zika virus develop durable neutralizing antibodies that prevent repeat infections. In the current study, we characterize a ZIKV-neutralizing human monoclonal antibody isolated from a patient after recovery. Our studies establish a novel site on the viral envelope targeted by human neutralizing antibodies. Our results are relevant to understanding how antibodies block infection and for guiding the design and evaluation of candidate vaccines.

immunology↗

bioRxiv2020

Convergence of a common solution to broad ebolavirus neutralization by glycan cap directed human antibodies

Antibodies that target the glycan cap epitope on ebolavirus glycoprotein (GP) are common in the adaptive response of survivors. A subset is known to be broadly neutralizing, but the details of their epitopes and basis for neutralization is not well-understood. Here we present cryo-electron microscopy (cryo-EM) structures of several glycan cap antibodies that variably synergize with GP base-binding antibodies. These structures describe a conserved site of vulnerability that anchors the mucin-like domains (MLD) to the glycan cap, which we name the MLD-anchor and cradle. Antibodies that bind to the MLD-cradle share common features, including the use of IGHV1-69 and IGHJ6 germline genes, which exploit hydrophobic residues and form beta-hairpin structures to mimic the MLD-anchor, disrupt MLD attachment, destabilize GP quaternary structure and block cleavage events required for receptor binding. Our results collectively provide a molecular basis for ebolavirus neutralization by broadly reactive glycan cap antibodies.

immunology↗

bioRxiv2020

An affinity-matured human monoclonal antibody targeting fusion loop epitope of dengue virus with in vivo therapeutic potency

Dengue virus (DENV), from the genus flavivirus of the family flaviviridae, causes serious health problems globally. Human monoclonal antibodies (HuMAb) can be used to elucidate the mechanisms of neutralization and antibody-dependent enhancement (ADE) of DENV infections, leading to the development of a vaccine or therapeutic antibodies. Here, we generated eight HuMAb clones from an Indonesian patient infected with DENV. These HuMAbs exhibited the typical characteristics of weak neutralizing antibodies including high cross-reactivity with other flaviviruses and targeting of the fusion loop epitope (FLE). However, one of the HuMAbs, 3G9, exhibited strong neutralization ability (NT50 < 0.1 {micro}g/ml) and possessed a high somatic hyper-mutation rate of the variable region, indicating affinity-maturation. Administration of this antibody significantly improved the survival rate of interferon-/{beta}/{gamma} receptor knockout C57BL/6 mice after a lethal DENV challenge. Additionally, Fc-modified 3G9 molecules that had lost their in vitro ADE activity showed significantly enhanced therapeutic potency in vivo and competed strongly with an ADE-prone antibody in vitro. Taken together, the affinity-matured FLE-targeting antibody 3G9 exhibits several promising features for therapeutic application including a low NT50 value, potential for pan-flavivirus infection treatment, and suppression of ADE. This study demonstrates the therapeutic potency of affinity-matured FLE-targeting antibodies.

microbiology↗

bioRxiv2020

Integrated technology platform for accelerated discovery of antiviral antibody therapeutics

The emergence and reemergence of highly virulent viral pathogens with pandemic potential has created an urgent need for accelerated discovery of antiviral therapeutics. Antiviral human monoclonal (mAbs) are promising drug candidates to prevent or treat severe viral diseases, but the long timelines needed for discovery limits their rapid deployment and use. Here, we report the development of an integrated sequence of technologies incorporating advances in single-cell mRNA sequence analysis, bioinformatics, synthetic biology, and high-throughput functional analysis that allowed us to discover highly potent antiviral human mAbs and validate their activity in vivo at an unprecedented scale, speed, and efficiency. In a 78-day study, modeling deployment of a rapid response platform to an outbreak, we isolated >100 individual Zika virus (ZIKV) specific human mAbs, assessed their function, identified 29 broadly-neutralizing mAbs, and verified therapeutic potency of lead candidates with antibody-encoding mRNA formulation and/or IgG protein delivery in mice and nonhuman primates. Our work provides a roadmap for the rapid antibody discovery programs against viral pathogens of global concern.

immunology↗

bioRxiv2020

Antigenicity, stability, and reproducibility of Zika reporter virus particles for long-term applications

The development of vaccines against flaviviruses, including Zika virus (ZIKV) and dengue virus (DENV), continues to be a major challenge, hindered by the lack of efficient and reliable methods for screening neutralizing activity of sera or antibodies. To address this need, we previously developed a plasmid-based, replication-incompetent DENV reporter virus particle (RVP) production system as an efficient and safe alternative to the Plaque Reduction Neutralization Test (PRNT). As part of the response to the 2015-2016 ZIKV outbreak, we recently developed pseudo-infectious ZIKV RVPs by modifying our DENV RVP system. The use of ZIKV RVPs as critical reagents in human clinical trials requires their further validation using stability and reproducibility metrics for large-scale applications. In the current study, we validated ZIKV RVPs using infectivity, neutralization, and enhancement assays with monoclonal antibodies (MAbs) and human ZIKV-positive patient serum. ZIKV RVPs are antigenically identical to live virus based on binding ELISA and neutralization results and are nonreplicating based on the results of plaque formation assays. We demonstrate reproducible neutralization titer data (NT50 values) across different RVP production lots, volumes, time frames, and laboratories. We also show RVP stability across experimentally relevant time intervals and temperatures. Our results demonstrate that ZIKV RVPs provide a safe, rapid, and reproducible reagent for large-scale, long-term studies of neutralizing antibodies and sera, which can facilitate large-scale screening and epidemiological studies to help expedite ZIKV vaccine development. AUTHOR SUMMARYZIKV is a mosquito-borne virus that can cause severe birth defects and other disorders. Large outbreaks of ZIKV occurred in 2015 and 2016 and there are still no drugs or vaccines available to protect against ZIKV infection. Vaccine development has been hindered by the lack of safe and efficient methods to screen ZIKV neutralizing properties of patient sera or antibodies, especially in the context of large clinical trials. To address this unmet need, we developed and validated the use of ZIKV reporter virus particles (RVPs), a safe, high-throughput and quantitative alternative to using live virus for neutralization studies. We show that ZIKV RVPs are stable, show lot-to-lot consistency and provide reproducible neutralization data that is suitable for large-scale studies are needed for development of a ZIKV vaccine, epidemiologic surveillance, and high-throughput screening.

microbiology↗

bioRxiv2019

Functional characterization and lineage analysis of broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics

Eliciting broadly neutralizing antibodies (bNAbs) against the four dengue virus serotypes (DENV1-4) that are spreading into new territories is an important goal of vaccine design. To delineate bNAb targets, we characterized 28 monoclonal antibodies belonging to expanded and hypermutated clonal families identified by transcriptomic analysis of single plasmablasts from DENV-infected individuals. Among these, we identified two somatically related bNAbs that potently neutralized DENV1-4. Mutagenesis studies revealed that the major recognition determinants of these bNAbs are in E protein domain I, distinct from the only known class of human bNAbs against flaviviruses with a well-defined epitope. B cell repertoire analysis from acute-phase peripheral blood suggested a memory origin and divergent somatic hypermutation pathways for these bNAbs, and a limited number of mutations was sufficient for neutralizing activity. Our study suggests multiple B cell evolutionary pathways leading to DENV bNAbs targeting a novel epitope that can be exploited for vaccine design.

microbiology↗