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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 145 records · Page 8
All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Genome-wide association study of long COVID

Abstract Infections can lead to persistent symptoms and diseases such as shingles after varicella zoster or rheumatic fever after streptococcal infections. Similarly, severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection can result in long coronavirus disease (COVID), typically manifesting as fatigue, pulmonary symptoms and cognitive dysfunction. The biological mechanisms behind long COVID remain unclear. We performed a genome-wide association study for long COVID including up to 6,450 long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We discovered an association ofFOXP4with long COVID, independent of its previously identified association with severe COVID-19. The signal was replicated in 9,500 long COVID cases and 798,835 population controls. Given the transcription factor FOXP4’s role in lung physiology and pathology, our findings highlight the importance of lung function in the pathophysiology of long COVID.

Genetics & Heredity↗
DOE OSTI2021

Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

Prevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Exposing structural variations in SARS-CoV-2 evolution

The mutation of SARS-CoV-2 influences viral function as residue replacements affect both physiochemical properties and folding conformations. Although a large amount of data on SARS-CoV-2 is available, the investigation of how viral functions change in response to mutations is hampered by a lack of effective structural analysis. Here, we exploit the advances of protein structure fingerprint technology to study the folding conformational changes induced by mutations. With integration of both protein sequences and folding conformations, the structures are aligned for SARS-CoV to SARS-CoV-2, including Alpha variant (lineage B.1.1.7) and Delta variant (lineage B.1.617.2). The results showed that the virus evolution with change in mutational positions and physicochemical properties increased the affinity between spike protein and ACE2, which plays a critical role in coronavirus entry into human cells. Additionally, these structural variations impact vaccine effectiveness and drug function over the course of SARS-CoV-2 evolution. The analysis of structural variations revealed how the coronavirus has gradually evolved in both structure and function and how the SARS-CoV-2 variants have contributed to more severe acute disease worldwide.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Hepatitis C virus NS3/4A inhibitors and other drug-like compounds as covalent binders of SARS-CoV-2 main protease

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), threatens global public health. The world needs rapid development of new antivirals and vaccines to control the current pandemic and to control the spread of the variants. Among the proteins synthesized by the SARS-CoV-2 genome, main protease (M pro also known as 3CL pro ) is a primary drug target, due to its essential role in maturation of the viral polyproteins. In this study, we provide crystallographic evidence, along with some binding assay data, that three clinically approved anti hepatitis C virus drugs and two other drug-like compounds covalently bind to the M pro Cys145 catalytic residue in the active site. Also, molecular docking studies can provide additional insight for the design of new antiviral inhibitors for SARS-CoV-2 using these drugs as lead compounds. One might consider derivatives of these lead compounds with higher affinity to the M pro as potential COVID-19 therapeutics for further testing and possibly clinical trials.

36 MATERIALS SCIENCE↗
DOE OSTI2023

Sequence similarity between SARS-CoV-2 nucleocapsid and multiple sclerosis-associated proteins provides insight into viral neuropathogenesis following infection

Abstract The novel coronavirus SARS-CoV-2 continues to cause death and disease throughout the world, underscoring the necessity of understanding the virus and host immune response. From the start of the pandemic, a prominent pattern of central nervous system (CNS) pathologies, including demyelination, has emerged, suggesting an underlying mechanism of viral mimicry to CNS proteins. We hypothesized that immunodominant epitopes of SARS-CoV-2 share homology with proteins associated with multiple sclerosis (MS). Using PEPMatch, a newly developed bioinformatics package which predicts peptide similarity within specific amino acid mismatching parameters consistent with published MHC binding capacity, we discovered that nucleocapsid protein shares significant overlap with 22 MS-associated proteins, including myelin proteolipid protein (PLP). Further computational evaluation demonstrated that this overlap may have critical implications for T cell responses in MS patients and is likely unique to SARS-CoV-2 among the major human coronaviruses. Our findings substantiate the hypothesis of viral molecular mimicry in the pathogenesis of MS and warrant further experimental exploration.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

2'-O methylation of RNA cap in SARS-CoV-2 captured by serial crystallography

The genome of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus has a capping modification at the 5'-untranslated region (UTR) to prevent its degradation by host nucleases. These modifications are performed by the Nsp10/14 and Nsp10/16 heterodimers using S-adenosylmethionine as the methyl donor. Nsp10/16 heterodimer is responsible for the methylation at the ribose 2'-O position of the first nucleotide. To investigate the conformational changes of the complex during 2'-O methyltransferase activity, we used a fixed-target serial synchrotron crystallography method at room temperature. We determined crystal structures of Nsp10/16 with substrates and products that revealed the states before and after methylation, occurring within the crystals during the experiments. Here we report the crystal structure of Nsp10/16 in complex with Cap-1 analog ( m7 GpppA m2'-O ). Inhibition of Nsp16 activity may reduce viral proliferation, making this protein an attractive drug target.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants

Antivirals with broad coronavirus activity are important for treating high-risk individuals exposed to the constantly evolving SARS-CoV-2 variants of concern (VOCs) as well as emerging drug-resistant variants. We developed and characterized a novel class of active-site-directed 3-chymotrypsin-like protease (3CLpro) inhibitors (C2-C5a). Our lead direct-acting antiviral (DAA), C5a, is a non-covalent, non-peptide with a dissociation constant of 170 nM against recombinant SARS-CoV-2 3CLpro. The compounds C2-C5a exhibit broad-spectrum activity against Omicron subvariants (BA.5, BQ.1.1, and XBB.1.5) and seasonal human coronavirus-229E infection in human cells. Notably, C5a has median effective concentrations of 30-50 nM against BQ.1.1 and XBB.1.5 in two different human cell lines. X-ray crystallography has confirmed the unique binding modes of C2-C5a to the 3CLpro, which can limit virus cross-resistance to emerging Paxlovid-resistant variants. We tested the effect of C5a with two of our newly discovered host-directed antivirals (HDAs): N-0385, a TMPRSS2 inhibitor, and bafilomycin D (BafD), a human vacuolar H+-ATPase [V-ATPase] inhibitor. We demonstrated a synergistic action of C5a in combination with N-0385 and BafD against Omicron BA.5 infection in human Calu-3 lung cells. Our findings underscore that a SARS-CoV-2 multi-targeted treatment for circulating Omicron subvariants based on DAAs (C5a) and HDAs (N-0385 or BafD) can lead to therapeutic benefits by enhancing treatment efficacy. Furthermore, the high-resolution structures of SARS-CoV-2 3CLpro in complex with C2-C5a will facilitate future rational optimization of our novel broad-spectrum active-site-directed 3C-like protease inhibitors.

3CLpro inhibitor↗
DOE OSTI2023

Breath analysis by ultra-sensitive broadband laser spectroscopy detects SARS-CoV-2 infection

Rapid testing is essential to fighting pandemics such as coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Exhaled human breath contains multiple volatile molecules providing powerful potential for non-invasive diagnosis of diverse medical conditions. We investigated breath detection of SARS-CoV-2 infection using cavity-enhanced direct frequency comb spectroscopy (CE-DFCS), a state-of-the-art laser spectroscopic technique capable of a real-time massive collection of broadband molecular absorption features at ro-vibrational quantum state resolution and at parts-per-trillion volume detection sensitivity. Using a total of 170 individual breath samples (83 positive and 87 negative with SARS-CoV-2 based on reverse transcription polymerase chain reaction tests), we report excellent discrimination capability for SARS-CoV-2 infection with an area under the receiver-operating-characteristics curve of 0.849(4). Our results support the development of CE-DFCS as an alternative, rapid, non-invasive test for COVID-19 and highlight its remarkable potential for optical diagnoses of diverse biological conditions and disease states.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Genetic and Structural Analysis of SARS-CoV-2 Spike Protein for Universal Epitope Selection

Evaluation of immunogenic epitopes for universal vaccine development in the face of ongoing SARS-CoV-2 evolution remains a challenge. Herein, we investigate the genetic and structural conservation of an immunogenically relevant epitope (C662–C671) of spike (S) protein across SARS-CoV-2 variants to determine its potential utility as a broad-spectrum vaccine candidate against coronavirus diseases. Comparative sequence analysis, structural assessment, and molecular dynamics simulations of C662–C671 epitope were performed. Mathematical tools were employed to determine its mutational cost. We found that the amino acid sequence of C662–C671 epitope is entirely conserved across the observed major variants of SARS-CoV-2 in addition to SARS-CoV. Its conformation and accessibility are predicted to be conserved, even in the highly mutated Omicron variant. Costly mutational rate in the context of energy expenditure in genome replication and translation can explain this strict conservation. These observations may herald an approach to developing vaccine candidates for universal protection against emergent variants of coronavirus.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

mRNA SARS-CoV-2 Immunization Confers Robust Antibody Response in Occupational Healthcare Workers and Fosters Workplace Safety

Immunization against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a major step in protecting the healthcare worker beyond standard pandemic precautions and infection control measures. Healthcare workers (HCW) are at high risk for SARS-CoV-2 exposure and infection placing burden on the workplace. Hence, reducing SARS-CoV-2 infection of HCWs serves multiple goals in the occupational health arena. These include protecting the health and safety of the HCW as well as reducing transmission of Coronavirus Disease 2019 (COVID-19) in the clinic and the larger workplace it serves. Furthermore, when HCWs demonstrate appropriate pandemic precautions and health practices, they serve as strategic models for other workers. Here, this modeling represents leadership which can inspire optimism and hope in a workforce beleaguered by the pandemic.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (M pro )

The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or M pro , is a promising target for the development of novel antiviral therapeutics. Previous X-ray crystal structures of M pro were obtained at cryogenic temperature or room temperature only. Here we report a series of high-resolution crystal structures of unliganded M pro across multiple temperatures from cryogenic to physiological, and another at high humidity. We interrogate these data sets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a perturbation-dependent conformational landscape for M pro , including a mobile zinc ion interleaved between the catalytic dyad, mercurial conformational heterogeneity at various sites including a key substrate-binding loop, and a far-reaching intramolecular network bridging the active site and dimer interface. Our results may inspire new strategies for antiviral drug development to aid preparation for future coronavirus pandemics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

The Potential of Low Molecular Weight Heparin to Mitigate Cytokine Storm in Severe COVID‐19 Patients: A Retrospective Cohort Study

On March 11, 2020, the World Health Organization declared its assessment of coronavirus disease 2019 (COVID‐19) as a global pandemic. However, specific anti‐severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) drugs are still under development, and patients are managed by multiple complementary treatments. We performed a retrospective analysis to compare and evaluate the effect of low molecular weight heparin (LMWH) treatment on disease progression. For this purpose, the clinical records and laboratory indicators were extracted from electronic medical records of 42 patients with COVID‐19 (21 of whom were treated with LMWH, and 21 without LMWH) hospitalized (Union Hospital of Huazhong University of Science and Technology) from February 1 to March 15, 2020. Changes in the percentage of lymphocytes before and after LMWH treatment were significantly different from those in the control group ( P = 0.011). Likewise, changes in the levels of D‐dimer and fibrinogen degradation products in the LMWH group before and after treatment were significantly different from those in the control group ( P = 0.035). Remarkably, IL‐6 levels were significantly reduced after LMWH treatment ( P = 0.006), indicating that, besides other beneficial properties, LMWH may exert an anti‐inflammatory effect and attenuate in part the “cytokine storm” induced by the virus. Our results support the use of LMWH as a potential therapeutic drug for the treatment of COVID‐19, paving the way for a subsequent well‐controlled clinical study.

Shi, Chen↗
DOE OSTI2020

Development and evaluation of a Novel RT‐PCR system for reliable and rapid SARS‐CoV ‐2 screening of blood donations

Abstract Background The ongoing outbreak of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has caused great global concerns. In contrast to SARS, some SARS‐CoV‐2–infected people can be asymptomatic or have only mild nonspecific symptoms. Furthermore, there is evidence that SARS‐CoV‐2 may be infectious during an asymptomatic incubation period. With the discovery that SARS‐CoV‐2 can be detected in plasma or serum, blood safety is worthy of consideration. Study Design and Methods We developed a nucleic acid test (NAT) screening system for SARS‐CoV‐2 targeting nucleocapsid protein (N) and open reading frame 1ab (ORF 1ab) gene that could screen 5076 samples every 24 hours. The 2019 novel coronavirus RNA standard was used to evaluate linearity of standard curves. Diagnostic sensitivity and reproducibility were evaluated using artificial SARS‐CoV‐2. Specificity was evaluated with 61 other respiratory pathogens. Diagnostic performance was evaluated by testing two sputum and nine oropharyngeal swab specimens. The reverse transcription polymerase chain reaction (RT‐PCR) assay was used to screen SARS‐CoV‐2 RNA in blood donor specimens collected during the outbreak of SARS‐CoV‐2 in Chengdu. Results Limits of detection of the SARS‐CoV‐2 RT‐PCR assay for N and ORF 1ab gene were 12.5 and 27.58 copies/mL, respectively. Intra‐assay and interassay for the SARS‐CoV‐2 RT‐PCR assay based on cycle threshold were acceptably low. No cross‐reactivity was observed with other respiratory virus and bacterial isolates. The overall agreement value between the SARS‐CoV‐2 RT‐PCR assay and clinical diagnostic results was 100%. A total of 16 287 blood specimens collected from blood donors during SARS‐CoV‐2 surveillance were tested negative. Conclusions A high‐throughput NAT screening system was developed for SARS‐CoV‐2 screening of blood donations during the outbreak of SARS‐CoV‐2.

Li, Meng↗
DOE OSTI2022

Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities

Soluble angiotensin-converting enzyme 2 (ACE2) constitutes an attractive antiviral capable of targeting a wide range of coronaviruses using ACE2 as their receptor. Using structure-guided approaches, we developed a series of bivalent ACE2-Fcs harboring functionally and structurally validated mutations that enhance severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain recognition by up to ~12-fold and remove angiotensin enzymatic activity. The lead variant M81 potently cross-neutralized SARS-CoV-2 variants of concern (VOCs), including Omicron, at subnanomolar half-maximal inhibitory concentration and was capable of robust Fc-effector functions, including antibody-dependent cellular cytotoxicity, phagocytosis, and complement deposition. When tested in a stringent K18-hACE2 mouse model, Fc-enhanced ACE2-Fc delayed death by 3 to 5 days or effectively resolved lethal SARS-CoV-2 infection in both prophylactic and therapeutic settings via the combined effects of neutralization and Fc-effector functions. These data add to the demonstrated utility of soluble ACE2 as a valuable SARS-CoV-2 antiviral and indicate that Fc-effector functions may constitute an important component of ACE2-Fc therapeutic activity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

COVID-19 Exposure Assessment Tool (CEAT): Exposure quantification based on ventilation, infection prevalence, group characteristics, and behavior

The coronavirus disease 2019 (COVID-19) Exposure Assessment Tool (CEAT) allows users to compare respiratory relative risk to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for various scenarios, providing understanding of how combinations of protective measures affect risk. CEAT incorporates mechanistic, stochastic, and epidemiological factors including the (i) emission rate of virus, (ii) viral aerosol degradation and removal, (iii) duration of activity/exposure, (iv) inhalation rates, (v) ventilation rates (indoors/outdoors), (vi) volume of indoor space, (vii) filtration, (viii) mask use and effectiveness, (ix) distance between people (taking into account both near-field and far-field effects of proximity), (x) group size, (xi) current infection rates by variant, (xii) prevalence of infection and immunity in the community, (xiii) vaccination rates, and (xiv) implementation of COVID-19 testing procedures. CEAT applied to published studies of COVID-19 transmission events demonstrates the model’s accuracy. We also show how health and safety professionals at NASA Ames Research Center used CEAT to manage potential risks posed by SARS-CoV-2 exposures.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Genomic surveillance reveals multiple introductions of SARS-CoV-2 into Northern California

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally, with >365,000 cases in California as of 17 July 2020. We investigated the genomic epidemiology of SARS-CoV-2 in Northern California from late January to mid-March 2020, using samples from 36 patients spanning nine counties and the Grand Princess cruise ship. Phylogenetic analyses revealed the cryptic introduction of at least seven different SARS-CoV-2 lineages into California, including epidemic WA1 strains associated with Washington state, with lack of a predominant lineage and limited transmission among communities. Lineages associated with outbreak clusters in two counties were defined by a single base substitution in the viral genome. These findings support contact tracing, social distancing, and travel restrictions to contain the spread of SARS-CoV-2 in California and other states.

59 BASIC BIOLOGICAL SCIENCES↗