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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 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Novel adaptive immune systems in pristine Antarctic soils

Antarctic environments are dominated by microorganisms, which are vulnerable to viral infection. Although several studies have investigated the phylogenetic repertoire of bacteria and viruses in these poly-extreme environments with freezing temperatures, high ultra violet irradiation levels, low moisture availability and hyper-oligotrophy, the evolutionary mechanisms governing microbial immunity remain poorly understood. Using genome-resolved metagenomics, we test the hypothesis that Antarctic poly-extreme high-latitude microbiomes harbour diverse adaptive immune systems. Our analysis reveals the prevalence of prophages in bacterial genomes (Bacteroidota and Verrucomicrobiota), suggesting the significance of lysogenic infection strategies in Antarctic soils. Furthermore, we demonstrate the presence of diverse CRISPR-Cas arrays, including Class 1 arrays (Types I-B, I-C, and I-E), alongside systems exhibiting novel gene architecture among their effector cas genes. Notably, a Class 2 system featuring type V variants lacks CRISPR arrays, encodes Cas1 and Cas2 adaptation module genes. Phylogenetic analysis of Cas12 effector proteins hints at divergent evolutionary histories compared to classified type V effectors and indicates that TnpB is likely the ancestor of Cas12 nucleases. Our findings suggest substantial novelty in Antarctic cas sequences, likely driven by strong selective pressures. These results underscore the role of viral infection as a key evolutionary driver shaping polar microbiomes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Histopathological characteristics of PRRS and expression profiles of viral receptors in the piglet immune system

Porcine reproductive and respiratory syndrome (PRRS) is a highly contagious viral disease that causes significant economic losses to the swine industry worldwide. PRRS virus (PRRSV) infection is a receptor-mediated endocytosis and replication process. The purpose of this study was to determine the localization and expression of four important PRRSV receptors in immunological organs of piglets. After piglets were infected with PRRSV, Hematoxylin and Eosin staining, immunofluorescence, and Western blot were used to perform histopathological examination and receptors distribution analysis. The results showed that PRRSV caused severe damage to the piglets’ immune organs, including atrophy of the thymus and swelling of lymph node. Histopathological lesions were mainly observed in the lung and lymph node and were characterized by interstitial pneumonia, collapsed follicles, exhaustion of germinal centers, and extensive hemorrhage. Immunofluorescence staining and Western blot results showed that the receptors of CD163 and NMHCII-A were mainly distributed in the thymus, hilar lymph nodes, and mesenteric lymph nodes. However, Sn and vimentin receptors were expressed at low levels in the immune organs of piglets. The distribution of the four receptors in the immune organs was more concentrated in the cortex but was more scattered in the medulla. Compared to the control group, the relative expression of the four receptors increased significantly in most immune organs after viral infection. In conclusion, our study examined the distribution and expression of four PRRSV receptors in immunological organs. We observed a significant increase in the expression of Sn, CD163, and vimentin following viral infection. These findings may provide potential targets for future antiviral reagent design or vaccine development.

Chen, Hong↗
DOE OSTI2024

Nucleic acid mediated activation of a short prokaryotic Argonaute immune system

A short prokaryotic Argonaute (pAgo) TIR-APAZ (SPARTA) defense system, activated by invading DNA to unleash its TIR domain for NAD(P) + hydrolysis, was recently identified in bacteria. We report the crystal structure of SPARTA heterodimer in the absence of guide-RNA/target-ssDNA (2.66 Å) and a cryo-EM structure of the SPARTA oligomer (tetramer of heterodimers) bound to guide-RNA/target-ssDNA at nominal 3.15–3.35 Å resolution. The crystal structure provides a high-resolution view of SPARTA, revealing the APAZ domain as equivalent to the N, L1, and L2 regions of long pAgos and the MID domain containing a unique insertion (insert57). Cryo-EM structure reveals regions of the PIWI (loop10-9) and APAZ (helix αN) domains that reconfigure for nucleic-acid binding and decrypts regions/residues that reorganize to expose a positively charged pocket for higher-order assembly. The TIR domains amass in a parallel-strands arrangement for catalysis. We visualize SPARTA before and after RNA/ssDNA binding and uncover the basis of its active assembly leading to abortive infection.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Developmental Ethanol Exposure Impacts Purkinje Cells but Not Microglia in the Young Adult Cerebellum

Fetal alcohol spectrum disorders (FASD) caused by developmental ethanol exposure lead to cerebellar impairments, including motor problems, decreased cerebellar weight, and cell death. Alterations in the sole output of the cerebellar cortex, Purkinje cells, and central nervous system immune cells, microglia, have been reported in animal models of FASD. To determine how developmental ethanol exposure affects adult cerebellar microglia and Purkinje cells, we used a human third-trimester binge exposure model in which mice received ethanol or saline from postnatal (P) days 4–9. In adolescence, cerebellar cranial windows were implanted and mice were aged to young adulthood for examination of microglia and Purkinje cells in vivo with two-photon imaging or in fixed tissue. Ethanol had no effect on microglia density, morphology, dynamics, or injury response. However, Purkinje cell linear frequency was reduced by ethanol. Microglia–Purkinje cell interactions in the Purkinje Cell Layer were altered in females compared to males. Overall, developmental ethanol exposure had few effects on cerebellar microglia in young adulthood and Purkinje cells appeared to be more susceptible to its effects.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Host-Directed, Bioelectronic Immunomodulation for Protection Against Emerging Pathogens

Acute care of patients with severe infections often relies on systemic administration of pharmaceuticals and monitoring of complex physiological symptoms to identify immune system dysfunction, which can lead to increased mortality. Furthermore, determining disease-specific treatment plans often leads to a delay in patient care. To address this, we proposed an immune modulation system that electrically detects and responds to a patient’s immune system status, creating an agnostic means of treating illness and infection. Two pieces of hardware were developed for this task: a minimally-invasive sensor and a vagus nerve stimulator. Stimulation of the vagus nerve is known to modulate the immune system. The sensor is a microfabricated, silicon-based microneedle array capable of interfacing with interstitial fluid to detect small molecules such as inflammatory proteins (cytokines) and pharmaceuticals (vancomycin). Process optimization to manufacture the needles refined the silicon etch process, creating needle patches long enough to penetrate skin and reach interstitial fluid. The needles were tested for mechanical strength and stability, and did not shatter when inserted into skin models. The needles are coated with a thin film metal, turning them into electrodes for electrochemical sensing of our target molecules. We hybridized aptamers to the surface of the electrode to act as the sensing layer and were able to detect changes in the conformation of the aptamer electrochemically in the presence of the target molecule. The stimulator was a cuff electrode that encircled the vagus nerve. Rodent studies were conducted in which rodents were exposed to an inflammatory event and vagus nerve stimulation (VNS) was applied. It was demonstrated that optimized electrical stimulation of the vagus nerve created measurably different levels of cytokines in blood samples, and certain cytokines released during the inflammatory event were either upregulated or downregulated. In sum, this project successfully developed new platforms and technologies that can, with further development, enable better temporal insight into biomarker changes in the body, letting healthcare providers know of possible immune system dysfunction before they are detected physiologically. We also demonstrated the value of VNS and its possible use in treating immune system response to inflammation and illness.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Recurrent acquisition of nuclease-protease pairs in antiviral immunity

Antiviral immune systems diversify by integrating new genes into existing pathways, creating new mechanisms of viral resistance. We identified genes encoding a predicted nuclease paired with a trypsin-like protease repeatedly acquired by multiple, otherwise unrelated antiviral immune systems in bacteria. Cell-based and biochemical assays revealed that the nuclease is a proenzyme that cleaves DNA only after activation by its partner protease. Two distinct immune systems, Hachiman and AVAST (antiviral adenosine triphosphatase/nucleoside triphosphatase of the STAND superfamily, Avs), use the same mechanism of proteolytic activation despite their independent evolutionary origins. Examination of nuclease-protease inheritance patterns identified caspase-nuclease (canu) genomic loci that confer antiviral defense in a pathway reminiscent of eukaryotic caspase activation. These results uncover the coordinated activities of pronucleases and their activating proteases within different immune systems and show how coevolution enables defense system innovation.

Tuck, Owen T↗
DOE OSTI2023

Modeling immunity in microphysiological systems

There is a need for better predictive models of the human immune system to evaluate safety and efficacy of immunomodulatory drugs and biologics for successful product development and regulatory approvals. Current in vitro models, which are often tested in two-dimensional (2D) tissue culture polystyrene, and preclinical animal models fail to fully recapitulate the function and physiology of the human immune system. Microphysiological systems (MPSs) that can model key microenvironment cues of the human immune system, as well as of specific organs and tissues, may be able to recapitulate specific features of the in vivo inflammatory response. This minireview provides an overview of MPS for modeling lymphatic tissues, immunity at tissue interfaces, inflammatory diseases, and the inflammatory tumor microenvironment in vitro and ex vivo. Broadly, these systems have utility in modeling how certain immunotherapies function in vivo, how dysfunctional immune responses can propagate diseases, and how our immune system can combat pathogens.

Research & Experimental Medicine↗
DOE OSTI2024

Logistics of defense: The contribution of endomembranes to plant innate immunity

Phytopathogens cause plant diseases that threaten food security. Unlike mammals, plants lack an adaptive immune system and rely on their innate immune system to recognize and respond to pathogens. Plant response to a pathogen attack requires precise coordination of intracellular traffic and signaling. Spatial and/or temporal defects in coordinating signals and cargo can lead to detrimental effects on cell development. The role of intracellular traffic comes into a critical focus when the cell sustains biotic stress. In this review, we discuss the current understanding of the post-immune activation logistics of plant defense. Specifically, we focus on packaging and shipping of defense-related cargo, rerouting of intracellular traffic, the players enabling defense-related traffic, and pathogen-mediated subversion of these pathways. We highlight the roles of the cytoskeleton, cytoskeleton–organelle bridging proteins, and secretory vesicles in maintaining pathways of exocytic defense, acting as sentinels during pathogen attack, and the necessary elements for building the cell wall as a barrier to pathogens. We also identify points of convergence between mammalian and plant trafficking pathways during defense and highlight plant unique responses to illustrate evolutionary adaptations that plants have undergone to resist biotic stress.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Using CRISPR/Cas13a technologies to detect miRNA [DOE SULI Internship Report]

Micro ribonucleic acids (miRNA) give our immune systems the ability to recognize viruses and other pathogens by their complementary single-stranded RNA (ssRNA) produced in the reproduction of the pathogen in our cells. When miRNA of a specific sequence is detected in a cell sample, it can be assumed that the immune system is activated and attempting to track down the infection. This pathway can be utilized to diagnose infection from a pathogen before the individual even develops symptoms, aiding in early disease detection and proper treatment. One of the ways that we can detect miRNA is through an assay of clustered regularly interspaced short palindromic repeats or “CRISPR” and the bacterial protein Cas13a. This report details discoveries made while attempting to optimize this assay for miRNA detection. After looking at several different factors within the assay, it was determined that some factors, such as reporter type and metallic ion concentration, are more impactful on the overall assay sensitivity than other factors, such as the overall concentration of Cas13a, CRISPR RNA (crRNA), or ssRNA reporter. It was also discovered that different sequences with different lengths require renewed optimization efforts, as each target has a unique binding affinity determined by the sequence length and composition. This information is crucial in the development of point of care molecular detection devices as they become sensitive enough to identify pathogens before they spread.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Morphologic characterization and cytokine response of chicken bone-marrow derived dendritic cells to infection with high and low pathogenic avian influenza virus

Dendritic cells (DCs) are professional antigen-presenting cells, which are key components of the immune system and involved in early immune responses. DCs are specialized in capturing, processing, and presenting antigens to facilitate immune interactions. Chickens infected with avian influenza virus (AIV) demonstrate a wide range of clinical symptoms, based on pathogenicity of the virus. Low pathogenic avian influenza (LPAI) viruses typically induce mild clinical signs, whereas high pathogenic avian influenza (HPAI) induce more severe disease, which can lead to death. For this study, chicken bone marrow-derived DC (ckBM-DC)s were produced and infected with high and low pathogenic avian influenza viruses of H5N2 or H7N3 subtypes to characterize innate immune responses, study effect on cell morphologies, and evaluate virus replication. A strong proinflammatory response was observed at 8 hours post infection, via upregulation of chicken interleukin-1β and stimulation of the interferon response pathway. Microscopically, the DCs underwent morphological changes from classic elongated dendrites to a more general rounded shape that eventually led to cell death with the presence of scattered cellular debris. Differences in onset of morphologic changes were observed between H5 and H7 subtypes. Increases in viral titers demonstrated that both HPAI and LPAI are capable of infecting and replicating in DCs. The increase in activation of infected DCs may be indicative of a dysregulated immune response typically seen with HPAI infections.

Immunology↗
DOE OSTI2023

Genome expansion by a CRISPR trimmer-integrase

CRISPR–Cas adaptive immune systems capture DNA fragments from invading mobile genetic elements and integrate them into the host genome to provide a template for RNA-guided immunity. CRISPR systems maintain genome integrity and avoid autoimmunity by distinguishing between self and non-self, a process for which the CRISPR/Cas1–Cas2 integrase is necessary but not sufficient. In some microorganisms, the Cas4 endonuclease assists CRISPR adaptation, but many CRISPR–Cas systems lack Cas4. Here we show here that an elegant alternative pathway in a type I-E system uses an internal DnaQ-like exonuclease (DEDDh) to select and process DNA for integration using the protospacer adjacent motif (PAM). The natural Cas1–Cas2/exonuclease fusion (trimmer-integrase) catalyses coordinated DNA capture, trimming and integration. Five cryo-electron microscopy structures of the CRISPR trimmer-integrase, visualized both before and during DNA integration, show how asymmetric processing generates size-defined, PAM-containing substrates. Before genome integration, the PAM sequence is released by Cas1 and cleaved by the exonuclease, marking inserted DNA as self and preventing aberrant CRISPR targeting of the host. Together, these data support a model in which CRISPR systems lacking Cas4 use fused or recruited exonucleases for faithful acquisition of new CRISPR immune sequences.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Challenges in cybersecurity: Lessons from biological defense systems

Defending against novel, repeated, or unpredictable attacks, while avoiding attacks on the ‘self’, are the central problems of both mammalian immune systems and computer systems. Both systems have been studied in great detail, but with little exchange of information across the different disciplines. Here, we present a conceptual framework for structured comparisons across the fields of biological immunity and cybersecurity, by framing the context of defense, considering different (combinations of) defensive strategies, and evaluating defensive performance. Throughout this paper, we pose open questions for further exploration. In this work we hope to spark the interdisciplinary discovery of general principles of optimal defense, which can be understood and applied in biological immunity, cybersecurity, and other defensive realms.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Antibiotic Treatment Prior to Injury Abrogates the Detrimental Effects of LPS in STR/ort Mice Susceptible to Osteoarthritis Development

Post traumatic osteoarthritis (PTOA) is a form of secondary osteoarthritis (OA) that develops in ~50% of cases of severe articular joint injuries and leads to chronic and progressive degradation of articular cartilage and other joint tissues. PTOA progression can be exacerbated by repeated injury and systemic inflammation. Few studies have examined approaches for blunting or slowing down PTOA progression with emphasis on systemic inflammation; most arthritis studies focused on the immune system have been in the context of rheumatoid arthritis. To examine how the gut microbiome affects systemic inflammation during PTOA development, we used a chronic antibiotic treatment regimen starting at weaning for 6 weeks before anterior cruciate ligament (ACL) rupture in STR/ort mice combined with lipopolysaccharide (LPS)-induced systemic inflammation. STR/ort mice develop spontaneous OA as well as a more severe PTOA phenotype than C57Bl/6J mice. By 6 weeks post injury, histological examination showed a more robust cartilage staining in the antibiotic-treated (AB) STR/ort mice than in the untreated STR/ort controls. Furthermore, we also examined the effects of AB treatment on systemic inflammation and found that the effects of LPS administration before injury are also blunted by AB treatment in STR/ort mice. The AB- or AB+LPS-treated STR/ort injured joints more closely resembled the C57Bl/6J VEH OA phenotypes than the vehicle- or LPS-treated STR/ort, suggesting that antibiotic treatment has the potential to slow disease progression and should be further explored therapeutically as prophylactic post injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Structural basis for the activity and specificity of the immune checkpoint inhibitor lirilumab

The clinical success of immune checkpoint inhibitors has underscored the key role of the immune system in controlling cancer. Current FDA-approved immune checkpoint inhibitors target the regulatory receptor pathways of cytotoxic T-cells to enhance their anticancer responses. Despite an abundance of evidence that natural killer (NK) cells can also mediate potent anticancer activities, there are no FDA-approved inhibitors targeting NK cell specific checkpoint pathways. Lirilumab, the most clinically advanced NK cell checkpoint inhibitor, targets inhibitory killer immunoglobulin-like receptors (KIRs), however it has yet to conclusively demonstrate clinical efficacy. Here we describe the crystal structure of lirilumab in complex with the inhibitory KIR2DL3, revealing the precise epitope of lirilumab and the molecular mechanisms underlying KIR checkpoint blockade. Notably, the epitope includes several key amino acids that vary across the human population, and binding studies demonstrate the importance of these amino acids for lirilumab binding. These studies reveal how KIR variations in patients could influence the clinical efficacy of lirilumab and reveal general concepts for the development of immune checkpoint inhibitors targeting NK cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Making a Monkey out of Human Immunodeficiency Virus/Simian Immunodeficiency Virus Pathogenesis: Immune Cell Depletion Experiments as a Tool to Understand the Immune Correlates of Protection and Pathogenicity in HIV Infection

Understanding the underlying mechanisms of HIV pathogenesis is critical for designing successful HIV vaccines and cure strategies. However, achieving this goal is complicated by the virus’s direct interactions with immune cells, the induction of persistent reservoirs in the immune system cells, and multiple strategies developed by the virus for immune evasion. Meanwhile, HIV and SIV infections induce a pandysfunction of the immune cell populations, making it difficult to untangle the various concurrent mechanisms of HIV pathogenesis. Over the years, one of the most successful approaches for dissecting the immune correlates of protection in HIV/SIV infection has been the in vivo depletion of various immune cell populations and assessment of the impact of these depletions on the outcome of infection in non-human primate models. Here, we present a detailed analysis of the strategies and results of manipulating SIV pathogenesis through in vivo depletions of key immune cells populations. Although each of these methods has its limitations, they have all contributed to our understanding of key pathogenic pathways in HIV/SIV infection.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2023

Elucidating Mechanisms of Rust Pathogenesis for Engineering Resistance in Poplar

The overall objective of this research was to elucidate the molecular basis for the virulence of Melampsora larici-populina towards Populus spp. in order to address the formidable challenge of engineering durable resistance in poplar against leaf rust. Our original research plan was built on the technically innovative approach of using dual host systems and known host defense proteins and pathogen avirulent effectors along with genome-wide approaches to identify key pathogenesis effectors of Melampsora larici-populina that target poplar defense and nutrient acquisition. Our efforts focused on developing high-throughput experimental approaches and systems to enable us to address our overarching hypothesis that rust effectors with homology to other fungal effectors will either bypass the poplar immune system and/or suppress effector-triggered immunity through conserved mechanisms, and that an analysis of these interaction networks would provide for new approaches to develop rust-resistant poplar. Three main objectives were originally proposed: (1) mine key rust effectors that suppress host immunity; (2) elucidate interaction networks in poplar targeted by key rust effectors; (3) generate transgenic poplar resources for identification of genes involved in pathogen infection or host defense triggered by rust. Generally, we worked towards all three objectives by developing and applying complementary molecular, genomic, biochemical and plant transformation approaches.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2025

scRNA seq of an F1 cross of Marek’s disease resistant and susceptible chickens identifies allele specific expression signatures enriched in transcription modulators

Abstract Marek’s disease (MD), a T cell lymphoma disease in chickens, is caused by the Marek’s disease virus (MDV) found ubiquitously in the poultry industry. Genetically resistant Line 6 3 (L6) and susceptible Line 7 2 (L7) chickens have been instrumental to research on avian immune system response to MDV infection. In this study we characterized molecular signatures unique to splenic immune cell types across different genetic backgrounds 6 days after infection. Using three populations, L6, L7, and an F1 cross between L6xL7, we evaluated the immune cell transcriptome of responding cell types using single cell RNA sequencing. Several MDV genes were found expressed mainly in cytotoxic T cells while ICP4 and MEQ MDV genes were expressed across infected cell types. Using the F1 we quantified allele specific expression (ASE) of biallelic SNPs and found biased expression of parental alleles specific to immune cell subtypes. We identified 22 SNPs with ASE in response to MDV infection mapped to gene rich regions surrounding 59 genes of critical importance for chromatin remodeling and transcriptional regulation. Histone deacetylase genes (HDAC1 and HDAC8) had increased expression of L6 alleles, while small nuclear RNA genes (SNORA68 and SNORA72) expressed higher levels of L7 alleles with infection in T cell subsets. SNPs with ASE also mapped genes important for an adequate immune response including GNLY (cytotoxic activity) and PDIA3 (component of MHC class I peptide loading complex), and genes known to promote viral replication (MCM5 and EIF3M). These results show that functional variants associated with susceptibility to MD may have a bigger impact in subsets of immune cell types, and by characterizing the transcriptomes of these subtypes we can unravel molecular signatures specific to MD genomic resistance.

Science & Technology - Other Topics↗
DOE OSTI2025

De novo synthesis and near atomic resolution imaging of host immune receptors critical for pathogen recognition (Abbreviated Final Report)

The innate immune system serves as the body’s first line of defense against invading pathogens, responding rapidly through the deployment of immune cells at common sites of infection, such as the skin and airways. These immune-cell sentinels express a range of highly conserved receptors, including Toll-like receptors (TLRs), which recognize and bind to pathogen-derived components. This recognition event triggers intracellular signaling cascades that initiate and coordinate immune responses. Despite their significance, the complete structural characterization of full-length TLRs, including their extracellular domain (ECD), transmembrane domain (TMD), and Toll/interleukin-1 receptor (TIR) domain, remains incomplete. In this study, we examined the expression and isolation of human TLR4 incorporated into nanodiscs using two approaches: a cell-free synthesis system and a cell-based transfection strategy employing Expi293F cells derived from the human embryonic kidney lineage. Our findings demonstrate that NLP-bound human TLR4 produced via the cell-based method yielded functional protein suitable for time-resolved single-particle cryo-electron microscopy (cryo-EM). This advancement enables structural characterization of full-length TLR4, maintaining the integrity of its extracellular domain, transmembrane domain, and Toll/Interleukin-1 receptor (TIR) domain.

59 BASIC BIOLOGICAL SCIENCES↗