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At least 55 records · Page 3
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies

HIV-specific CD8+ T cells partially control viral replication and delay disease progression, but they rarely provide lasting protection, largely due to immune escape. Here, we show that engrafting mice with memory CD4+ T cells from HIV+ donors uniquely allows for the in vivo evaluation of autologous T cell responses while avoiding graft-versus-host disease and the need for human fetal tissues that limit other models. Treating HIV-infected mice with clinically relevant HIV-specific T cell products resulted in substantial reductions in viremia. In vivo activity was significantly enhanced when T cells were engineered with surface-conjugated nanogels carrying an IL-15 superagonist, but it was ultimately limited by the pervasive selection of a diverse array of escape mutations, recapitulating patterns seen in humans. By applying mathematical modeling, we show that the kinetics of the CD8+ T cell response have a profound impact on the emergence and persistence of escape mutations. This “participant-derived xenograft” model of HIV provides a powerful tool for studying HIV-specific immunological responses and facilitating the development of effective cell-based therapies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Harnessing Nanobodies for Precision Targeting of Proteoforms: Opportunities and Challenges in Therapeutics and Diagnostics

Proteoforms are biologically distinct yet structurally similar proteins that play key roles in driving disease progression but are rarely accounted for in the development of therapeutics and diagnostics. Nanobodies (Nbs) have emerged as a therapeutic and diagnostic “silver bullet” as they possess unique structural and functional attributes that offer advantages over traditional antibodies. One of the most profound advantages of Nbs is the heightened sensitivity and ability to distinguish subtle changes in the conformation of a given protein. Thus, Nbs have significant potential as therapeutic and diagnostic agents that can identify and distinguish specific pathological proteoforms that underlie a given disease. However, there remain significant challenges in obtaining sufficient quantities and purities of specific proteoform antigens that are required for engineering proteoform-specific Nbs. Recent advancements in chemical biology tools for precision proteoform synthesis have made this task feasible for the first time. In this perspective, we discuss the advantages and challenges associated with developing proteoform-specific Nbs and how success in this endeavor will significantly advance the fields of therapeutics and diagnostics.

Antigens↗
DOE OSTI2021

Decoding Cancer Variants of Unknown Significance for Helicase–Nuclease–RPA Complexes Orchestrating DNA Repair During Transcription and Replication

All tumors have DNA mutations, and a predictive understanding of those mutations could inform clinical treatments. However, 40% of the mutations are variants of unknown significance (VUS), with the challenge being to objectively predict whether a VUS is pathogenic and supports the tumor or whether it is benign. To objectively decode VUS, we mapped cancer sequence data and evolutionary trace (ET) scores onto crystallography and cryo-electron microscopy structures with variant impacts quantitated by evolutionary action (EA) measures. As tumors depend on helicases and nucleases to deal with transcription/replication stress, we targeted helicase–nuclease–RPA complexes: (1) XPB-XPD (within TFIIH), XPF-ERCC1, XPG, and RPA for transcription and nucleotide excision repair pathways and (2) BLM, EXO5, and RPA plus DNA2 for stalled replication fork restart. As validation, EA scoring predicts severe effects for most disease mutations, but disease mutants with low ET scores not only are likely destabilizing but also disrupt sophisticated allosteric mechanisms. For sites of disease mutations and VUS predicted to be severe, we found strong co-localization to ordered regions. Rare discrepancies highlighted the different survival requirements between disease and tumor mutations, as well as the value of examining proteins within complexes. In a genome-wide analysis of 33 cancer types, we found correlation between the number of mutations in each tumor and which pathways or functional processes in which the mutations occur, revealing different mutagenic routes to tumorigenesis. We also found upregulation of ancient genes including BLM, which supports a non-random and concerted cancer process: reversion to a unicellular, proliferation-uncontrolled, status by breaking multicellular constraints on cell division. Together, these genes and global analyses challenge the binary “driver” and “passenger” mutation paradigm, support a gradient impact as revealed by EA scoring from moderate to severe at a single gene level, and indicate reduced regulation as well as activity. The objective quantitative assessment of VUS scoring and gene overexpression in the context of functional interactions and pathways provides insights for biology, oncology, and precision medicine.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Distant-acting Enhancers in Development and Disease

Multiple converging lines of evidence from experimental and human genetic studies indicate that both common and rare sequence variants involving enhancers play major roles in Mendelian and complex human disease phenotypes. We use a combination of sequence-based molecular approaches including chromatin mapping and synthesis-enabled modification of enhancer sequences, large-scale transgenic mouse studies (http://enhancer.lbl.gov), and CRISPR genome editing in the mouse model to study the in vivofunction of enhancers in developmental, evolutionary, and disease-related processes. Using examples from our ongoing work, I will illustrate how these methods provide insight into the function and evolution of distant-acting regulatory sequences and offer a starting point for understanding their role in human disease. I will discuss how improved in vivo mouse assays can be used to study candidate pathogenic human mutations in enhancers at scale, revealing the extent to which human genetic studies alone can be insufficient to identify truly causal mutations in enhancers. I will also show how such assays can be used to explore the sensitivity of enhancers that are extremely conserved ("ultraconserved") in evolution to mutations, revealing a remarkable functional robustness to sequence changes that contrasts with apparent evolutionary constraints.

Visel, A↗
DOE OSTI2024

Novel mutation leading to splice donor loss in a conserved site of DMD gene causes Duchenne muscular dystrophy with cryptorchidism

Background As one of the most common congenital abnormalities in male births, cryptorchidism has been found to have a polygenic aetiology according to previous studies of common variants. However, little is known about genetic predisposition of rare variants for cryptorchidism, since rare variants have larger effective size on diseases than common variants. Methods In this study, a cohort of 115 Chinese probands with cryptorchidism was analysed using whole-genome sequencing, alongside 19 parental controls and 2136 unaffected men. Additionally, CRISPR-Cas9 editing of a conserved variant was performed in a mouse model, with MRI screening used to observe the phenotype. Results In 30 of 115 patients (26.1%), we identified four novel genes ( ARSH , DMD , MAGEA4 and SHROOM2 ) affecting at least five unrelated patients and four known genes ( USP9Y , UBA1 , BCORL1 and KDM6A ) with the candidate rare pathogenic variants affecting at least two cases. Burden tests of rare variants revealed the genome-wide significances for newly identified genes (p<2.5×10 −6 ) under the Bonferroni correction. Surprisingly, novel and known genes were mainly found on X chromosome (seven on X and one on Y) and all rare X-chromosomal segregating variants exhibited a maternal inheritance rather than de novo origin. CRISPR-Cas9 mouse modelling of a splice donor loss variant in DMD (NC_000023.11:g.32454661C>G), which resides in a conserved site across vertebrates, replicated bilateral cryptorchidism phenotypes, confirmed by MRI at 4 and 10 weeks. The movement tests further revealed symptoms of Duchenne muscular dystrophy (DMD) in transgenic mice. Conclusion Our results revealed the role of the DMD gene mutation in causing cryptorchidism. The results also suggest that maternal-X inheritance of pathogenic defects could have a predominant role in the development of cryptorchidism.

Chen, Jianhai (ORCID:0000000300932003)↗
DOE OSTI2025

Precipitation of gadolinium from magnetic resonance imaging contrast agents may be the Brass tacks of toxicity

The formation of gadolinium-rich nanoparticles in multiple tissues from intravenous magnetic resonance imaging contrast agents may be the initial step in rare earth metallosis. The mechanism of gadolinium-induced diseases is poorly understood, as is how these characteristic nanoparticles are formed. Gadolinium deposition has been observed with all magnetic resonance imaging contrast agent brands. Aside from endogenous metals and acidic conditions, little attention has been paid to the role of the biological milieu in the degradation of magnetic resonance imaging contrast agents into nanoparticles. Herein, we describe the decomposition of the commercial magnetic resonance imaging contrast agents Omniscan and Dotarem in the presence of oxalic acid, a well-known endogenous compound. Omniscan dechelated rapidly and preluded measurement by the means available, while Dotarem underwent a two-step decomposition process. The decomposition of both magnetic resonance imaging contrast agents by oxalic acid formed gadolinium oxalate (Gd 2 [C 2 O 4 ] 3 , Gd 2 Ox 3 ). Furthermore, both observed steps of the Dotarem reaction involved the associative addition of oxalic acid. Adding protein (bovine serum albumin) increased the rate of dechelation. Displacement reactions could occur at lysosomal pH. Through these studies, we have demonstrated that magnetic resonance imaging contrast agents can be dissociated by endogenous molecules, thus illustrating a metric by which gadolinium-based contrast agents (GBCAs) might be destabilized in vivo.

Gadodiamide↗
DOE OSTI2023

Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability

Accurate predictions of the pathogenicity of mutations associated with genetic diseases are key to the success of precision medicine. Inherited missense mutations in the myocilin (MYOC) gene, within its olfactomedin (OLF) domain, constitute the strongest genetic link to primary open-angle glaucoma via a toxic gain of function, and thus MYOC is an attractive precision-medicine target. However, not all mutations in MYOC cause glaucoma, and common variants are expected to be neutral polymorphisms. The Genome Aggregation Database (gnomAD) lists ~100 missense variants documented within OLF, all of which are relatively rare (allele frequency <0.001%) and nearly all are of unknown pathogenicity. To distinguish disease-causing OLF variants from benign OLF variants, we first characterized the most prevalent population-based variants using a suite of cellular and biophysical assays, and identified two variants with features of aggregation-prone familial disease variants. Next, we considered all available biochemical and clinical data to demonstrate that pathogenic and benign variants can be differentiated statistically based on a single metric: the thermal stability of OLF. Our results motivate genotyping MYOC in patients for clinical monitoring of this widespread, painless and irreversible ocular disease.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

The progeria research foundation 10 th international scientific workshop; researching possibilities, ExTENding lives – webinar version scientific summary

Progeria is an ultra-rare (prevalence 1 in 20 million), fatal, pediatric autosomal dominant premature aging disease caused by a mutation in the LMNA gene. This mutation results in accumulation of a high level of an aberrant form of the nuclear membrane protein, Lamin A. This aberrant protein, termed progerin, accumulates in many tissues and is responsible for the diverse array of disease phenotypes. Children die predominantly from premature atherosclerotic cardiovascular disease. The Progeria Research Foundation’s 10th International Scientific Workshop took place via webinar on November 2 and 3, 2020. Participants from 30 countries joined in this new, virtual meeting format. Patient family presentations led the program, followed by updates on Progeria’s first-ever application for FDA drug approval as well as initial results from the only current Progeria clinical trial. This was followed by presentations of unpublished preclinical data on drugs in development targeting the disease-causing DNA mutation, the aberrant mRNA, progerin protein, and its downstream effector proteins. Tying bench to bedside, clinicians presented new discoveries on the natural history of disease to inform future clinical trial development and new Progeria aortic valve replacement procedures. The program engaged the Progeria research community as a single unit with a common goal – to treat and cure children with Progeria worldwide.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

A Process-based Model with Temperature, Water, and Lab-derived Data Improves Predictions of Daily Culex pipiens/restuans Mosquito Density

While the number of human cases of mosquito-borne diseases has increased in North America in the last decade, accurate modeling of mosquito population density has remained a challenge. Longitudinal mosquito trap data over the many years needed for model calibration, and validation is relatively rare. In particular, capturing the relative changes in mosquito abundance across seasons is necessary for predicting the risk of disease spread as it varies from year to year. We developed a discrete, semi-stochastic, mechanistic process-based mosquito population model that captures life-cycle egg, larva, pupa, adult stages, and diapause for Culex pipiens (Diptera, Culicidae) and Culex restuans (Diptera, Culicidae) mosquito populations. This model combines known models for development and survival into a fully connected age-structured model that can reproduce mosquito population dynamics. Mosquito development through these stages is a function of time, temperature, daylight hours, and aquatic habitat availability. The time-dependent parameters are informed by both laboratory studies and mosquito trap data from the Greater Toronto Area. The model incorporates city-wide water-body gauge and precipitation data as a proxy for aquatic habitat. This approach accounts for the nonlinear interaction of temperature and aquatic habitat variability on the mosquito life stages. We demonstrate that the full model predicts the yearly variations in mosquito populations better than a statistical model using the same data sources. This improvement in modeling mosquito abundance can help guide interventions for reducing mosquito abundance in mitigating mosquito-borne diseases like West Nile virus.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1997

Clinical utility of T-wave alternans

Electrical alternans represents a variation in the morphology of electrocardiographic complexes on an every-other-beat basis in an ABABAB... pattern. Apparent electrical alternans associated with pericardial effusion results from rotation of the heart in the pericardial sac, and not true alternation in electrical conduction patterns. In contrast, true electrical alternans results from an alternation in electrical conduction patterns in the heart itself. Repolarization alternans is true electrical alternans associated with the ST segment and T wave of the electrocardiogram (ECG). Here we will focus on T-wave alternans (TWA) and its association with susceptibility to ventricular tachyarrhythmias. Electrical alternans was reported in the literature as early as 1909. Historically, electrical alternans has been regarded as a fairly rare electrocardiographic abnormality. Case reports of electrical alternans have been associated with a variety of disease states, including acute ischemia, Prinzmetal's angina, a variety of electrolyte abnormalities, and the long QT syndrome. Interestingly, patients born with the prolonged QT syndrome have a very high incidence of sudden cardiac death at an early age. Schwartz and Malliani showed that patients with the prolonged QT syndrome who do not demonstrate alternans at rest, may evidence alternans during stress such as emotional excitement. Thus, over the years electrical alternans has been associated anecdotally with conditions associated with an increased risk of ventricular arrhythmias. In 1948, Kalter reviewed the world literature on electrical alternans and found a total of 41 reported cases. In addition, he reviewed clinical ectrocardiograms from 6059 patients and found five new cases (incidence of less than 1 in 1000 patients). Interestingly, he found a very high mortality, 62%, associated with this condition. Despite the clinical associations reported in the literature, the consensus view of electrical alternans until recent years has been that alternans is an electrocardiographic curiosity rarely encountered in clinical practice which, when identified, does not have specific clinical significance.

Review, Tutorial↗
DOE OSTI2021

Exosomes secreted from mesenchymal stem cells mediate the regeneration of endothelial cells treated with rapamycin by delivering pro-angiogenic microRNAs

Highlights: • MSC-derived exosomes play an important role in promoting endothelial regeneration treated with rapamycin in vitro. • A distinct class of exosomal miRNAs is identified to be tightly related to endothelial regeneration. • The therapeutic effects of MSC-exosomes may be ascribed to the delivery of pro-angiogenic miRNAs to endothelial cells. • MSC-exosomes may serve as a cell-free therapy for clinical treatment of delayed endothelial healing after DES implantation. Delayed endothelial healing after drug eluting stent (DES) implantation is a critical clinical problem in treatment of coronary artery diseases. Exosomes exhibit proangiogenic potential in a variety of ischemic diseases. However, the association of exosomes with endothelial regeneration after DES implantation has been rarely reported. In this study, we aimed to investigate the therapeutic effects of mesenchymal stem cell (MSC)-derived exosomes on endothelial cells treated with rapamycin and explore the potential mechanisms of MSC-derived exosomes in promoting endothelial regeneration. Exosomes were isolated from MSCs by ultracentrifugation and identified by transmission electron microscopy, nanoparticle tracking analysis, and Western blot assay. The in vitro effects of MSC-derived exosomes on the proliferation and migration of endothelial cells treated with rapamycin were evaluated by integrated experiment, cell counting kit-8, scratch, tube formation, and transwell assays. And the apoptosis of rapamycin-induced endothelial cells loaded with MSC-derived exosomes was detected using TUNEL and Annexin-V FITC and PI double-staining assays. The microRNA (miRNA) cargo of MSC-derived exosomes was identified by high-throughput RNA sequencing. Pro-angiogenic miRNAs and key pathways were further characterized. Our results indicated that MSC-derived exosomes could be ingested into umbilical vein endothelial cells (HUVECs) and significantly enhanced cell proliferation rate, migratory and tube-forming capabilities in vitro. MSC-derived exosomes also inhibited the apoptosis of HUVECs induced by rapamycin. A distinct class of exosomal miRNAs was further identified, including six miRNAs tightly related to neovasculogenesis. Silencing the expression of exosomal miRNA-21–5p and let-7c-5p attenuated the pro-proliferative and pro-migratory capacity of MSC-derived exosomes. Moreover, functional enrichment analysis indicated that metabolic pathways might contribute to reendothelialization. This study highlights a proregenerative effect of MSC-derived exosomes in vitro, which may be partly explained by the delivery of pro-angiogenic miRNAs to endothelial cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Characterization of a monoclonal antibody specific to California serogroup orthobunyaviruses and development as a chimeric immunoglobulin M-positive control in human diagnostics

ABSTRACT California serogroup viruses (CSGVs) of medical importance in the United States include La Crosse virus, Jamestown Canyon virus (JCV), California encephalitis virus, and snowshoe hare virus. Current diagnosis of CSGVs relies heavily on serologic techniques for detecting immunoglobulin M (IgM), an indication of a recent CSGV infection. However, human-positive control sera reactive to viruses in the serogroup are scarce because detection of recent infections is rare. Here, we describe the development of new murine monoclonal antibodies (MAbs) reactive to CSGVs and the engineering of a human-murine chimeric antibody by combining the variable regions of the broadly CSGV cross-reactive murine MAb, 3-3B6/2-3B2 and the constant region of the human IgM. MAb 3-3B6/2-3B2 recognizes a tertiary epitope on the Gn/Gc heterodimer, and epitopes important in JCV neutralization were mapped to the Gc glycoprotein. This engineered human IgM constitutively expressed in a HEK-293 stable cell line can replace human-positive control sera in diagnostic serological techniques such as IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA). Compared to the parent murine MAbs, the human-chimeric IgM antibody had identical serological activity to CSGVs in ELISA and demonstrated equivalent reactivity compared to human immune sera in the MAC-ELISA. Importance Orthobunyaviruses in the California serogroup cause severe neurological disease in children and adults. While these viruses are known to circulate widely in North America, their occurrence is rare. Serological testing for CSGVs is hindered by the limited availability and volumes of human-positive specimens needed as controls in serologic assays. Here, we described the development of a murine monoclonal antibody cross-reactive to CSGVs engineered to contain the variable regions of the murine antibody on the backbone of human IgM. The chimeric IgM produced from the stably expressing HEK293 cell line was evaluated for use as a surrogate human-positive control in a serologic diagnostic test.

Microbiology↗
NASA NTRS1977

Space Suit (Mobil Biological Isolation)

A Houston five-year-old known as David is getting a "space suit," a vitally important gift that will give him mobility he has never known. David suffers from a rare malady called severe combined immune deficiency, which means that be was born without natural body defenses against disease; germs that would have little or no effect on most people could cause his death. As a result, he has spent his entire life in germ-free isolation rooms, one at Houston's Texas Children's hospital, another at his home. The "space suit" David is getting will allow him to spend four hours ata a time in a mobile sterile environment outside his isolation rooms. Built by NASA's Johnson Space Center, it is a specially-designed by product of Space Suit technology known as the mobile biological isolation system.

Source record↗
DOE OSTI2024

Fungal elemental profiling unleashed through rapid laser-induced breakdown spectroscopy (LIBS)

ABSTRACT Elemental profiling of fungal species as a phenotyping tool is an understudied topic and is typically performed to examine plant tissue or non-biological materials. Traditional analytical techniques such as inductively coupled plasma–optical emission spectroscopy (ICP-OES) and inductively coupled plasma–mass spectrometry (ICP-MS) have been used to identify elemental profiles of fungi; however, these techniques can be cumbersome due to the difficulty of preparing samples. Additionally, the instruments used for these techniques can be expensive to procure and operate. Laser-induced breakdown spectroscopy (LIBS) is an alternative elemental analytical technique—one that is sensitive across the periodic table, easy to use on various sample types, and is cost-effective in both procurement and operation. LIBS has not been used on axenic filamentous fungal isolates grown in substrate media. In this work, as a proof of concept, we used LIBS on two genetically distinct fungal species grown on a nutrient-rich and nutrient-poor substrate media to determine whether robust elemental profiles can be detected and whether differences between the fungal isolates can be identified. Our results demonstrate a distinct correlation between fungal species and their elemental profile, regardless of the substrate media, as the same strains shared a similar uptake of carbon, zinc, phosphorus, manganese, and magnesium, which could play a vital role in their survival and propagation. Independently, each fungal species exhibited a unique elemental profile. This work demonstrates a unique and valuable approach to rapidly phenotype fungi through optical spectroscopy, and this approach can be critical in understanding these fungi's behavior and interactions with the environment. IMPORTANCE Historically, ionomics, the elemental profiling of an organism or materials, has been used to understand the elemental composition in waste materials to identify and recycle heavy metals or rare earth elements, identify the soil composition in space exploration on the moon or Mars, or understand human disorders or disease. To our knowledge, ionomic profiling of microbes, particularly fungi, has not been investigated to answer applied and fundamental biological questions. The reason is that current ionomic analytical techniques can be laborious in sample preparation, fail to measure all potential elements accurately, are cost-prohibitive, or provide inconsistent results across replications. In our previous efforts, we explored whether laser-induced breakdown spectroscopy (LIBS) could be used in determining the elemental profiles of poplar tissue, which was successful. In this proof-of-concept endeavor, we undertook a transdisciplinary effort between applied and fundamental mycology and elemental analytical techniques to address the biological question of how LIBS can used for fungi grown axenically in a nutrient-rich and nutrient-poor environment.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Assessing complexity and dynamics in epidemics: geographical barriers and facilitators of foot-and-mouth disease dissemination

Introduction: Physical and non-physical processes that occur in nature may influence biological processes, such as dissemination of infectious diseases. However, such processes may be hard to detect when they are complex systems. Because complexity is a dynamic and non-linear interaction among numerous elements and structural levels in which specific effects are not necessarily linked to any one specific element, cause-effect connections are rarely or poorly observed. Methods: To test this hypothesis, the complex and dynamic properties of geo-biological data were explored with high-resolution epidemiological data collected in the 2001 Uruguayan foot-and-mouth disease (FMD) epizootic that mainly affected cattle. County-level data on cases, farm density, road density, river density, and the ratio of road (or river) length/county perimeter were analyzed with an open-ended procedure that identified geographical clustering in the first 11 epidemic weeks. Two questions were asked: (i) do geo-referenced epidemiologic data display complex properties? and (ii) can such properties facilitate or prevent disease dissemination? Results: Emergent patterns were detected when complex data structures were analyzed, which were not observed when variables were assessed individually. Complex properties–including data circularity–were demonstrated. The emergent patterns helped identify 11 counties as ‘disseminators’ or ‘facilitators’ (F) and 264 counties as ‘barriers’ (B) of epidemic spread. In the early epidemic phase, F and B counties differed in terms of road density and FMD case density. Focusing on non-biological, geographical data, a second analysis indicated that complex relationships may identify B-like counties even before epidemics occur. Discussion: Geographical barriers and/or promoters of disease dispersal may precede the introduction of emerging pathogens. If corroborated, the analysis of geo-referenced complexity may support anticipatory epidemiological policies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Uncovering heterogeneous intercommunity disease transmission from neutral allele frequency time series

The COVID-19 pandemic has underscored the need for accurate epidemic forecasting to predict pathogen spread, evolution, and evaluate intervention strategies. Forecast reliability hinges on detailed knowledge of disease transmission across population segments, which may be inferred from contact surveys or mobility data. However, these indirect approaches make it difficult to estimate rare transmissions between socially or geographically distant communities. We show that the steep ramp-up of genome sequencing surveillance during the pandemic can be leveraged to directly identify transmission patterns between geographically defined communities. Our approach uses a hidden Markov model to infer the fraction of infections a community imports from others based on how rapidly allele frequencies in the focal community converge to those in the donor communities. Applying this method to SARS-CoV-2 sequencing data from England and the United States, we uncover networks of intercommunity transmission that reflect geographical relationships while exposing significant long-range interactions. The scaling of importation rate with distance is consistent across both countries, yet weaker than expected based on mobility data, highlighting limitations of indirect inference. We show that transmission patterns can change between waves of variants of concern and analyze how the inferred heterogeneity in intercommunity transmission impacts evolutionary forecasts. While applied here to geographically defined communities, our approach could be applied to those defined by other traits (e.g., age, socioeconomic status), provided time-series data can be stratified accordingly. Overall, our study highlights population genomic time series data as a crucial record of epidemiological interactions, which can be deciphered using tree-free inference methods.

Okada, Takashi [Department of Physics; University ↗
DOE OSTI2020

Cross-Neutralization of a SARS-CoV-2 Antibody to a Functionally Conserved Site Is Mediated by Avidity

Most antibodies isolated from individuals with coronavirus disease 2019 (COVID-19) are specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here, we determined a crystal structure of the COVA1-16 antibody fragment (Fab) with the SARS-CoV-2 receptor-binding domain (RBD) and negative-stain electron microscopy reconstructions with the spike glycoprotein trimer to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long complementarity-determining region (CDR) H3, and competes with the angiotensin-converting enzyme 2 (ACE2) receptor because of steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with the structural and functional rationale for epitope conservation, provide insights for development of more universal SARS-like coronavirus vaccines and therapies.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Delineating the mechanism of anti-Lassa virus GPC-A neutralizing antibodies

Lassa virus (LASV) is the etiologic agent of Lassa Fever, a hemorrhagic disease that is endemic to West Africa. During LASV infection, LASV glycoprotein (GP) engages with multiple host receptors for cell entry. Neutralizing antibodies against GP are rare and principally target quaternary epitopes displayed only on the metastable, pre-fusion conformation of GP. Currently, the structural features of the neutralizing GPC-A antibody competition group are understudied. Structures of two GPC-A antibodies presented here demonstrate that they bind the side of the pre-fusion GP trimer, bridging the GP1 and GP2 subunits. Complementary biochemical analyses indicate that antibody 25.10C, which is broadly specific, neutralizes by inhibiting binding of the endosomal receptor LAMP1 and also by blocking membrane fusion. The other GPC-A antibody, 36.1F, which is lineage-specific, prevents LAMP1 association only. These data illuminate a site of vulnerability on LASV GP and will guide efforts to elicit broadly reactive therapeutics and vaccines.

59 BASIC BIOLOGICAL SCIENCES↗