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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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12 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Improved Zika virus plaque assay using Vero/TMPRSS2 cell line

Plaque assay is the gold standard for the quantification of viable cytopathic viruses like Zika virus (ZIKV). Some strains of ZIKV produce plaques that are very difficult to accurately visualize and count on the commonly used Vero cell line. From data generated in our lab, we became curious if Vero/TMPRSS2 cells may be a better alternative; therefore, we compared the plaque forming units of two strains of ZIKV on Vero/TMPRSS2 cells to those produced by Vero cells. We also compared the virus stock titer generated on Vero/TMPRSS2 cells to that generated by the Vero cell line. Although the Vero cells generated higher quantity of ZIKV stocks, the Vero/TMPRSS2 cells produced plaques with significantly improved morphology and visibility and may, therefore, be a better alternative to use for performing plaque assays for strains of ZIKV that are more difficult to titer on regular Vero cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Zika virus RNA structure controls its unique neurotropism by bipartite binding to Musashi-1

Human RNA binding protein Musashi-1 (MSI1) plays a critical role in neural progenitor cells (NPCs) by binding to various host RNA transcripts. The canonical MSI1 binding site (MBS), A/GU (1-3) AG single-strand motif, is present in many RNA virus genomes, but only Zika virus (ZIKV) genome has been demonstrated to bind MSI1. Herein, we identified the AUAG motif and the AGAA tetraloop in the Xrn1-resistant RNA 2 (xrRNA2) as the canonical and non-canonical MBS, respectively, and both are crucial for ZIKV neurotropism. More importantly, the unique AGNN-type tetraloop is evolutionally conserved, and distinguishes ZIKV from other known viruses with putative MBSs. Integrated structural analysis showed that MSI1 binds to the AUAG motif and AGAA tetraloop of ZIKV in a bipartite fashion. Thus, our results not only identified an unusual viral RNA structure responsible for MSI recognition, but also revealed a role for the highly structured xrRNA in controlling viral neurotropism.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

In vitro enhancement of Zika virus infection by preexisting West Nile virus antibodies in human plasma-derived immunoglobulins revealed after P2 binding site-specific enrichment

ABSTRACT Human immunoglobulin preparations contain a diverse range of polyclonal antibodies that reflect past immune responses against pathogens encountered by the blood donor population. In this study, we examined a panel of intravenous immunoglobulins (IGIVs) manufactured over the past two decades (1998–2020) for their capacity to neutralize or enhance Zika virus (ZIKV) infectionin vitro. These IGIVs were selected specifically based on their production dates in relation to the occurrences of two flavivirus outbreaks in the U.S.: the West Nile virus (WNV) outbreak in 1999 and the ZIKV outbreak in 2015. As demonstrated by enzyme-linked immunosorbent assay (ELISA) experiments, IGIVs made before the ZIKV outbreak already harbored antibodies that bind to various peptides across the envelope protein of ZIKV because of the WNV outbreak. Using phage display, the most dominant binding site was mapped precisely to the P2 peptide between residues 211 and 230 within domain II, where BF1176-56, an anti-ZIKV monoclonal antibody, also binds. When tested in permissive Vero E6 cells for ZIKV neutralization, the IGIVs, even after undergoing rigorous enrichment for P2 binding specificity, failed, as did BF1176-56. Meanwhile, BF1176-56 enhanced ZIKV infection in both FcγRII-expressing K562 cells and human peripheral blood mononuclear cells. However, for enhancement by the IGIVs to be detected in these cells, a substantial increase in their P2 binding specificity was required, thus linking the P2 site with ZIKV enhancementin vitro. Our findings warrant further study of the significance of elevated levels of anti-WNV antibodies in IGIVs, considering that various mechanisms operatingin vivomay modulate ZIKV infection outcomes. IMPORTANCE We investigated the capacity of intravenous immunoglobulins manufactured previously over two decades (1998–2020) to neutralize or enhance Zika virus infectionin vitro. West Nile virus antibodies in IGIVs could not neutralize Zika virus initially; however, once the IGIVs were concentrated further, they enhanced its infection. These findings lay the groundwork for exploring how preexisting WNV antibodies in IGIVs could impact Zika infection, bothin vitroandin vivo. Our observations are historically significant, since we tested a panel of IGIV lots that were carefully selected based on their production dates which covered two major flavivirus outbreaks in the U.S.: the WNV outbreak in 1999 and the ZIKV outbreak in 2015. These findings will facilitate our understanding of the interplay among closely related viral pathogens, particularly from a historical perspective regarding large blood donor populations. They should remain relevant for future outbreaks of emerging flaviviruses that may potentially affect vulnerable populations.

Microbiology↗
DOE OSTI2026

Impact of Selenium and Vitamin E Deficiency on Zika Virus Pathogenesis and Immune Response in Mice

Micronutrient status is recognized to influence host susceptibility to viral infections, yet its impact on Zika virus (ZIKV) pathogenesis remains incompletely understood. We investigated the effects of dietary selenium and combined selenium plus vitamin E deficiency on ZIKV infection outcomes in a type I interferon α/β receptor knockout (Ifnar1 −/− ) murine model. Mice maintained on deficient diets exhibited significantly lower neutralizing antibody titers and reduced levels of key antiviral cytokines (IFN-γ, TNF-α, IFN-α, IFN-β, IL-12p70, CCL5) compared to controls. Correspondingly, higher viral RNA loads were detected in the brains of double-deficient mice, which also experienced greater weight loss and increased mortality. Deep sequencing revealed no major differences in overall viral genome diversity across diet groups; however, specific mutations, including V330L and D67E in the E gene, and V360I in the NS3 gene, were enriched or detected in nutritionally deficient animals. These findings suggest that antioxidant micronutrient deficiency impairs both humoral and cellular immune responses to ZIKV, potentially facilitating enhanced neuroinvasion. While the functional consequences of the identified mutations warrant further investigation, our results underscore the importance of adequate micronutrient intake for optimal antiviral defense. Further studies are needed to clarify the epidemiological significance of these observations.

Biological and medical 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↗
DOE OSTI2024

High-resolution RNA tertiary structures in Zika virus stem-loop A for the development of inhibitory small molecules

Flaviviruses such as Zika (ZIKV) and dengue virus (DENV) are positive-sense RNA viruses belonging to Flaviviridae. The flavivirus genome contains a 5’ end stem-loop promoter sequence known as stem-loop A (SLA) that is recognized by the flavivirus polymerase NS5 during viral RNA synthesis and 5’ guanosine cap methylation. The crystal structures of ZIKV and DENV SLAs show a well-defined fold, consisting of a bottom stem, side loop, and top stem-loop, providing unique interaction sites for small-molecule inhibitors to disrupt the promoter function. To facilitate identification of small molecule binding sites in flavivirus SLA, we determined high-resolution structures of bottom and top stems of ZIKV SLA, which contain a single U- or G-bulge, respectively. Both bulge nucleotides exhibit multiple orientations, from folded back on the adjacent nucleotide to flipped out of the helix, and are stabilized by stacking or base triple interactions. These structures suggest that even a single unpaired nucleotide can provide flexibility to RNA structures and its conformation is mainly determined by the stabilizing chemical environment. To facilitate discovery of small molecule inhibitors that interfere with the functions of ZIKV SLA, we screened and identified compounds that bind to the bottom and top stems of ZIKV SLA.

Biochemistry & Molecular Biology↗
DOE OSTI2023

Small molecule inhibitors for treatment of alpha viruses

An in vitro assay was designed to measure the activity of the alphavirus non-structural protein 2 (nsP2), which is the viral protease and is required for viral replication. By taking advantage of fluorescence-resonance energy transfer between two proteins, a protease cleavage assay was generated. This was utilized for high-throughput screening of 40,000 small molecules. Inhibitors were validated using cell-based assays to measure alphavirus infection and cytotoxicity. Certain compounds were then characterized for anti-viral efficacy in various cell lines in numerous assays. Compounds were tested against Chikungunya virus, Venezuelan Equine Encephalitis virus, Rift Valley Fever virus, and Zika virus. Three compounds (compounds I, II, and III) showed pan-alphavirus anti-viral efficacy at concentrations that did not result in cell toxicity. An additional compound, structure IV, showed broad spectrum inhibition of all viruses tested. Pharmaceutical preparations and methods of treatment including these compounds are provided herein.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Zika-specific neutralizing antibodies targeting inter-dimer envelope epitopes

Zika virus (ZIKV) is an emerging pathogen that causes devastating congenital defects. The overlapping epidemiology and immunologic cross-reactivity between ZIKV and dengue virus (DENV) pose complex challenges to vaccine design, given the potential for antibody-dependent enhancement of disease. Therefore, classification of ZIKV-specific antibody targets is of notable value. From a ZIKV-infected rhesus macaque, we identify ZIKV-reactive B cells and isolate potent neutralizing monoclonal antibodies (mAbs) with no cross-reactivity to DENV. We group these mAbs into four distinct antigenic groups targeting ZIKV-specific cross-protomer epitopes on the envelope glycoprotein. Co-crystal structures of representative mAbs in complex with ZIKV envelope glycoprotein reveal envelope-dimer epitope and unique dimer-dimer epitope targeting. All four specificities are serologically identified in convalescent humans following ZIKV infection, and representative mAbs from all four groups protect against ZIKV replication in mice. These results provide key insights into ZIKV-specific antigenicity and have implications for ZIKV vaccine, diagnostic, and therapeutic development.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2016

Mapping Past, Present, and Future Climatic Suitability for Invasive Aedes Aegypti and Aedes Albopictus in the United States: A Process-Based Modeling Approach Using CMIP5 Downscaled Climate Scenarios

The ongoing spread of the mosquitoes, Aedes aegypti and Aedes albopictus, in the continental United States leaves new areas at risk for local transmission of dengue, chikungunya, and Zika viruses. All three viruses have caused major disease outbreaks in the Americas with infected travelers returning regularly to the U.S. The expanding range of these mosquitoes raises questions about whether recent spread has been enabled by climate change or other anthropogenic influences. In this analysis, we used downscaled climate scenarios from the NASA Earth Exchange Global Daily Downscaled Projections (NEX GDDP) dataset to model Ae. aegypti and Ae. albopictus population growth rates across the United States. We used a stage-structured matrix population model to understand past and present climatic suitability for these vectors, and to project future suitability under CMIP5 climate change scenarios. Our results indicate that much of the southern U.S. is suitable for both Ae. aegypti and Ae. albopictus year-round. In addition, a large proportion of the U.S. is seasonally suitable for mosquito population growth, creating the potential for periodic incursions into new areas. Changes in climatic suitability in recent decades for Ae. aegypti and Ae. albopictus have occurred already in many regions of the U.S., and model projections of future climate suggest that climate change will continue to reshape the range of Ae. aegypti and Ae. albopictus in the U.S., and potentially the risk of the viruses they transmit.

process-based modeling↗
DOE OSTI2024

Structure of an RNA G-quadruplex from the West Nile virus genome

Potential G-quadruplex sites have been identified in the genomes of DNA and RNA viruses and proposed as regulatory elements. The genus Orthoflavivirus contains arthropod-transmitted, positive-sense, single-stranded RNA viruses that cause significant human disease globally. Computational studies have identified multiple potential G-quadruplex sites that are conserved across members of this genus. Subsequent biophysical studies established that some G-quadruplexes predicted in Zika and tickborne encephalitis virus genomes can form and known quadruplex binders reduced viral yields from cells infected with these viruses. The susceptibility of RNA to degradation and the variability of loop regions have made structure determination challenging. Despite these difficulties, we report a high-resolution structure of the NS5-B quadruplex from the West Nile virus genome. Analysis reveals two stacked tetrads that are further stabilized by a stacked triad and transient noncanonical base pairing. This structure expands the landscape of solved RNA quadruplex structures and demonstrates the diversity and complexity of biological quadruplexes. We anticipate that the availability of this structure will assist in solving further viral RNA quadruplexes and provides a model for a conserved antiviral target in Orthoflavivirus genomes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Opportunities in multiscale modeling of mosquito-borne flaviviruses

Mosquito-borne flaviviruses, such as Zika, dengue, West Nile, and yellow fever virus, represent a growing public health concern due to their widespread distribution and the severe diseases they cause. These viruses are difficult to control as climate change and urbanization help mosquitoes expand into new areas, increasing the risk of outbreaks. Mathematical models play a key role in understanding their spread, providing insights at every level—from how the virus multiplies inside cells to how it circulates through entire populations. This review examines various approaches used in modeling arboviruses, including microscale models that focus on cellular and molecular dynamics, mesoscale models that address within-host processes, and macroscale models that capture population-level transmission. We briefly summarize the methodology used for models at each scale, which primarily consists of sets of differential equations with parameters that represent physical rates of change for different subprocesses. We particularly highlight how temperature affects virus transmission, which is key to understanding the impact of climate change. We also show how multiscale models can connect viral replication, immune response, and the spread of infection at a larger scale. This is essential for developing better vaccines and treatments, evaluating disease control measures, predicting the impact of climate change, and improving public health responses to outbreaks.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2021

Climate Predicts Geographic and Temporal Variation in Mosquito-Borne Disease Dynamics on Two Continents

Climate drives population dynamics through multiple mechanisms, which can lead to seemingly context-dependent effects of climate on natural populations. For climate-sensitive diseases such as dengue, chikungunya, and Zika, climate appears to have opposing effects in different contexts. Here we show that a model, parameterized with laboratory measured climate-driven mosquito physiology, captures three key epidemic characteristics across ecologically and culturally distinct settings in Ecuador and Kenya: the number, timing, and duration of outbreaks. The model generates a range of disease dynamics consistent with observed Aedes aegypti abundances and laboratory-confirmed arboviral incidence with variable accuracy (28–85% for vectors, 44–88%for incidence). The model predicted vector dynamics better in sites with a smaller proportion of young children in the population, lower mean temperature, and homes with piped water and made of cement. Models with limited calibration that robustly capture climate-virus relationships can help guide intervention efforts and climate change disease projections.

Climate-change ecology↗