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49 records · Page 3
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Proteo-Genomic Analysis Identifies Two Major Sites of Vulnerability on Ebolavirus Glycoprotein for Neutralizing Antibodies in Convalescent Human Plasma

Three clinically relevant ebolaviruses – Ebola (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) viruses, are responsible for severe disease and occasional deadly outbreaks in Africa. The largest Ebola virus disease (EVD) epidemic to date in 2013-2016 in West Africa highlighted the urgent need for countermeasures, leading to the development and FDA approval of the Ebola virus vaccine rVSV-ZEBOV (Ervebo ® ) in 2020 and two monoclonal antibody (mAb)-based therapeutics (Inmazeb ® [atoltivimab, maftivimab, and odesivimab-ebgn] and Ebanga ® (ansuvimab-zykl) in 2020. The humoral response plays an indispensable role in ebolavirus immunity, based on studies of mAbs isolated from the antibody genes in peripheral blood circulating ebolavirus-specific human memory B cells. However, antibodies in the body are not secreted by circulating memory B cells in the blood but rather principally by plasma cells in the bone marrow. Little is known about the protective polyclonal antibody responses in convalescent plasma. Here we exploited both single-cell antibody gene sequencing and proteomic sequencing approaches to assess the composition of the ebolavirus glycoprotein (GP)-reactive antibody repertoire in the plasma of an EVD survivor. We first identified 1,512 GP-specific mAb variable gene sequences from single cells in the memory B cell compartment. Using mass spectrometric analysis of the corresponding GP-specific plasma IgG, we found that only a portion of the large B cell antibody repertoire was represented in the plasma. Molecular and functional analysis of proteomics-identified mAbs revealed recognition of epitopes in three major antigenic sites - the GP head domain, the glycan cap, and the base region, with a high prevalence of neutralizing and protective mAb specificities that targeted the base and glycan cap regions on the GP. Polyclonal plasma antibodies from the survivor reacted broadly to EBOV, BDBV, and SUDV GP, while reactivity of the potently neutralizing mAbs we identified was limited mostly to the homologous EBOV GP. Together these results reveal a restricted diversity of neutralizing humoral response in which mAbs targeting two antigenic sites on GP – glycan cap and base – play a principal role in plasma-antibody-mediated protective immunity against EVD.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Quantification of heterogeneity in human CD8 + T cell responses to vaccine antigens: an HLA-guided perspective

Vaccines have historically played a pivotal role in controlling epidemics. Effective vaccines for viruses causing significant human disease, e.g., Ebola, Lassa fever, or Crimean Congo hemorrhagic fever virus, would be invaluable to public health strategies and counter-measure development missions. Here, we propose coverage metrics to quantify vaccine-induced CD8 + T cell-mediated immune protection, as well as metrics to characterize immuno-dominant epitopes, in light of human genetic heterogeneity and viral evolution. Proof-of-principle of our approach and methods are demonstrated for Ebola virus, SARS-CoV-2, and Burkholderia pseudomallei (vaccine) proteins.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Omics-Lethal Human Viruses, Interferon-Stimulated Response Experiment IFNaCL001

The purpose of this experiment was to evaluate the host interferon-stimulated cellular response to interferon alpha (IFNα) treatment. Sample data was obtained from human lung adenocarcinoma cells (Calu-3) treated with or without IFNα for mRNA and miRNA transcriptome expression analysis. Secondary host-associated viral dataset downloads contain one or more statistically processed (normalization data transformation) quantitative dataset collections resulting in qualitative expression analyses of primary host-pathogen experimental study designs. Transcriptomics dataset download have a direct relationship to a primary sample submission corresponding to a specific interferon response to viral infection.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

A compendium of multi-omics data illuminating host responses to lethal human virus infections

Human infections caused by viral pathogens trigger a complex gamut of host responses that limit disease, resolve infection, generate immunity, and contribute to severe disease or death. Here, we present experimental methods and multi-omics data capture approaches representing the global host response to infection generated from 45 individual experiments involving human viruses from the Orthomyxoviridae, Filoviridae, Flaviviridae, and Coronaviridae families. Analogous experimental designs were implemented across human or mouse host model systems, longitudinal samples were collected over defined time courses, and global multi-omics data (transcriptomics, proteomics, metabolomics, and lipidomics) were acquired by microarray, RNA sequencing, or mass spectrometry analyses. For comparison, we have included transcriptomics datasets from cells treated with type I and type II human interferon. Raw multi-omics data and metadata were deposited in public repositories, and we provide a central location linking the raw data with experimental metadata and ready-to-use, quality-controlled, statistically processed multi-omics datasets not previously available in any public repository. This compendium of infection-induced host response data for reuse will be useful for those endeavouring to understand viral disease pathophysiology and network biology.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Glycan shield of the ebolavirus envelope glycoprotein GP

The envelope glycoprotein GP of the ebolaviruses is essential for host cell entry and the primary target of the host antibody response. GP is heavily glycosylated with up to 17 N-linked sites, numerous O-linked glycans in its disordered mucin-like domain (MLD), and three predicted C-linked mannosylation sites. Glycosylation is important for host cell attachment, GP stability and fusion activity, and shielding from neutralization by serum antibodies. Here, we use glycoproteomics to profile the site-specific glycosylation patterns of ebolavirus GP. We detect up to 16 unique O-linked glycosylation sites in the MLD, and two O-linked sites in the receptor-binding GP1 subunit. Multiple O-linked glycans are observed within N-linked glycosylation sequons, suggesting crosstalk between the two types of modifications. We confirmed C-mannosylation of W288 in full-length trimeric GP. We find complex glycosylation at the majority of N-linked sites, while the conserved sites N257 and especially N563 are enriched in unprocessed glycans, suggesting a role in host-cell attachment via DC-SIGN/L-SIGN. Our findings illustrate how N-, O-, and C-linked glycans together build the heterogeneous glycan shield of GP, guiding future immunological studies and functional interpretation of ebolavirus GP-antibody interactions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Handheld Biosensor for COVID-19 Screening

We have made significant progress toward the development of an integrated nucleic acid amplification system for Autonomous Medical Devices Incorporated (AMDIs) Optikus handheld diagnostic device. In this effort, we developed a set of loop-mediated isothermal amplification (LAMP) primers for SARS-CoV-2 and then demonstrate amplification directly on a surface acoustic wave (SAW) sensor. We built associated hardware and developed a C-code to control the amplification process. The goal of this project was to develop a nucleic amplification assay that is compatible with SAW sensors to enable both nucleic and serological testing in a single handheld diagnostic device. Toward this goal, AMDI is collaborating Sandia National Laboratories to develop a rapid, portable diagnostic screening device that utilizes Sandias unique surface acoustic wave biosensor (SAW) for COVID-19 detection. Previously, the SANDIA- AMDI SAW sensor has successfully detected multiple high-profile bacteria viruses, including Ebola, HIV, Sin Nombre, and Anthrax. Over the last two years, AMDI and SANDIA have significantly improved the sensitivity and detection capability of the SAW biosensor and have also developed a modular hand-held, portable platform called the Optikus, which uses CD microfluidics and handheld instrumentation to automate all sample preparation, reagent introduction, sample delivery, and measurement for a number of different assay targets. We propose to use this platform for the development of a rapid (%3C30 minutes), point-of-care diagnostic test for detection of COVID-19 from nasal swab samples.

47 OTHER INSTRUMENTATION↗
DOE OSTI2022

Editorial: Nanotechnology for natural products

Humans around the globe have lived through an unprecedented time. The emergence and rapid spread of coronavirus disease 2019 (COVID-19) have resulted in the loss of millions of lives, and this number is still climbing every day and hour. As a consequence, there have been drastic changes over the past two years in how we live, communicate, and work, some of which may have changed forever: remote conferencing has become a new norm for businesses, schools, and academia; work-from-home and hybrid working is now more than just acceptable in many industries; most importantly, COVID-19 has raised global awareness of infectious diseases and pandemic responses to an exceptional level. Certainly, COVID-19 is not the only disease that is causing human suffering at this moment. Other highly contagious and lethal viruses, such as the human immunodeficiency virus (HIV), Ebola, and the recent addition to the list, Monkeypox, pose extraordinary challenges to modern civilizations. On the other hand, non-communicable diseases, such as heart disease, stroke, and cancer, are still claiming the majority of deaths on a global level (World Health Organization, 2020). Before the availability of synthetic drugs, civilizations worldwide relied on natural products extracted from the environment and various organisms for healthcare. Natural products and their derivatives continue to be critical components in the drug library available today. Indeed, almost a quarter of the new drugs approved by the US Food and Drug Administration (FDA) since 1981 are natural products, botanical mixtures, or their derivatives (Newman and Cragg, 2020). Recent developments in analytical characterization, genome mining, and engineering have further increased interest in drug discovery from the pool of natural products (Atanasov et al., 2021). This Research Topic celebrates a collection of studies at the intersection of natural product research and nanotechnological advances. As a successor and extension of the Research Topic in “Nanotechnology in Traditional Medicines and Natural Products” published last year (Zhang et al., 2021), the present collection focused more on recent developments in employing the synthesis and characterization of nanostructures for the delivery of functional natural products. Specifically, the use of carrier nanostructures to conjugate or encapsulate therapeutically active natural products with carrier nanostructures could enable their robust, targeted delivery tailored to either tackle a specific disease or unlock a drug administration pathway. Over the last decade, nanostructures such as liposomes (Pattni et al., 2015) and lipid nanoparticles (Hou et al., 2021) have been developed as versatile platforms for the inclusion and delivery of a wide range of therapeutical compounds; a significant advance in this aspect is the stabilization of mRNA strands for COVID-19 vaccination recently produced by Pfizer/BioNTech and Moderna (Tenchov et al., 2021). Such engineered nanomaterials are now widely used in the development of new drugs, while regulatory forces, such as the US FDA, remain cautious with the evaluation of each product on a case-by-case basis (Wang and Grainger, 2022). In this collection, Zeng et al. provided a timely review of natural products conjugated to and contained within nanomaterials for the ongoing COVID-19 pandemic. Natural products that are potentially useful in the mitigation of this disease, such as chloroquine and curcumin, supported in nanocarrier systems, have been discussed in detail. More broadly, Cheng et al. comprehensively reviewed the use of liposomes as a nanocarrier for natural products. This article provides a summary of natural product compounds and extracts used to form liposomal structures. Readers can further enjoy the practical aspects of these engineered drugs for the treatment of specific diseases as well as insights into future directions in this field.

peptides↗
DOE OSTI2021

Targeted disruption of pi–pi stacking in Malaysian banana lectin reduces mitogenicity while preserving antiviral activity

Lectins, carbohydrate-binding proteins, have been regarded as potential antiviral agents, as some can bind glycans on viral surface glycoproteins and inactivate their functions. However, clinical development of lectins has been stalled by the mitogenicity of many of these proteins, which is the ability to stimulate deleterious proliferation, especially of immune cells. We previously demonstrated that the mitogenic and antiviral activities of a lectin (banana lectin, BanLec) can be separated via a single amino acid mutation, histidine to threonine at position 84 (H84T), within the third Greek key. The resulting lectin, H84T BanLec, is virtually non-mitogenic but retains antiviral activity. Decreased mitogenicity was associated with disruption of pi–pi stacking between two aromatic amino acids. To examine whether we could provide further proof-of-principle of the ability to separate these two distinct lectin functions, we identified another lectin, Malaysian banana lectin (Malay BanLec), with similar structural features as BanLec, including pi–pi stacking, but with only 63% amino acid identity, and showed that it is both mitogenic and potently antiviral. We then engineered an F84T mutation expected to disrupt pi–pi stacking, analogous to H84T. As predicted, F84T Malay BanLec (F84T) was less mitogenic than wild type. However, F84T maintained strong antiviral activity and inhibited replication of HIV, Ebola, and other viruses. The F84T mutation disrupted pi–pi stacking without disrupting the overall lectin structure. These findings show that pi–pi stacking in the third Greek key is a conserved mitogenic motif in these two jacalin-related lectins BanLec and Malay BanLec, and further highlight the potential to rationally engineer antiviral lectins for therapeutic purposes.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2003

The Forest, The Fly, and the Virus?

All known outbreaks of Ebola have been linked to tropical forests. We undertook a study of environmental conditions associated with Ebola hemorrhagic fever after preliminary reports strongly suggested that simultaneous outbreaks occurred, during two limited time periods in the 1970s and 1990s, immediately following sudden transitions between dry and wet seasons.

Tucker, Compton J.↗
DOE OSTI2020

Quantifying the contribution of Fc-mediated effector functions to the antiviral activity of anti–HIV-1 IgG1 antibodies in vivo

In combating viral infections, the Fab portion of an antibody could mediate virus neutralization, whereas Fc engagement of Fc-γ receptors (FcγRs) could mediate an array of effector functions. Evidence abounds that effector functions are important in controlling infections by influenza, Ebola, or HIV-1 in animal models. However, the relative contribution of virus neutralization versus effector functions to the overall antiviral activity of an antibody remains unknown. To address this fundamental question in immunology, here we utilized our knowledge of HIV-1 dynamics to compare the kinetics of the viral load decline (ΔVL) in infected animals given a wild-type (WT) anti–HIV-1 immunoglobulin G1 (IgG1) versus those given a Fc-Null variant of the same antibody. In three independent experiments in HIV-1–infected humanized mice and one pivotal experiment in simian–human immunodeficiency virus (SHIV)-infected rhesus macaques, an earlier and sharper decline in viral load was consistently detected for the WT antibody. Quantifications of the observed differences indicate that Fc-mediated effector functions accounted for 25–45% of the total antiviral activity in these separate experiments. In this study, Fc-mediated effector functions have been quantified in vivo relative to the contribution of virus neutralization mediated by the Fab.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Machine learning guided selection of broad-spectrum epitope-specific functional antibodies for "Disease X"

Our project established and demonstrated a transfer learning framework that enables prediction of antibody–antigen interactions across related viruses. The approach focused on three major activities: 1. Conserved region and epitope identification – We compared viral protein structures and sequences to identify shared receptor-binding domains and neutralizing epitope regions across variants and related viruses. These conserved features formed the foundation for discovering broadly functional antibodies. 2. Machine learning model development – We built neural network–based models that integrate epitope features with antibody sequence information. Instead of relying solely on structural or physical properties, the models learned transferable patterns that describe antibody binding potential across different viral families. 3. Transfer learning and validation – Using SARS-CoV-2 and Ebola as source systems, we successfully transferred learned epitope features to predict antibody interactions for SARS CoV-1 and Marburg virus. Iterative cycles of dataset generation, retraining, and evaluation improved generalization and predictive power, ensuring the framework can adapt to new threats.

59 BASIC BIOLOGICAL SCIENCES↗