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At least 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Dysregulation of lung epithelial cell homeostasis and immunity contributes to Middle East respiratory syndrome coronavirus disease severity

Coronaviruses (CoV) emerge suddenly from animal reservoirs to cause novel diseases in new hosts. Discovered in 2012, the Middle East respiratory syndrome coronavirus (MERS-CoV) is endemic in camels in the Middle East and is continually causing local outbreaks and epidemics. While all three newly emerging human CoVs from the past 20 years (SARS-CoV, SARS-CoV-2, and MERS-CoV) cause respiratory disease, each CoV has unique host interactions that drive differential pathogeneses. To better understand the virus and host interactions driving lethal MERS-CoV infection, we performed a longitudinal multi-omics analysis of sublethal and lethal MERS-CoV infection in mice. Significant differences were observed in body weight loss, virus titers, and acute lung injury among lethal and sub-lethal virus doses. Virus-induced apoptosis of type I and II alveolar epithelial cells suggests that loss or dysregulation of these key cell populations was a major driver of severe disease. Omics analysis suggested differential pathogenesis was multi-factorial with clear differences among innate and adaptive immune pathways as well as those that regulate lung epithelial homeostasis. Infection of mice lacking functional T and B cells showed that adaptive immunity was important in controlling viral replication but also increased pathogenesis. In summary, we provide a high-resolution host response atlas for MERS-CoV infection and disease severity. Multi-omics studies of viral pathogenesis offer a unique opportunity to not only better understand the molecular mechanisms of disease but also to identify genes and pathways that can be exploited for therapeutic intervention all of which is important for our future pandemic preparedness.

MERS-CoV↗
DOE OSTI2021

Pre-existing humoral immunity to human common cold coronaviruses negatively impacts the protective SARS-CoV-2 antibody response

SARS-CoV-2 infection causes diverse outcomes ranging from asymptomatic infection to respiratory distress and death. A major unresolved question is whether prior immunity to endemic, human common cold coronaviruses (hCCCoVs) impacts susceptibility to SARS-CoV-2 infection or immunity following infection and vaccination. Therefore, we analyzed samples from the same individuals before and after SARS-CoV-2 infection or vaccination. We found hCCCoV antibody levels increase after SARS-CoV-2 exposure, demonstrating cross-reactivity. However, a case-control study indicates that baseline hCCCoV antibody levels are not associated with protection against SARS-CoV-2 infection. Rather, higher magnitudes of pre-existing betacoronavirus antibodies correlate with more SARS-CoV-2 antibodies following infection, an indicator of greater disease severity. Additionally, immunization with hCCCoV spike proteins before SARS-CoV-2 immunization impedes the generation of SARS-CoV-2-neutralizing antibodies in mice. Together, these data suggest that pre-existing hCCCoV antibodies hinder SARS-CoV-2 antibody-based immunity following infection and provide insight on how pre-existing coronavirus immunity impacts SARS-CoV-2 infection, which is critical considering emerging variants.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Structural insights into the modulation of coronavirus spike tilting and infectivity by hinge glycans

Abstract Coronavirus spike glycoproteins presented on the virion surface mediate receptor binding, and membrane fusion during virus entry and constitute the primary target for vaccine and drug development. How the structure dynamics of the full-length spikes incorporated in viral lipid envelope correlates with the virus infectivity remains poorly understood. Here we present structures and distributions of native spike conformations on vitrified human coronavirus NL63 (HCoV-NL63) virions without chemical fixation by cryogenic electron tomography (cryoET) and subtomogram averaging, along with site-specific glycan composition and occupancy determined by mass spectrometry. The higher oligomannose glycan shield on HCoV-NL63 spikes than on SARS-CoV-2 spikes correlates with stronger immune evasion of HCoV-NL63. Incorporation of cryoET-derived native spike conformations into all-atom molecular dynamic simulations elucidate the conformational landscape of the glycosylated, full-length spike that reveals a role of hinge glycans in modulating spike bending. We show that glycosylation at N1242 at the upper portion of the stalk is responsible for the extensive orientational freedom of the spike crown. Subsequent infectivity assays implicated involvement of N1242-glyan in virus entry. Our results suggest a potential therapeutic target site for HCoV-NL63.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Coronavirus neutralizing humanized antibodies and uses thereof

The present disclosure relates to an isolated or purified antibody, or a fragment thereof, having a binding domain that binds to a coronavirus (e.g., SARS-COV-2) or a portion thereof. In other embodiments, the antibody includes a binding domain that competes with binding to angiotensin converting enzyme 2 (ACE2) or a portion thereof. Methods of using such antibodies are also described herein, such as methods of treating or delaying the progression of a disease associated with a coronavirus.

Harmon, Brooke Nicole↗
DOE OSTI2023

Quantification of early nonpharmaceutical interventions aimed at slowing transmission of Coronavirus Disease 2019 in the Navajo Nation and surrounding states (Arizona, Colorado, New Mexico, and Utah)

During an early period of the Coronavirus Disease 2019 (COVID-19) pandemic, the Navajo Nation, much like New York City, experienced a relatively high rate of disease transmission. Yet, between January and October 2020, it experienced only a single period of growth in new COVID-19 cases, which ended when cases peaked in May 2020. The daily number of new cases slowly decayed in the summer of 2020 until late September 2020. In contrast, the surrounding states of Arizona, Colorado, New Mexico, and Utah all experienced at least two periods of growth in the same time frame, with second surges beginning in late May to early June. Here, we investigated these differences in disease transmission dynamics with the objective of quantifying the contributions of non-pharmaceutical interventions (NPIs) (e.g., behaviors that limit disease transmission). We considered a compartmental model accounting for distinct periods of NPIs to analyze the epidemic in each of the five regions. We used Bayesian inference to estimate region-specific model parameters from regional surveillance data (daily reports of new COVID-19 cases) and to quantify uncertainty in parameter estimates and model predictions. Our results suggest that NPIs in the Navajo Nation were sustained over the period of interest, whereas in the surrounding states, NPIs were relaxed, which allowed for subsequent surges in cases. Our region-specific model parameterizations allow us to quantify the impacts of NPIs on disease incidence in the regions of interest.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Trajectory of Growth of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants in Houston, Texas, January through May 2021, Based on 12,476 Genome Sequences

Certain genetic variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of substantial concern because they may be more transmissible or detrimentally alter the pandemic course and disease features in individual patients. SARS-CoV-2 genome sequences from 12,476 patients in the Houston Methodist health care system diagnosed from January 1 through May 31, 2021 are reported here. Prevalence of the B.1.1.7 (Alpha) variant increased rapidly and caused 63% to 90% of new cases in the latter half of May. Eleven B.1.1.7 genomes had an E484K replacement in spike protein, a change also identified in other SARS-CoV-2 lineages. Compared with non–B.1.1.7-infected patients, individuals with B.1.1.7 had a significantly lower cycle threshold (a proxy for higher virus load) and significantly higher hospitalization rate. Other variants [eg, B.1.429 and B.1.427 (Epsilon), P.1 (Gamma), P.2 (Zeta), and R.1] also increased rapidly, although the magnitude was less than that in B.1.1.7. Twenty-two patients infected with B.1.617.1 (Kappa) or B.1.617.2 (Delta) variants had a high rate of hospitalization. Breakthrough cases (n = 207) in fully vaccinated patients were caused by a heterogeneous array of virus genotypes, including many not currently designated variants of interest or concern. Finally, in the aggregate, this study delineates the trajectory of SARS-CoV-2 variants circulating in a major metropolitan area, documents B.1.1.7 as the major cause of new cases in Houston, TX, and heralds the arrival of B.1.617 variants in the metroplex.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

Human Coronavirus 229E Infection Alters Histone Proteoforms

Viruses rely on host machinery to replicate, and growing evidence demonstrates that they utilize host epigenetic regulation, including histone modification, to modulate host gene expression for their benefit. Herein, we employed top-down proteomics to quantify histone proteoforms in a model human lung cell line following human coronavirus 229E (HCoV-229E) infection and compared them to mock-infected controls. A total of 572 proteoforms from mock-infected and HCoV-229E infected human lung fibroblast (MRC5) cells (N = 5 per condition) were identified; this included 461 histone proteoforms that were assigned to H2A, H2B, H3, or H4. 200 histone proteoforms were quantifiable, and differential abundance analysis revealed several statistically significant changes in both reversible post-translational modifications (e.g. phosphorylation, acetylation) and the truncation states of core histones. Notably, we found decreased abundance of C-terminally truncated histone H2A and N-terminally truncated histone H3 in HCoV-229E-infected samples. These findings underscore the power of top-down proteomics to resolve unique truncation states of proteoforms and support the hypothesis that viruses alter histone length (removing regulatory sites) to influence host gene expression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors

To date, effective therapeutic treatments that confer strong attenuation against coronaviruses (CoVs) remain elusive. Among potential drug targets, the helicase of CoVs is attractive due to its sequence conservation and indispensability. We rely on atomistic molecular dynamics simulations to explore the structural coordination and dynamics associated with the SARS-CoV-2 Nsp13 apo enzyme, as well as their complexes with natural ligands. A complex communication network is revealed among the five domains of Nsp13, which is differentially activated because of the presence of the ligands, as shown by shear strain analysis, principal components analysis, dynamical cross-correlation matrix analysis, and water transport analysis. The binding free energy and the corresponding mechanism of action are presented for three small molecules that were shown to be efficient inhibitors of the previous SARS-CoV Nsp13 enzyme. Together, our findings provide critical fresh insights for rational design of broad-spectrum antivirals against CoVs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

A human antibody reveals a conserved site on beta-coronavirus spike proteins and confers protection against SARS-CoV-2 infection

Broadly neutralizing antibodies (bnAbs) to coronaviruses (CoVs) are valuable in their own right as prophylactic and therapeutic reagents to treat diverse CoVs and as templates for rational pan-CoV vaccine design. We recently described a bnAb, CC40.8, from a CoV disease 2019 (COVID-19) convalescent donor that exhibits broad reactivity with human β-CoVs. Here, we showed that CC40.8 targets the conserved S2 stem helix region of the CoV spike fusion machinery. We determined a crystal structure of CC40.8 Fab with a SARS-CoV-2 S2 stem peptide at 1.6-Å resolution and found that the peptide adopted a mainly helical structure. Conserved residues in β-CoVs interacted with CC40.8 antibody, thereby providing a molecular basis for its broad reactivity. CC40.8 exhibited in vivo protective efficacy against SARS-CoV-2 challenge in two animal models. In both models, CC40.8-treated animals exhibited less weight loss and reduced lung viral titers compared to controls. Furthermore, we noted that CC40.8-like bnAbs are relatively rare in human COVID-19 infection, and therefore, their elicitation may require rational structure-based vaccine design strategies. Overall, our study describes a target on β-CoV spike proteins for protective antibodies that may facilitate the development of pan–β-CoV vaccines.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Unfolded Protein Response Inhibition Reduces Middle East Respiratory Syndrome Coronavirus-Induced Acute Lung Injury

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe atypical pneumonia in infected individuals, but the underlying mechanisms of pathogenesis remain unknown. While much has been learned from the few reported autopsy cases, an in-depth understanding of the cells targeted by MERS-CoV in the human lung and their relative contribution to disease outcomes is needed.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Comparative Assessment of Severe Acute Respiratory Syndrome Coronavirus 2 Variants in the Ferret Model

The continued spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans necessitates evaluation of variants for enhanced virulence and transmission. We used the ferret model to perform a comparative analysis of four SARS-CoV-2 strains, including an early pandemic isolate from the United States (WA1), and representatives of the Alpha, Beta, and Delta lineages. While Beta virus was not capable of pronounced replication in ferrets, WA1, Alpha, and Delta viruses productively replicated in the ferret upper respiratory tract, despite causing only mild disease with no overt histopathological changes. Strain-specific transmissibility was observed; WA1 and Delta viruses transmitted in a direct contact setting, whereas Delta virus was also capable of limited airborne transmission. Viral RNA was shed in exhaled air particles from all inoculated animals but was highest for Delta virus. Prior infection with SARS-CoV-2 offered varied protection against reinfection with either homologous or heterologous variants. Notable genomic variants in the spike protein were most frequently detected following WA1 and Delta virus infection.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Building a Computational and Experimental Rapid Response Pipeline to Counter the Coronavirus Disease 2019 Outbreak and Emerging Biothreats

The LDRD ER “Building a Computational and Experimental Rapid Response Pipeline to Counter the Coronavirus Disease 2019 Outbreak and Emerging Biothreats” was conceived to address a need for rapid, scalable, evaluation of computationally designed therapeutic or prophylactic antibodies and vaccine antigens, two important classes of protein medical countermeasure (MCM). This was done in complement to a computationally driven LDRD 20ERD032 “Active Learning for Rapid Design of Vaccines and Antibodies.” Natural antibodies and antigens are often insufficiently broad or robust across different pathogens and their variants. Leveraging a collaboration of simulation driven machine learning, structural expertise, and high-throughput characterization of candidate antibodies, we successfully re-targeted three different anti-SARS-CoV-1 antibodies to neutralize SARS-CoV-2 in vitro. Our antibody design work reached its most important stage in rapid response to the emergence of the Omicron variant of concern (VOC) in late 2021. In a matter of weeks, we computationally designed derivative antibodies of COV2-2130, one of two antibodies from Vanderbilt that form the basis of the AstraZeneca Evusheld prophylactic drug product. This drug product suffers a serious loss of efficacy against Omicron BA.1 and BA.1.1, the first Omicron strains. Our designs were successful, including a pair of designs which provide potent neutralization of not only Omicron BA.1 and BA.1.1, but also the earlier Delta variant, and subsequent Omicron strains including BA.2, BA.4, BA.5, and BA.2.75, demonstrating that our multi-target design process can, by its nature, produce robust antibody designs that strictly improve over the parental antibody. These results, recognized by a 2022 Director’s Science and Technology award, have enabled the follow-on GUIDE program, to commence in FY23.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Interventions to Disrupt Coronavirus Disease Transmission at a University, Wisconsin, USA, August–October 2020

University settings have demonstrated potential for coronavirus disease (COVID-19) outbreaks; they combine congregate living, substantial social activity, and a young population predisposed to mild illness. Using genomic and epidemiologic data, we describe a COVID-19 outbreak at the University of Wisconsin-Madison, Madison, Wisconsin, USA. During August-October 2020, a total of 3,485 students, including 856/6,162 students living in dormitories, tested positive. Case counts began rising during move-in week, August 25–31, 2020, then rose rapidly during September 1–11, 2020. The university initiated multiple prevention efforts, including quarantining 2 dormitories; a subsequent decline in cases was observed. Genomic surveillance of cases from Dane County, in which the university is located, did not find evidence of transmission from a large cluster of cases in the 2 quarantined dorms during the outbreak. Coordinated implementation of prevention measures can reduce COVID-19 spread in university settings and may limit spillover to the surrounding community.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Molecular evolution of human coronavirus-NL63, -229E, -HKU1 and -OC43 in hospitalized children in China

Human coronaviruses (HCoVs) HCoV-NL63, HCoV-229E, HCoV-HKU1 and HCoV-OC43 have been circulated in the human population worldwide, and they are associated with a broad range of respiratory diseases with varying severity. However, there are neither effective therapeutic drugs nor licensed vaccines available for the treatment and prevention of infections by the four HCoVs. In this study, we collected nasopharyngeal aspirates of children hospitalized for respiratory tract infection in China during 2014–2018 and conducted next-generation sequencing. Sequences of four HCoVs were then selected for an in-depth analysis. Genome sequences of 2 HCoV-NL63, 8 HCoV-229E, 2 HCoV-HKU1, and 6 HCoV-OC43 were obtained. Based on the full-length S gene, a strong temporal signal was found in HCoV-229E and the molecular evolutionary rate was 6 × 10 −4 substitutions/site/year. Based on the maximum-likelihood (ML) phylogenetic tree of complete S gene, we designated H78 as a new sub-genotype C2 of HCoV-HKU1, and the obtained P43 sequence was grouped into the reported novel genotype K of HCoV-OC43 circulating in Guangzhou, China. Based on the complete genome, potential recombination events were found to occur as two phenomena, namely intraspecies and interspecies. Moreover, we observed two amino acid substitutions in the S1 subunit of obtained HCoV-NL63 (G534V) and HCoV-HKU1 (H512R), while residues 534 and 512 are important for the binding of angiotensin-converting enzyme 2 and neutralizing antibodies, respectively. Our findings might provide a clue for the molecular evolution of the four HCoVs and help in the early diagnosis, treatment and prevention of broad-spectrum HCoV infection.

Shao, Nan↗
DOE OSTI2021

Quantifying T Cell Cross-Reactivity: Influenza and Coronaviruses

If viral strains are sufficiently similar in their immunodominant epitopes, then populations of cross-reactive T cells may be boosted by exposure to one strain and provide protection against infection by another at a later date. This type of pre-existing immunity may be important in the adaptive immune response to influenza and to coronaviruses. Patterns of recognition of epitopes by T cell clonotypes (a set of cells sharing the same T cell receptor) are represented as edges on a bipartite network. We describe different methods of constructing bipartite networks that exhibit cross-reactivity, and the dynamics of the T cell repertoire in conditions of homeostasis, infection and re-infection. Cross-reactivity may arise simply by chance, or because immunodominant epitopes of different strains are structurally similar. We introduce a circular space of epitopes, so that T cell cross-reactivity is a quantitative measure of the overlap between clonotypes that recognize similar (that is, close in epitope space) epitopes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Systematic Screening of COVID-19 Disease Based on Chest CT and RT-PCR for Cancer Patients Undergoing Radiation Therapy in a Coronavirus French Hotspot

Patients with cancer are presumed to be more vulnerable to COVID-19. We evaluated a screening strategy combining chest computed tomography (CT) and reverse-transcription polymerase chain reaction (RT-PCR) for patients treated with radiation therapy at our cancer center located in a COVID-19 French hotspot during the first wave of the pandemic.

62 RADIOLOGY AND NUCLEAR MEDICINE↗