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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 397 records · Page 22
All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Virus-induced gene editing free from tissue culture

Virus-induced gene editing (VIGE) has reached an inflection point. Although conceived as an alternative to traditional methods of producing gene-edited plants, VIGE has historically relied on the very technologies it was meant to supersede—specifically, tissue-culture-mediated transgenesis. Recent VIGE innovations, however, have finally proved its viability as an independent method for plant gene editing. Here we discuss the advances in plant genome engineering VIGE may unlock, what progress has been made towards achieving these advances and the challenges that continue to impede that progress.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2024

Machine learning approaches for influenza A virus risk assessment identifies predictive correlates using ferret model in vivo data

In vivo assessments of influenza A virus (IAV) pathogenicity and transmissibility in ferrets represent a crucial component of many pandemic risk assessment rubrics, but few systematic efforts to identify which data from in vivo experimentation are most useful for predicting pathogenesis and transmission outcomes have been conducted. To this aim, we aggregated viral and molecular data from 125 contemporary IAV (H1, H2, H3, H5, H7, and H9 subtypes) evaluated in ferrets under a consistent protocol. Three overarching predictive classification outcomes (lethality, morbidity, transmissibility) were constructed using machine learning (ML) techniques, employing datasets emphasizing virological and clinical parameters from inoculated ferrets, limited to viral sequence-based information, or combining both data types. Among 11 different ML algorithms tested and assessed, gradient boosting machines and random forest algorithms yielded the highest performance, with models for lethality and transmission consistently better performing than models predicting morbidity. Comparisons of feature selection among models was performed, and highest performing models were validated with results from external risk assessment studies. Our findings show that ML algorithms can be used to summarize complex in vivo experimental work into succinct summaries that inform and enhance risk assessment criteria for pandemic preparedness that take in vivo data into account.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Molecular recognition of a host protein by NS1 of pandemic and seasonal influenza A viruses

The 1918 influenza A virus (IAV) caused the most severe flu pandemic in recorded human history. Nonstructural protein 1 (NS1) is an important virulence factor of the 1918 IAV. NS1 antagonizes host defense mechanisms through interactions with multiple host factors. One pathway by which NS1 increases virulence is through the activation of phosphoinositide 3-kinase (PI3K) by binding to its p85β subunit. Here we present the mechanism underlying the molecular recognition of the p85β subunit by 1918 NS1. Using X-ray crystallography, we determine the structure of 1918 NS1 complexed with p85β of human PI3K. We find that the 1918 NS1 effector domain (1918 NS1 ED ) undergoes a conformational change to bind p85β. Using NMR relaxation dispersion and molecular dynamics simulation, we identify that free 1918 NS1 ED exists in a dynamic equilibrium between p85β-binding–competent and –incompetent conformations in the submillisecond timescale. Moreover, we discover that NS1 ED proteins of 1918 (H1N1) and Udorn (H3N2) strains exhibit drastically different conformational dynamics and binding kinetics to p85β. These results provide evidence of strain-dependent conformational dynamics of NS1. Using kinetic modeling based on the experimental data, we demonstrate that 1918 NS1 ED can result in the faster hijacking of p85β compared to Ud NS1 ED , although the former has a lower affinity to p85β than the latter. Our results suggest that the difference in binding kinetics may impact the competition with cellular antiviral responses for the activation of PI3K. We anticipate that our findings will increase the understanding of the strain-dependent behaviors of influenza NS1 proteins.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Omicron mutations enhance infectivity and reduce antibody neutralization of SARS-CoV-2 virus-like particles

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant contains extensive sequence changes relative to the earlier-arising B.1, B.1.1, and Delta SARS-CoV-2 variants that have unknown effects on viral infectivity and response to existing vaccines. Using SARS-CoV-2 virus-like particles (VLPs), we examined mutations in all four structural proteins and found that Omicron and Delta showed 4.6-fold higher luciferase delivery overall relative to the ancestral B.1 lineage, a property conferred mostly by enhancements in the S and N proteins, while mutations in M and E were mostly detrimental to assembly. Thirty-eight antisera samples from individuals vaccinated with Pfizer/BioNTech, Moderna, or Johnson & Johnson vaccines and convalescent sera from unvaccinated COVID-19 survivors had 15-fold lower efficacy to prevent cell transduction by VLPs containing the Omicron mutations relative to the ancestral B.1 spike protein. A third dose of Pfizer vaccine elicited substantially higher neutralization titers against Omicron, resulting in detectable neutralizing antibodies in eight out of eight subjects compared to one out of eight preboosting. Furthermore, the monoclonal antibody therapeutics casirivimab and imdevimab had robust neutralization activity against B.1 and Delta VLPs but no detectable neutralization of Omicron VLPs, while newly authorized bebtelovimab maintained robust neutralization across variants. Our results suggest that Omicron has similar assembly efficiency and cell entry compared to Delta and that its rapid spread is due mostly to reduced neutralization in sera from previously vaccinated subjects. In addition, most currently available monoclonal antibodies will not be useful in treating Omicron-infected patients with the exception of bebtelovimab.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Therapeutic efficacy of a potent anti-Venezuelan equine encephalitis virus antibody is contingent on Fc effector function

The development of specific, safe, and potent monoclonal antibodies (Abs) has led to novel therapeutic options for infectious disease. In addition to preventing viral infection through neutralization, Abs can clear infected cells and induce immunomodulatory functions through engagement of their crystallizable fragment (Fc) with complement proteins and Fc receptors on immune cells. Little is known about the role of Fc effector functions of neutralizing Abs in the context of encephalitic alphavirus infection. To determine the role of Fc effector function in therapeutic efficacy against Venezuelan equine encephalitis virus (VEEV), we compared the potently neutralizing anti-VEEV human IgG F5 (hF5) Ab with intact Fc function (hF5-WT) or containing the loss of function Fc mutations L234A and L235A (hF5-LALA) in the context of VEEV infection. We observed significantly reduced binding to complement and Fc receptors, as well as differential in vitro kinetics of Fc-mediated cytotoxicity for hF5-LALA compared to hF5-WT. The in vivo efficacy of hF5-LALA was comparable to hF5-WT at -24 and + 24 h post infection, with both Abs providing high levels of protection. However, when hF5-WT and hF5-LALA were administered + 48 h post infection, there was a significant decrease in the therapeutic efficacy of hF5-LALA. Together these results demonstrate that optimal therapeutic Ab treatment of VEEV, and possibly other encephalitic alphaviruses, requires neutralization paired with engagement of immune effectors via the Fc region.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Pathogenesis of Chapare Virus in Cynomolgus Macaques

Chapare virus (CHAPV) is an emerging New World arenavirus that is the causative agent of Chapare hemorrhagic fever (CHHF) responsible for recent outbreaks with alarmingly high case fatality rates in Bolivia near the Brazilian border. Here, we describe a nonhuman primate (NHP) model of CHHF infection which represents an essential tool to understand this emerging biological threat agent. Cynomolgus macaques challenged intravenously with CHAPV develop clinical disease, which recapitulates several key features of human CHHF. All subjects lost weight and had clinical scores following CHAPV challenge. Notably, one of four NHPs developed lethal disease with viral hepatitis and hemorrhagic features. Clinical chemistry and hematology revealed leukopenia, anemia, thrombocytopenia, and increased transaminase levels. In all four subjects, viremia was detectable for the first week following challenge and viral RNA was detectable in serum and many tissues persisting 35 days-post challenge. Several medical countermeasures (MCM) have efficacy against CHAPV infection in vitro, but the current model for MCM testing and approval of new drugs is reliant on the availability of animal models. This work lays the foundation for future CHHF MCM development.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Direct measurement of Stokes–Einstein diffusion of Cowpea mosaic virus with 19 µs-resolved XPCS

Brownian motion of Cowpea mosaic virus (CPMV) in water was measured using small-angle X-ray photon correlation spectroscopy (SA-XPCS) at 19.2 µs time resolution. It was found that the decorrelation time τ(Q) = 1/DQ 2 up to Q = 0.091 nm -1 . The hydrodynamic radius R H determined from XPCS using Stokes–Einstein diffusion D = kT/(6πηR H ) is 43% larger than the geometric radius R 0 determined from SAXS in the 0.007 M K 3 PO 4 buffer solution, whereas it is 80% larger for CPMV in 0.5 M NaCl and 104% larger in 0.5 M (NH 4 ) 2 SO 4 , a possible effect of aggregation as well as slight variation of the structures of the capsid resulting from the salt–protein interactions.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
DOE OSTI2022

Nonclassical autophagy activation pathways are essential for production of infectious Influenza A virus in vitro

Autophagy is a critical mechanism deployed by eukaryotic cells in response to stress, including viral infection, to boost the innate antimicrobial responses. However, an increasing number of pathogens hijack the autophagic machinery to facilitate their own replication. Influenza A virus (IAV), responsible for several global pandemics, has an intricate dependence on autophagy for successful replication in mammalian cells. To elucidate key chokepoints in the host stress responses facilitating IAV replication, we constructed a meta-transcriptome of IAV and host gene expression dynamics during early (1–3 hpi), mid (4–6 hpi), and late (8–12 hpi) stages of the viral replication cycle at two multiplicities of infection (MOI): 1 and 5. We supplemented the global transcriptome study with phosphoproteomic analysis of stress-activated protein kinase (SAPK/JNK) signaling in lung carcinoma (predominantly used as an in vitro model of IAV replication) and normal human bronchial epithelial cells. We report significant differences in the activation profiles of autophagy regulating genes upon IAV infection at the two MOI as well as divergent dependence on ULK1 signaling within the normal and cancer cells. Regardless of the cell model, JNK-Thr187 signaling was crucial for the production of infectious viral particles.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Understanding Hepatitis B Virus Dynamics and the Antiviral Effect of Interferon Alpha Treatment in Humanized Chimeric Mice

Whereas the mode of action of lamivudine (LAM) against hepatitis B virus (HBV) is well established, the inhibition mechanism(s) of interferon alpha (IFN-α) is less completely defined. To advance our understanding, we, for this study, mathematically modeled HBV kinetics during 14-day pegylated IFN-α-2a (pegIFN), LAM, or pegIFN-plus-LAM (pegIFN+LAM) treatment of 39 chronically HBV-infected humanized uPA/SCID chimeric mice. Serum HBV DNA and intracellular HBV DNA were measured frequently. We developed a multicompartmental mathematical model and simultaneously fit it to the serum and intracellular HBV DNA data. Unexpectedly, even in the absence of an adaptive immune response, a biphasic decline in serum HBV DNA and intracellular HBV DNA was observed in response to all treatments. Kinetic analysis and modeling indicate that the first phase represents inhibition of intracellular HBV DNA synthesis and secretion, which was similar under all treatments with an overall mean efficacy of 98%. In contrast, there were distinct differences in HBV decline during the second phase, which was accounted for in the model by a time-dependent inhibition of intracellular HBV DNA synthesis, with the steepest decline observed during pegIFN+LAM treatment (1.28/day) and the slowest (0.1/day) during pegIFN monotherapy. Reminiscent of observations in patients treated with pegIFN and/or LAM, a biphasic HBV decline was observed in treated humanized mice in the absence of an adaptive immune response. Interestingly, combination treatment did not increase the initial inhibition of HBV production but rather enhanced second-phase decline, providing insight into the dynamics of HBV treatment response and the mode of action of IFN-α against HBV.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

Many paths, similar destinations: viruses and bacterial microcompartments form polyhedra inside cells

A large number of biological entities assemble into icosahedral structures, and these are ubiquitous throughout nature. Examples include eukaryotic and prokaryotic viral capsids and more recently discovered bacterial microcompartments. Viral capsids and bacterial microcompartments are both composed of pentameric and hexameric subunits; however, they differ in the type of cargo they encapsulate: nucleic acid or protein. Also, both depart from strict icosahedral symmetry: while this is less common in viruses, among bacterial microcompartments, diverse and heterogeneous polyhedra are common. We review shared principles and key distinctions between the self-directed assembly of various icosahedral architectures and their polyhedral variants in nature and explore the concept that there are multiple paths, influenced by their cargo, to arriving at similar protein cage morphologies.

bacterial microcompartments↗
DOE OSTI2024

MVP: a modular viromics pipeline to identify, filter, cluster, annotate, and bin viruses from metagenomes

While numerous computational frameworks and workflows are available for recovering prokaryote and eukaryote genomes from metagenome data, only a limited number of pipelines are designed specifically for viromics analysis. With many viromics tools developed in the last few years alone, it can be challenging for scientists with limited bioinformatics experience to easily recover, evaluate quality, annotate genes, dereplicate, assign taxonomy, and calculate relative abundance and coverage of viral genomes using state-of-the-art methods and standards. Here, we describe Modular Viromics Pipeline (MVP) v.1.0, a user-friendly pipeline written in Python and providing a simple framework to perform standard viromics analyses. MVP combines multiple tools to enable viral genome identification, characterization of genome quality, filtering, clustering, taxonomic and functional annotation, genome binning, and comprehensive summaries of results that can be used for downstream ecological analyses. Overall, MVP provides a standardized and reproducible pipeline for both extensive and robust characterization of viruses from large-scale sequencing data including metagenomes, metatranscriptomes, viromes, and isolate genomes. As a typical use case, we show how the entire MVP pipeline can be applied to a set of 20 metagenomes from wetland sediments using only 10 modules executed via command lines, leading to the identification of 11,656 viral contigs and 8,145 viral operational taxonomic units (vOTUs) displaying a clear beta-diversity pattern. Further, acting as a dynamic wrapper, MVP is designed to continuously incorporate updates and integrate new tools, ensuring its ongoing relevance in the rapidly evolving field of viromics. MVP is available at https://gitlab.com/ccoclet/mvp and as versioned packages in PyPi and Conda.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

The pathogenesis of a North American H5N2 clade 2.3.4.4 group A highly pathogenic avian influenza virus in surf scoters (Melanitta perspicillata)

Aquatic waterfowl, particularly those in the order Anseriformes and Charadriiformes, are the ecological reservoir of avian influenza viruses (AIVs). Dabbling ducks play a recognized role in the maintenance and transmission of AIVs. Furthermore, the pathogenesis of highly pathogenic AIV (HPAIV) in dabbling ducks is well characterized. In contrast, the role of diving ducks in HPAIV maintenance and transmission remains unclear. In this study, the pathogenesis of a North American A/Goose/1/Guangdong/96-lineage clade 2.3.4.4 group A H5N2 HPAIV, A/Northern pintail/Washington/40964/2014, in diving sea ducks (surf scoters, Melanitta perspicillata) was characterized.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

A new class of antibodies that overcomes a steric barrier to cross-group neutralization of influenza viruses

Antibody titers that inhibit the influenza virus hemagglutinin (HA) from engaging its receptor are the accepted correlate of protection from infection. Many potent antibodies with broad, intra-subtype specificity bind HA at the receptor binding site (RBS). One barrier to broad H1-H3 cross-subtype neutralization is an insertion (133a) between positions 133 and 134 on the rim of the H1 HA RBS. We describe here a class of antibodies that overcomes this barrier. These genetically unrestricted antibodies are abundant in the human B cell memory compartment. Analysis of the affinities of selected members of this class for historical H1 and H3 isolates suggest that they were elicited by H3 exposure and broadened or diverted by later exposure(s) to H1 HA. RBS mutations in egg-adapted vaccine strains cause the new H1 specificity of these antibodies to depend on the egg adaptation. The results suggest that suitable immunogens might elicit 133a-independent, H1-H3 cross neutralization by RBS-directed antibodies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Evidence of co-exposure with Brucella spp, Coxiella burnetii , and Rift Valley fever virus among various species of wildlife in Kenya

Co-infection, especially with pathogens of dissimilar genetic makeup, may result in a more devastating impact on the host. Investigations on co-infection with neglected zoonotic pathogens in wildlife are necessary to inform appropriate prevention and control strategies to reduce disease burden in wildlife and the potential transmission of these pathogens between wildlife, livestock and humans. This study assessed co-exposure of various Kenyan wildflife species with Brucella spp, Coxiella burnetii and Rift Valley fever virus (RVFV). A total of 363 sera from 16 different wildlife species, most of them (92.6%) herbivores, were analysed by Enzyme-linked immunosorbent assay (ELISA) for IgG antibodies against Brucella spp, C. burnetii and RVFV. Further, 280 of these were tested by PCR to identify Brucella species. Of the 16 wildlife species tested, 15 (93.8%) were seropositive for at least one of the pathogens. Mean seropositivities were 18.9% (95% CI: 15.0–23.3) for RVFV, 13.7% (95% CI: 10.3–17.7) for Brucella spp and 9.1% (95% CI: 6.3–12.5) for C. burnetii. Buffaloes (n = 269) had higher seropositivity for Brucella spp. (17.1%, 95% CI: 13.0–21.7%) and RVFV (23.4%, 95% CI: 18.6–28.6%), while giraffes (n = 36) had the highest seropositivity for C. burnetii (44.4%, 95% CI: 27.9–61.9%). Importantly, 23 of the 93 (24.7%) animals positive for at least one pathogen were co-exposed, with 25.4% (18/71) of the positive buffaloes positive for brucellosis and RVFV. On molecular analysis, Brucella DNA was detected in 46 (19.5%, CI: 14.9–24.7) samples, with 4 (8.6%, 95% CI: 2.2–15.8) being identified as B. melitensis. The Fisher’s Exact test indicated that seropositivity varied significantly within the different animal families, with Brucella (p = 0.013), C. burnetii (p = <0.001) and RVFV (p = 0.007). Location was also significantly associated (p = <0.001) with Brucella spp. and C. burnetii seropositivities. Of ~20% of Kenyan wildlife that are seropositive for Brucella spp, C. burnetii and RVFV, almost 25% indicate co-infections with the three pathogens, particularly with Brucella spp and RVFV.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Self-Assembly of Virus Particle Based Materials for Hydrogen Catalysis

Viruses are sophisticated protein-based containers and their self-assembly from a small number of subunits into symmetrical, monodisperse architectures has inspired the work performed under this award. We have taken advantage of the robust self-assembly of the bacteriophage P22 for the encapsulation of enzymatic cargo materials and studied their activity in energy harvesting systems. The large internal cavity of the P22 is ideal for high-capacity loading of enzymes resulting in very high local catalyst concentrations. We have exploited the self-assembly properties of the bacteriophage P22 system for the packaging of a number of different enzymes, including a [NiFe] hydrogenase as well as enzymes capable of butanol biosynthesis, to create active and stable individual “nano-reactors”. Individual viral capsid-based nanoreactors are also ideal building blocks for the construction of higher order assemblies. We have demonstrated the construction of ordered 3-D arrays from active nanoparticle building blocks to form materials with collective behavior and properties beyond those of the individual particles and capable of catalyzing multi-step reactions. The successful implementation of the work performed under this DOE grant provides us with a great deal of knowledge about directed self-assembly at multiple lengthscales for the development of bioinspired catalytic materials for energy harvesting.

08 HYDROGEN↗
DOE OSTI2024

Single-cell and spatiotemporal transcriptomic profiling of brain immune infiltration following Venezuelan equine encephalitis virus infection

Neurotropic alphaviruses such as Venezuelan equine encephalitis virus (VEEV) are critical human pathogens that continually expand to naïve populations and for which there are no licensed vaccines or therapeutics. VEEV is highly infectious via the aerosol route and is a recognized weaponizable biothreat that causes neurological disease in humans. The neuropathology of VEEV has been attributed to an inflammatory immune response in the brain yet the underlying mechanisms and specific immune cell populations involved are not fully elucidated. This study uses single-cell RNA sequencing to produce a comprehensive transcriptional profile of immune cells isolated from the brain over a time course of infection in a mouse model of VEEV. Analyses reveal differentially activated subpopulations of microglia, including a distinct type I interferon-expressing subpopulation. This is followed by the sequential infiltration of myeloid cells and cytotoxic lymphocytes, also comprising subpopulations with unique transcriptional signatures. We identify a subpopulation of myeloid cells that form a distinct localization pattern in the hippocampal region whereas lymphocytes are widely distributed, indicating differential modes of recruitment, including that to specific regions of the brain. Altogether, this study provides a high-resolution analysis of the immune response to VEEV in the brain and highlights potential avenues of investigation for therapeutics that target neuroinflammation in the brain.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Neonatal Zika virus infection causes transient perineuronal net degradation

Perineuronal nets (PNNs) form a specialized extracellular matrix that predominantly surrounds parvalbumin (PV)-expressing GABAergic inhibitory interneurons and help regulate neuronal activity. Their formation early in the postnatal period is regulated by neuronal signaling and glial activation raising concerns that part of the long-term effects ascribed to perinatal viral infections could be mediated by altered PNN formation. Previously, we developed a model of neonatal Zika virus (ZIKV) infection where mice have lifelong neurological sequelae that includes motor disfunction and reduced anxiety coupled with a persistent low-grade expression in proinflammatory markers despite resolving the acute infection. Here, we demonstrate that ZIKV infection to P1 neonatal mice results in a reduction of PNN formation during the acute disease with significant reduction in Wisteria floribunda agglutinin (WFA) staining at the peak of infection [15 days post infection (dpi)] that persisted after the symptoms resolved (30 dpi). At 60 dpi, when there is residual inflammation in the CNS, the number of WFA + cells and the level of WFA staining as well as levels of aggrecan and brevican in the brains of convalescent mice were not different from those in uninfected controls, however, there was increased frequency of PNNs with an immature phenotype. Over time the impact of the perinatal infection became less evident and there were no clear differences in PNN morphology between the groups at 1 year post infection. Of note, the reduction in PNNs during acute ZIKV infection was not associated with decreased mRNA levels of aggrecan or brevican, but increased levels of degraded aggrecan and brevican indicating increased PNN degradation. These changes were associated with increased expression of matrix metalloproteinase 12 (MMP12) and MMP19, but not MMP9, a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) or ADAMTS5. Together our findings indicate that infection at the time of PNN development interferes with PNN formation, but the nets can reform once the infection and inflammation subside.

60 APPLIED LIFE SCIENCES↗