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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 127 records · Page 7
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

A Mathematical Model of the Dynamics of Cytokine Expression and Human Immune Cell Activation in Response to the Pathogen Staphylococcus aureus

Cell-based mathematical models have previously been developed to simulate the immune system in response to pathogens. Mathematical modeling papers which study the human immune response to pathogens have predicted concentrations of a variety of cells, including activated and resting macrophages, plasma cells, and antibodies. This study aims to create a comprehensive mathematical model that can predict cytokine levels in response to a gram-positive bacterium, S. aureus by coupling previous models. To accomplish this, the cytokines Tumor Necrosis Factor Alpha (TNF-α), Interleukin 6 (IL-6), Interleukin 8 (IL-8), and Interleukin 10 (IL-10) are included to quantify the relationship between cytokine release from macrophages and the concentration of the pathogen, S. aureus, ex vivo. Partial differential equations (PDEs) are used to model cellular response and ordinary differential equations (ODEs) are used to model cytokine response, and interactions between both components produce a more robust and more complete systems-level understanding of immune activation. In the coupled cellular and cytokine model outlined in this paper, a low concentration of S. aureus is used to stimulate the measured cellular response and cytokine expression. Results show that our cellular activation and cytokine expression model characterizing septic conditions can predict ex vivo mechanisms in response to gram-negative and gram-positive bacteria. Our simulations provide new insights into how the human immune system responds to infections from different pathogens. Novel applications of these insights help in the development of more powerful tools and protocols in infection biology.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1976

Bioprocessing development: Immune/cellular applications: Anti-Ig autoantibody and complement-mediated destruction of neoplastic cells

This space bioprocessing contract effort was comprised of four general objectives. These were: (1) the evaluation of current separation processes, (2) the identification of problems relevant to the separation of important biologicals, (3) the identification of ground-based assay methods needed for pre- and postflight analysis of space bioprocessing separation technology; and (4) the establishment of methods to determine the efficiency of space bioprocessing separation procedures. Immunology was deemed advantageous to study the diversity of cells and cell products involved and the extensive interest being given to their separation. Upon recognition of a cellular or molecular agent as foreign to the body, the immune system becomes activated to produce cells whose function is to destroy that agent and cell products whose function is to inactivate the agent and assist in its destruction. Long after the agent is removed from the body, some cells remain in a state of readiness to continue these destructive actions specifically against that agent should further exposure to it occur. This is the basis of acquired immunity to disease.

Twomey, J. J.↗
NASA NTRSDate not supplied

Creating Benchmark Data for Artificial Intelligence and Machine Learning Space Biology Research

To identify an appropriate AI/ML approach for a specific problem, the best practice is to measure algorithm performance through the benchmarking process. A scientific benchmark consists of an AI-ready dataset and a reference implementation on a specific scientific question. The NASA Science Mission Directorate (SMD) has started the “Benchmark Initiative for AI/ML to create scientific benchmark datasets in three applications: 1) scientific benchmarking, which finds the best algorithm for a specific problem; 2) application benchmarking, which measures algorithm performance against a set of parameters; and 3) system benchmarking, which evaluates performance of hardware and software architecture. Currently, there are no standardized datasets available to benchmark AI/ML algorithms in the domain of space biology. In this work, we constructed two AI/ML-ready biological datasets from experiments in space-flown mice: cellular imaging and RNA-seq. First, radiation-exposed immune cells harbor DNA damage foci that can be fluorescently marked to visualize the amount of damage following exposure to ionizing radiation. However, such large datasets are difficult to analyze visually, due to imaging inconsistencies and human bias, and classical image processing approaches can fail on imaging artifacts. AI/ML are therefore exciting alternative, providing the speed of machines and the accuracy of humans. We have made this dataset available at https://registry.opendata.aws/bps_microscopy/. Second, high-throughput nucleic acid sequencing (DNA-seq, RNA-seq) has become widespread in biomedical research due to the growing availability and affordability of these assays. However, most sequencing datasets suffer from high dimensionality and low sample count. In this work, we used a generative adversarial network to synthesize a standardized, AI-ready, publicly available benchmark dataset for space biology RNA-seq data with sufficient space-flown and ground control mouse liver samples from NASA GeneLab. This dataset is available at https://registry.opendata.aws/bps_rnaseq/. These datasets are now fully open the Space Biology community to test their favorite AI/ML approaches.

James Casaletto↗
NASA NTRS2025

Influence of Microgravity on Bacterial Pathogen Virulence and Immune Cell Function—Relevance for Infectious Disease Risk During Spaceflight

Spaceflight has measurable impacts on astronaut immune profiles as well as the virulence patterns of bacterial pathogens. Data with respect to human immunity indicate diminished T and NK cell function, altered cytokine profiles, persistent inflammation, and latent herpesvirus reactivation. Furthermore, evaluation of International Space Station (ISS) crewmembers gives evidence of compromised immunity, including atypical allergy, infectious disease, and dermatitis. Data with respect to certain human bacterial pathogens suggest modified virulence that may be enhanced. It is therefore critical to examine this interaction of immune dysregulation and increased microbial virulence and whether it might synergistically increase the risk of infectious disease to crew members. The goal of this study is to use modeled microgravity to study the impact of medically significant ISS bacteria that may have altered virulence on the immune response of the host. This study consists of two primary aims to assess this relationship. First, immune cells will be collected from healthy test subjects and cultured in static or in modeled microgravity conditions together with either control pathogens or with microgravity conditioned pathogens that were grown in bioreactors. Second, immune cells will be collected from astronauts before, during, and after flight and co-cultured with the control or the microgravity conditioned bacteria. Three pathogens were selected for this investigation: Pseudomonas aeruginosa , Salmonella enterica serovar Enteritidis and Burkholderia cepacia . Previously, the optimal cell to bacteria ratios that produce the greatest immune cell responses have been derived for these three bacteria. Cellular activation, as determined by the induction of cell surface activation markers and cytokine profiles, will be measured. Interactions between cells and bacteria will be assessed using fluorescent and electron microscopy techniques. This study will provide critical information to help understand how microgravity alters microbial virulence and the associated infectious disease risk to crewmembers during spaceflight missions. Over the past year, the Immunology and Microbiology laboratories at NASA Johnson Space Center have collaborated to process the astronaut subject samples to complete the last year of the flight portion of this study. This included the completion of four astronaut subjects full mission sampling sets. Sample processing included innate and adaptive cell flow cytometry as well as analysis of cytokine concentrations in the supernatant. The ground control segment of the study will take place during FY25 which involves parallel infections run under static and clinostat conditions. The acquired data sets over this 3-year study are now being analyzed to provide a comprehensive set of results and conclusions that will contribute to a more effective risk assessment for astronauts during spaceflight regarding this host-pathogen context.

Immunology↗
DOE OSTI2021

Next-generation yeast-two-hybrid analysis with Y2H-SCORES identifies novel interactors of the MLA immune receptor

Protein-protein interaction networks are one of the most effective representations of cellular behavior. In order to build these models, high-throughput techniques are required. Next-generation interaction screening (NGIS) protocols that combine yeast two-hybrid (Y2H) with deep sequencing are promising approaches to generate interactome networks in any organism. However, challenges remain to mining reliable information from these screens and thus, limit its broader implementation. Here, we present a computational framework, designated Y2H-SCORES, for analyzing high-throughput Y2H screens. Y2H-SCORES considers key aspects of NGIS experimental design and important characteristics of the resulting data that distinguish it from RNA-seq expression datasets. Three quantitative ranking scores were implemented to identify interacting partners, comprising: 1) significant enrichment under selection for positive interactions, 2) degree of interaction specificity among multi-bait comparisons, and 3) selection of in-frame interactors. Using simulation and an empirical dataset, we provide a quantitative assessment to predict interacting partners under a wide range of experimental scenarios, facilitating independent confirmation by one-to-one bait-prey tests. Simulation of Y2H-NGIS enabled us to identify conditions that maximize detection of true interactors, which can be achieved with protocols such as prey library normalization, maintenance of larger culture volumes and replication of experimental treatments. Y2H-SCORES can be implemented in different yeast-based interaction screenings, with an equivalent or superior performance than existing methods. Proof-of-concept was demonstrated by discovery and validation of novel interactions between the barley nucleotide-binding leucine-rich repeat (NLR) immune receptor MLA6, and fourteen proteins, including those that function in signaling, transcriptional regulation, and intracellular trafficking.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2001

Suppression of antigen-specific lymphocyte activation in modeled microgravity

Various parameters of immune suppression are observed in lymphocytes from astronauts during and after a space flight. It is difficult to ascribe this suppression to microgravity effects on immune cells in crew specimens, due to the complex physiological response to space flight and the resultant effect on in vitro immune performance. Use of isolated immune cells in true and modeled microgravity in immune performance tests, suggests a direct effect of microgravity on in vitro cellular function. Specifically, polyclonal activation of T-cells is severely suppressed in true and modeled microgravity. These recent findings suggest a potential suppression of oligoclonal antigen-specific lymphocyte activation in microgravity. We utilized rotating wall vessel (RWV) bioreactors as an analog of microgravity for cell cultures to analyze three models of antigen-specific activation. A mixed-lymphocyte reaction, as a model for a primary immune response, a tetanus toxoid response and a Borrelia burgdorferi response, as models of a secondary immune response, were all suppressed in the RWV bioreactor. Our findings confirm that the suppression of activation observed with polyclonal models also encompasses oligoclonal antigen-specific activation.

NASA Discipline Cell Biology↗
DOE OSTI2026

Human RNome Project draft human RNome sequence of GM12878, B-cell line, obtained by mass-spectrometry sequencing, long-read sequencing and short-read sequencing.

Here we report the first draft of the human RNome sequence, a reference map of RNA chemical modifications in a human B-cell line. RNA carries a diverse repertoire of chemical modifications that regulate gene expression, cellular function, and responses to physiological and pathological cues. Yet, unlike the genome, no reference map of RNA modifications is available for any human cell. To generate this resource, the Human RNome Project Consortium analyzed a shared RNA preparation from the well-characterized GM12878 B-cell line using short-read sequencing, long-read direct RNA sequencing, and mass spectrometry, generating more than 7.1 billion sequencing reads spanning approximately 1.2 trillion nucleotides. The resulting maps of the human RNome reveal that RNA modifications are organized according to function, transcript architecture, and cellular identity. Modifications concentrate at functional centers of ribosomal and transfer RNAs, follow the canonical topology of N6-methyladenosine in coding transcripts, and form coordinated hotspots in immune regulatory genes. This first reference human RNome provides a foundation for understanding how RNA chemistry shapes cellular identity, human disease, and the development of RNA-based therapeutics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Modeling dynamics of acute HIV infection incorporating density-dependent cell death and multiplicity of infection

Understanding the dynamics of acute HIV infection can offer valuable insights into the early stages of viral behavior, potentially helping uncover various aspects of HIV pathogenesis. The standard viral dynamics model explains HIV viral dynamics during acute infection reasonably well. However, the model makes simplifying assumptions, neglecting some aspects of HIV infection. For instance, in the standard model, target cells are infected by a single HIV virion. Yet, cellular multiplicity of infection (MOI) may have considerable effects in pathogenesis and viral evolution. Further, when using the standard model, we take constant infected cell death rates, simplifying the dynamic immune responses. Here, we use four models—1) the standard viral dynamics model, 2) an alternate model incorporating cellular MOI, 3) a model assuming density-dependent death rate of infected cells and 4) a model combining (2) and (3)—to investigate acute infection dynamics in 43 people living with HIV very early after HIV exposure. We find that all models qualitatively describe the data, but none of the tested models is by itself the best to capture different kinds of heterogeneity. Instead, different models describe differing features of the dynamics more accurately. For example, while the standard viral dynamics model may be the most parsimonious across study participants by the corrected Akaike Information Criterion (AICc), we find that viral peaks are better explained by a model allowing for cellular MOI, using a linear regression analysis as analyzed by R 2 . These results suggest that heterogeneity in within-host viral dynamics cannot be captured by a single model. Depending on the specific aspect of interest, a corresponding model should be employed.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

MCPIP1 is a positive regulator of type I interferons antiviral activity

Highlights: • MCPIP1 promotes innate antiviral immunity independently of its RNase activity. • MCPIP1 enhances IFN-I mediated antiviral activity. • MCPIP1 is an IFN-induced positive feedback signal for IFN signaling activation. • MCPIP1 promotes ISRE promoter activity and ISGs expression in IFN signaling. Type-I interferons (IFN-I) are widely used for antiviral immunotherapy in clinic. Therefore, identification of the regulators of IFN-I antiviral activity is important for developing novel targets for IFN-based antiviral therapy. Monocyte chemoattractant protein 1-induced protein 1 (MCPIP1) is critical for cellular inflammatory responses. However, the roles of MCPIP1 in interferons (IFNs)-mediated antiviral immunity are unexplored. In this study, we demonstrate for the first time that MCPIP1 is an important positive regulator of IFNs antiviral activity. We found that MCPIP1 can promote innate antiviral immunity independently of both its RNase and deubiquitinase activity. Furthermore, we reveal that MCPIP1 is an IFN-induced positive feedback signal molecule which promotes IFN-I-mediated antiviral efficacy. Mechanistically, MCPIP1 does not affect the activation of JAK/STAT upstream of IFN-I signaling, but significantly promotes IFN-I signaling by enhancing ISRE promoter activity and expression of interferon-stimulated genes (ISGs). And MCPIP1-mediated activation of IFN-I signaling is independently of its RNase and deubiquitinase activity. These findings uncover a novel innate antiviral mechanism mediated by the IFN-MCPIP1 axis, and may provide potential targets for enhancing IFNs antiviral therapy.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2000

Effects of JP-8 Jet Fuel on Homeostasis of Clone 9 Rat Liver Cells

Chronic exposure to JP-8 and other kerosene-based petroleum distillates has been associated with hepatic, renal, neurologic, pulmonary, and immune toxicity. However, the effects of kerosene-type jet fuels on cellular homeostasis hitherto have not been reported. Fluorescence imaging using a Meridian Ultima laser scanning fluorescence microscope was used to evaluate the effect of JP-8 jet fuel on a communication competent rat liver cell line. Several endpoints of cellular function were measured including gap junctional intercellular communication (GJIC), mitochondrial and plasma membrane potential (MMP and PMP, respectively), intracellular glutathione (GSH) concentration, glutathione-S-transferase (GST) activity, and reactive oxygen species (ROS) generation. Cells were treated with JP-8 (0.01 to 2% in ethanol (EtOH)) for the following time points: 1 h, 24 h, 48 h, and analysis immediately after addition of jet fuel. GJIC analyzed directly after addition of 1% JP-8 was reduced 4.9-fold relative to EtOH-dosed control groups and further reduction (12.6-fold) was observed in cells treated for 1 h. Moreover, GJIC was not recoverable in cells treated with 1% JP-8 for 1 h and subsequently washed and incubated in fresh medium for 1 h. Significant changes in GSH content and GST activity were observed in cells analyzed directly after addition of 1% JP-8. GSH content increased in cells treated for 1 h with less than 2% JP-8 whereas treatment with 2% JP-8 for 1 h resulted in a 50% reduction in intracellular GSH relative to EtOH-dosed controls. Cells treated with 1% JP-8 for 48 h exhibited changes in GSH levels. However, higher JP-8 concentrations exhibited more pronounced changes in GSH and GST, which led to suppression of GSH synthesis. ROS increased in a dose-responsive fashion at JP-8 concentrations up to 1%, but decreased to 80% of control values at 2% and 3% JP-8. A 25% reduction in PMP was observed in cells treated for 1 h with 1% JP-8. In contrast, cells treated for 48 h with 2% JP-8 exhibited a 25% increase when compared to control. No significant changes were noted in the 0.01 and 1% treatment groups. Moreover, no significant changes were observed in MMP or intracellular calcium concentrations in cells treated with 0.01 to 2% JP-8 for up to 48 h. In summary, the most significant effects observed in the present study which may contribute to the toxicity of JP-8 jet fuel in cultured rat liver cells include effects on GJIC, ROS production, and GSH depletion at high (i.e., greater than 2%) JP-8 concentrations.

Wilson, C. L.↗
DOE OSTI2020

Molecular characterization of a fungal gasdermin-like protein

Programmed cell death (PCD) in filamentous fungi prevents cytoplasmic mixing following fusion between conspecific genetically distinct individuals (allorecognition) and serves as a defense mechanism against mycoparasitism, genome exploitation, and deleterious cytoplasmic elements (i.e., senescence plasmids). Recently, we identified regulator of cell death-1 ( rcd-1 ), a gene controlling PCD in germinated asexual spores in the filamentous fungus Neurospora crassa . rcd-1 alleles are highly polymorphic and fall into two haplogroups in N. crassa populations. Coexpression of alleles from the two haplogroups, rcd-1–1 and rcd-1–2 , is necessary and sufficient to trigger a cell death reaction. Here, we investigated the molecular bases of rcd-1 -dependent cell death. Based on in silico analyses, we found that RCD-1 is a remote homolog of the N-terminal pore-forming domain of gasdermin, the executioner protein of a highly inflammatory cell death reaction termed pyroptosis, which plays a key role in mammalian innate immunity. We show that RCD-1 localizes to the cell periphery and that cellular localization of RCD-1 was correlated with conserved positively charged residues on predicted amphipathic α-helices, as shown for murine gasdermin-D. Similar to gasdermin, RCD-1 binds acidic phospholipids in vitro, notably, cardiolipin and phosphatidylserine, and interacts with liposomes containing such lipids. The RCD-1 incompatibility system was reconstituted in human 293T cells, where coexpression of incompatible rcd-1–1/rcd-1–2 alleles triggered pyroptotic-like cell death. Oligomers of RCD-1 were associated with the cell death reaction, further supporting the evolutionary relationship between gasdermin and rcd-1 . This report documents an ancient transkingdom relationship of cell death execution modules involved in organismal defense.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

The role of photorespiration in plant immunity

To defend themselves in the face of biotic stresses, plants employ a sophisticated immune system that requires the coordination of other biological and metabolic pathways. Photorespiration, a byproduct pathway of oxygenic photosynthesis that spans multiple cellular compartments and links primary metabolisms, plays important roles in defense responses. Hydrogen peroxide, whose homeostasis is strongly impacted by photorespiration, is a crucial signaling molecule in plant immunity. Photorespiratory metabolites, interaction between photorespiration and defense hormone biosynthesis, and other mechanisms, are also implicated. An improved understanding of the relationship between plant immunity and photorespiration may provide a much-needed knowledge basis for crop engineering to maximize photosynthesis without negative tradeoffs in plant immunity, especially because the photorespiratory pathway has become a major target for genetic engineering with the goal to increase photosynthetic efficiency.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Correlating transcription and protein expression profiles of immune biomarkers following lipopolysaccharide exposure in lung epithelial cells

Universal and early recognition of pathogens occurs through recognition of evolutionarily conserved pathogen associated molecular patterns (PAMPs) by innate immune receptors and the consequent secretion of cytokines and chemokines. The intrinsic complexity of innate immune signaling and associated signal transduction challenges our ability to obtain physiologically relevant, reproducible and accurate data from experimental systems. One of the reasons for the discrepancy in observed data is the choice of measurement strategy. Immune signaling is regulated by the interplay between pathogen-derived molecules with host cells resulting in cellular expression changes. However, these cellular processes are often studied by the independent assessment of either the transcriptome or the proteome. Correlation between transcription and protein analysis is lacking in a variety of studies. In order to methodically evaluate the correlation between transcription and protein expression profiles associated with innate immune signaling, we measured cytokine and chemokine levels following exposure of human cells to the PAMP lipopolysaccharide (LPS) from the Gram-negative pathogen Pseudomonas aeruginosa . Expression of 84 messenger RNA (mRNA) transcripts and 69 proteins, including 35 overlapping targets, were measured in human lung epithelial cells. We evaluated 50 biological replicates to determine reproducibility of outcomes. Following pairwise normalization, 16 mRNA transcripts and 6 proteins were significantly upregulated following LPS exposure, while only five (CCL2, CSF3, CXCL5, CXCL8/IL8, and IL6) were upregulated in both transcriptomic and proteomic analysis. This lack of correlation between transcription and protein expression data may contribute to the discrepancy in the immune profiles reported in various studies. The use of multiomic assessments to achieve a systems-level understanding of immune signaling processes can result in the identification of host biomarker profiles for a variety of infectious diseases and facilitate countermeasure design and development.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Interleukin-enhanced binding factor 2 interacts with NLRP3 to inhibit the NLRP3 inflammasome activation

Highlights: • The NLRP3 inflammasome activation is attenuated by PSMD10, BCL2L10, CTSS, and ILF2. • ILF2 represses inflammasome activation, pro-Casp-1 cleavege, and pro-IL-1β maturation. • ILF2 interacts with NLRP3 to inhibit the inflammasome activation in the cytoplasm. • ILF2 represses ATP-induced activation of endogenous NLRP3 inflammasome in macrophages. The activation of the NLRP3 inflammasome is a key process of host immune response that establishes the first line of defense against pathogen infections and cellular stresses, whereas excessive inflammasome activation may damage the hosts, and thus it must be precisely controlled. However, the mechanism underlying the repression of the NLRP3 inflammasome activation remains largely unknown. In this study, by establishing and using a reconstructed NLRP3 inflammasome activation system, we reveal that the NLRP3 inflammasome activation, pro-caspase-1 cleavage, and pro-interleukin-1β (pro-IL-1β) activation are repressed by the interleukin-enhanced binding factor 2 (ILF2). Further studies demonstrate that ILF2 represses the activation of NLRP3 inflammasome through interacting with the NACHT-associated domain (NAD) of NLRP3 and co-localized with NLRP3 in the cytoplasm of HEK293T cells. Finally, by generating a THP-1 cell line stably expressing ILF2 protein using the lentivirus infection system, we demonstrate that ILF2 represses ATP-induced activation of endogenous NLRP3 inflammasome in macrophages. Therefore, this study identifies a new role of ILF2 in the regulation of the NLRP3 inflammasome, and reveals a unique mechanism underlying the repression of the NLRP3 inflammasome activation.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1997

Changes in gravity inhibit lymphocyte locomotion through type I collagen

Immunity relies on the circulation of lymphocytes through many different tissues including blood vessels, lymphatic channels, and lymphoid organs. The ability of lymphocytes to traverse the interstitium in both nonlymphoid and lymphoid tissues can be determined in vitro by assaying their capacity to locomote through Type I collagen. In an attempt to characterize potential causes of microgravity-induced immunosuppression, we investigated the effects of simulated microgravity on human lymphocyte function in vitro using a specialized rotating-wall vessel culture system developed at the Johnson Space Center. This very low shear culture system randomizes gravitational vectors and provides an in vitro approximation of microgravity. In the randomized gravity of the rotating-wall vessel culture system, peripheral blood lymphocytes did not locomote through Type I collagen, whereas static cultures supported normal movement. Although cells remained viable during the entire culture period, peripheral blood lymphocytes transferred to unit gravity (static culture) after 6 h in the rotating-wall vessel culture system were slow to recover and locomote into collagen matrix. After 72 h in the rotating-wall vessel culture system and an additional 72 h in static culture, peripheral blood lymphocytes did not recover their ability to locomote. Loss of locomotory activity in rotating-wall vessel cultures appears to be related to changes in the activation state of the lymphocytes and the expression of adhesion molecules. Culture in the rotating-wall vessel system blunted the ability of peripheral blood lymphocytes to respond to polyclonal activation with phytohemagglutinin. Locomotory response remained intact when peripheral blood lymphocytes were activated by anti-CD3 antibody and interleukin-2 prior to introduction into the rotating-wall vessel culture system. Thus, in addition to the systemic stress factors that may affect immunity, isolated lymphocytes respond to gravitational changes by ceasing locomotion through model interstitium. These in vitro investigations suggest that microgravity induces non-stress-related changes in cell function that may be critical to immunity. Preliminary analysis of locomotion in true microgravity revealed a substantial inhibition of cellular movement in Type I collagen. Thus, the rotating-wall vessel culture system provides a model for analyzing the microgravity-induced inhibition of lymphocyte locomotion and the investigation of the mechanisms related to lymphocyte movement.

Weightlessness↗
NASA NTRS2004

Allograft tolerance induced by donor apoptotic lymphocytes requires phagocytosis in the recipient

Cell death through apoptosis plays a critical role in regulating cellular homeostasis. Whether the disposal of apoptotic cells through phagocytosis can actively induce immune tolerance in vivo, however, remains controversial. Here, we report in a rat model that without using immunosuppressants, transfusion of apoptotic splenocytes from the donor strain prior to transplant dramatically prolonged survival of heart allografts. Histological analysis verified that rejection signs were significantly ameliorated. Splenocytes from rats transfused with donor apoptotic cells showed a dramatically decreased response to donor lymphocyte stimulation. Most importantly, blockade of phagocytosis in vivo, either with gadolinium chloride to disrupt phagocyte function or with annexin V to block binding of exposed phosphotidylserine to its receptor on phagocytes, abolished the beneficial effect of transfused apoptotic cells on heart allograft survival. Our results demonstrate that donor apoptotic cells promote specific allograft acceptance and that phagocytosis of apoptotic cells in vivo plays a crucial role in maintaining immune tolerance.

NASA Discipline Regulatory Physiology↗
NASA NTRS1999

Altered Cytokine Production By Specific Human Peripheral Blood Cell Subsets Immediately Following Spaceflight

In this study, we have attempted to combine standard immunological assays with the cellular resolving power of the flow cytometer to positively identify the specific cell types involved in spaceflight-induced immune alterations. We have obtained whole blood samples from 27 astronauts collected at three timepoints (L-10, R+0 and R+3) surrounding four recent space shuttle missions. The duration of these missions ranged from 10 to 18 days. Assays performed included serum/urine cortisol, comprehensive subset phenotyping, assessment of cellular activation markers and intracellular cytokine production following mitogenic stimulation. Absolute levels of peripheral granulocytes were significantly elevated following spaceflight, but the levels of circulating lymphocytes and monocytes were unchanged. Lymphocyte subset analysis demonstrated trends towards a decreased percentage of T cells and an increased percentage of B cells. Nearly all of the astronauts exhibited an increased CD4:CD8 ratio, which was dramatic in some individuals. Assessment of memory (CD45RA+) vs. naive (CD45RO+) CD4+ T cell subsets was more ambiguous, with subjects tending to group more as a flight crew. All subjects from one mission demonstrated an increased CD45RA:CD45RO ratio, while all subjects from another Mission demonstrated a decreased ratio. While no significant trend was seen in the monocyte population as defined by scatter, a decreased percentage of the CD14+ CD16+ monocyte subset was seen following spaceflight in all subjects tested. In general, most of the cellular changes described above which were assessed at R+O and compared to L-10 trended to pre-flight levels by R+3. Although no significant differences were seen in the expression of the cellular activation markers CD69 and CD25 following exposure to microgravity, significant alterations were seen in cytokine production in response to mitogenic activation for specific subsets. T cell (CD3+) production of IL-2 was significantly decreased after at R+O as was IL-2 production by both CD4+ and CD8+ T cell subsets for most subjects. Production of IFN(sub gamma) did not appear to be affected by microgravity exposure in either T cells in general or in the CD8+ T cell subset. There was a spaceflight-induced decrease in IFN(sub gamma) production in the CD4+ T cell subset, however it did not reach statistical significance. Serum and urine stress-hormone analysis indicated significant physiologic stresses in astronauts following spaceflight. In summary, these results demonstrate alterations in the peripheral immune system of astronauts immediately after spaceflight of 10 to 18 days duration and support continued research regarding microgravity and immunology (including in-flight sampling) prior to routine long-term spaceflight for astronauts.

Crucian, Brian E.↗
DOE OSTI2018

Mitochondria-associated membranes (MAMs): An emerging platform connecting energy and immune sensing to metabolic flexibility

Highlights: • Both mitochondria and MAMs recently emerge as key nutrient and immune sensors. • MAMs are key hub connecting energy and immune sensing to metabolic flexibility. • ER-mitochondria miscommunication is involved in metabolic diseases. Living organisms have the capacity to sense both nutrients and immune signals in order to adapt their metabolism to the needs, and both metabolic inflexibility and exacerbated immune responses are associated with metabolic diseases. Over the past decade, mitochondria emerged as key nutrient and immune sensors regulating numerous signalling pathways, and mitochondria dysfunction has been extensively implicated in metabolic diseases. Interestingly, mitochondria interact physically and functionally with the endoplasmic reticulum (ER, in contact sites named mitochondria-associated membranes (MAMs), in order to exchange metabolites and calcium and regulate cellular homeostasis. Emerging evidences suggest that MAMs provide a platform for hormone and nutrient signalling pathways and for innate immune responses, then regulating mitochondrial bioenergetics and apoptosis. Here, I thus propose the concept that MAMs could be attractive nutrient and immune sensors that regulate mitochondria physiology in order to adapt metabolism and cell fate, and that organelle miscommunication could be involved in the metabolic inflexibility and the pro-inflammatory status associated with metabolic diseases.

60 APPLIED LIFE SCIENCES↗