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At least 73 records · Page 4

All sources NASA NTRS DOE OSTI

DOE OSTI2018

Repetitive restraint stress changes spleen immune cell subsets through glucocorticoid receptor or β-adrenergic receptor in a stage dependent manner

Highlights: • Repetitive restraint stress (RRS) changes the immune cell subsets in spleen. • RU486 reverses the changes of spleen immune cell subsets induced by 7 days of RRS. • Propranolol reverses the changes of spleen immune cell subsets induced by 21 days of RRS. Immune system is sensitive to stress. Spleen is the largest peripheral immune organ innervated with sympathetic nerves and controlled by adrenomedullary system in the body. However, the alterations and mechanism of spleen immune cell subsets caused by repetitive restraint stress (RRS) is poorly understood. In this study, we found that RRS reduced spleen index in mice, and induced an expansion of white pulp and involution of the red pulp. Meanwhile, the percentage of CD3{sup +}CD8{sup +} T lymphocytes, CD11b{sup +}F4/80{sup +} macrophages, CD11b{sup +}Ly-6G{sup −}Ly-6C{sup hi} monocytic myeloid derived suppressor cells (mMDSCs) and CD11b{sup +}Ly-6G{sup +}Ly-6C{sup int} granulocytic myeloid derived suppressor cells (gMDSCs) in spleen were significantly changed by RRS. Mechanistically, we found that the expression of norepinephrine (NE) and β-adrenergic receptor (β-AR) in spleen were up-regulated after 21 days of RRS, but not 7 days. The expression of corticosterone (CORT) and glucocorticoid receptor (GR) in spleen were up-regulated after 7 days of RRS but were lower after 21 days of RRS, even though they were still higher than that in mice without stress. By treating the stressed mice with RU486 (antagonist of GR) or propranolol (antagonist of β-AR), we demonstrated that GR was responsible for the changes of spleen induced by 7 days of RRS and β-AR was for 21 days of RRS. Our data suggest that RRS changes spleen immune cell subsets through GR or β-AR in a stage dependent manner.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

MCPIP1 negatively regulate cellular antiviral innate immune responses through DUB and disruption of TRAF3-TBK1-IKKε complex

IFNβ innate immune plays an essential role in antiviral immune. Previous reports suggested that many important regulatory proteins in innate immune pathway may be modified by ubiquitin and that many de-ubiquitination (DUB) proteins may affect immunity. Monocyte chemotactic protein-inducing protein 1 (MCPIP1), one of the CCCH Zn finger-containing proteins, was reported to have DUB function, but its effect on IFNβ innate immune was not fully understood. In this study, we uncovered a novel mechanism that may explain how MCPIP1 efficiently inhibits IFNβ innate immune. It was found that MCPIP1 negatively regulates the IFNβ expression activated by RIG-I, STING, TBK1, IRF3. Furthermore, MCPIP1 inhibits the nuclear translocation of IRF3 upon stimulation with virus, which plays a key role in type I IFN expression. Additionally, MCPIP1 interacts with important modulators of IFNβ expression pathway including IPS1, TRAF3, TBK1 and IKKε. Meanwhile, the interaction between the components in TRAF3-TBK1-IKKε complex was disrupted by MCPIP1. These results collectively suggest MCPIP1 as an innate immune regulator encoded by the host and point to a new mechanism through which MCPIP1 negatively regulates IRF3 activation and type I IFNβ expression.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Administration of plasmacytoid dendritic cell-stimulative lactic acid bacteria enhances antigen-specific immune responses

Lactic acid bacteria (LAB) have been reported to have beneficial effects on protective immunity against viruses and pathogenic bacteria by activating innate immune cells such as dendritic cells (DC) or macrophages. However, little is known about whether LAB contributes to antigen-specific immune responses. Because plasmacytoid DC (pDC) links innate and acquired immunity, here we investigated whether the pDC-stimulative LAB, Lactococcus lactis strain Plasma (LC-Plasma), influences antigen-specific immune responses. In in vitro co-culture experiments, LC-Plasma enhanced the expression of MHC class I and II, and CD80 and CD86 on both pDC and conventional DC, and this enhancement was abolished by treatment with a Toll-like receptor 9 antagonist. A subsequent in vitro study showed that LC-Plasma increased antigen-specific T cell responses via DC activation. In mice, oral administration of LC-Plasma in combination with intraperitoneal antigen administration enhanced the percentage of antigen-specific CD8{sup +} T cells and the amount of antigen-specific IgG. Furthermore, continuous intake of LC-Plasma increased T helper 1 responses, which contribute to antigen-specific cellular and humoral immune responses. Taken together, these results reveal that the oral intake of pDC-stimulative LAB enhances antigen-specific immune responses.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2019

Beyond pathogens: microbiota interactions with the plant immune system

Plant immune receptors perceive microbial molecules and initiate an array of biochemical responses that are effective against most invaders. The role of the plant immune system in detecting and controlling pathogenic microorganism has been well described. In contrast, much less is known about plant immunity in the context of the wealth of commensals that inhabit plants. Recent research indicates that, just like pathogens, commensals in the plant microbiome can suppress or evade host immune responses. Moreover, the plant immune system has an active role in microbiome assembly and controls microbial homeostasis in response to environmental variation. Here, we propose that the plant immune system shapes the microbiome, and that the microbiome expands plant immunity and acts as an additional layer of defense against pathogenic organisms.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity

Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8 + T cell function by enhancing JAK–STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.

60 APPLIED LIFE SCIENCES↗

NASA NTRS1977

Effect of space flight on cell-mediated immunity

The cell-mediated immune response to Listeria monocytogenes was studied in rats subjected to 20 days of flight aboard the Soviet biosatellite Kosmos 7820. Groups of rats were immunized with 1,000,000 formalin-killed Listeria suspended in Freunds Complete Adjuvant, 5 days prior to flight. Immunized rats subjected to the same environmental factors as the flight rats, except flight itself, and immunized and nonimmunized rats held in a normal animal colony served as controls. Following recovery, lymphocyte cultures were harvested from spleens of all rats, cultured in vitro in the presence of L. monocytogenes antigens, Phytohemagglutinin, Conconavlin A, or purified protein derivative (PPD), and measured for their uptake of H-3-thymidine. Although individual rats varied considerably, all flight and immunized control rats gave a blastogenic response to the Listeria antigens and PPD. With several mitogens, the lymphocytes of flight rats showed a significantly increased blastogenic response over the controls. The results of this study do not support a hypothesis of a detrimental effect of space flight on cell-mediated immunity. The data suggest a possible suppressive effect of stress and gravity on an in vitro correlate of cell-mediated immunity.

Mandel, A. D.↗

NASA NTRS2000

Integrated Circuit Immunity

This paper presents a DOD E3 program overview on integrated circuit immunity. The topics include: 1) EMI Immunity Testing; 2) Threshold Definition; 3) Bias Tee Function; 4) Bias Tee Calibration Set-Up; 5) EDM Test Figure; 6) EMI Immunity Levels; 7) NAND vs. and Gate Immunity; 8) TTL vs. LS Immunity Levels; 9) TP vs. OC Immunity Levels; 10) 7805 Volt Reg Immunity; and 11) Seventies Chip Set. This paper is presented in viewgraph form.

Sketoe, J. G.↗

NASA NTRSDate not supplied

Conditions of the Toll-Like Receptors System of the Human Innate Immunity Cells During the Long-Term Isolation

During long duration missions onboard the International Space Station (ISS), alterations in T cell function and plasma cytokine profiles have been observed. Recent studies involving pattern recognition receptors (PRRs) have established that adaptation of innate immunity to long duration space flight occurs through changes in signal PRRs, Toll-like receptors (TLRs). Despite the fact that fundamental research of PRR molecular biology is far from complete, there are an increasing number of arguments confirming the important role of this system in regulating the initial stages of the adaptive immune response, as well as in the formation of autoimmune and allergic diseases. Long duration isolation is widely used by NASA as an analog for space flight with previous missions including several Antarctic bases, an undersea research station (NEEMO), and other isolation chambers. ‘SIRIUS’ is a multi-compartment pressurized facility at the IMBP in Moscow, Russia, in which subjects will spend 8 months executing tasks similar to those performed by astronauts in space. Prolonged isolation studies like SIRIUS replicate many of the influences expected to occur during long duration spaceflight missions including isolation, stress, confinement, and living in remote conditions. The immune study to be performed on the upcoming SIRIUS mission is being led by Dr. Sergey Ponomarev at the Institute of Biomedical Problems in Moscow, Russia. The NASA JSC Immunology lab will provide analysis of immune cell function, serum cytokines and stress hormones, and salivary cortisol, cytokines, and viruses. This study will be conducted with SIRIUS subjects under the auspices of the parent program. The goal of the study is to evaluate the effect of the 8-month isolation mission on components of human innate immunity at the molecular and cellular level. Successful implementation and completion of this project will provide a unique assortment of new data, significantly expanding the current understanding of the molecular and cellular changes in TLRs during long-term isolation. We hypothesize that mission-like isolation in the Russian NEK facility, consisting of circadian misalignment, isolation, stress, and ‘station lifestyle’, will result in a pattern of immune dysregulation similar to that observed in astronauts onboard ISS. This pattern of alterations can be summarized as phenotypic changes (altered distribution of peripheral cytotoxic, central memory, CD8+ T cell subsets), reductions in T cell function, alterations in plasma cytokine profiles (increased inflammatory and certain chemokines), and reductions in mitogen stimulated cytokine profiles (spans Th1, Th2, Th17). We further hypothesize that these immune changes will correlate with the reactivation of latent herpesviruses (which persists during orbital flight), to be used as measurable adverse clinical manifestation or with other observed symptomology. The SIRIUS-21 mission began in November of 2021 and successfully concluded with the crew emerging in July of 2022. Currently, the logistics of shipping the samples from Russia to the United States is being organized.

Cody L Gutierrez↗

DOE OSTI2017

MtHsp70-CLIC1-pulsed dendritic cells enhance the immune response against ovarian cancer

Highlights: • Ovarian cancer (OC) has poor prognosis, due to recurrence and drug resistance. • Immune therapies using antigen-pulsed dendritic cells (DCs) are promising options. • Chloride intracellular channel 1 (CLIC1) is an OC biomarker with low antigenicity. • DCs were pulsed with a CLIC1/M. tuberculosis HSP70 (MtHsp70-CLIC1) fusion protein. • MtHsp70-CLIC1 showed significant anticancer effects in vitro and in vivo. Approximately 80% of ovarian cancer (OC) is diagnosed at late stages, and most patients die within 5 years of diagnosis due to recurrence or drug resistance. Novel treatments are required to improve patient survival. Immune therapy against cancer is promising; however, therapeutic vaccination has been limited by the inability of tumor antigens to induce effective immune responses. Chloride intracellular channel 1 (CLIC1) was previously identified as a possible tumor marker for OC. In this study, we constructed a recombinant protein by conjugating the extracellular domain of CLIC1 to the carboxyl terminus of Mycobacterium tuberculosis heat shock protein 70 (MtHsp70). Human dendritic cells (DCs) derived from cortical blood were pulsed with the fusion protein, and the antitumor effect of human cytotoxic T lymphocytes (CTLs) stimulated by autologous DCs was assessed in NOG mice. MtHsp70-CLIC1 promoted the phenotypic maturation of human DCs and the secretion of Th1-associated cytokines in vitro. MtHsp70-CLIC1-stimulated CTLs generated a CLIC1-specific immune response both in vitro and in vivo. These results indicate that DCs pulsed with MtHsp70-CLIC1 can enhance antitumor immunity against OC, providing a novel immune therapeutic strategy.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Pre-existing humoral immunity to human common cold coronaviruses negatively impacts the protective SARS-CoV-2 antibody response

SARS-CoV-2 infection causes diverse outcomes ranging from asymptomatic infection to respiratory distress and death. A major unresolved question is whether prior immunity to endemic, human common cold coronaviruses (hCCCoVs) impacts susceptibility to SARS-CoV-2 infection or immunity following infection and vaccination. Therefore, we analyzed samples from the same individuals before and after SARS-CoV-2 infection or vaccination. We found hCCCoV antibody levels increase after SARS-CoV-2 exposure, demonstrating cross-reactivity. However, a case-control study indicates that baseline hCCCoV antibody levels are not associated with protection against SARS-CoV-2 infection. Rather, higher magnitudes of pre-existing betacoronavirus antibodies correlate with more SARS-CoV-2 antibodies following infection, an indicator of greater disease severity. Additionally, immunization with hCCCoV spike proteins before SARS-CoV-2 immunization impedes the generation of SARS-CoV-2-neutralizing antibodies in mice. Together, these data suggest that pre-existing hCCCoV antibodies hinder SARS-CoV-2 antibody-based immunity following infection and provide insight on how pre-existing coronavirus immunity impacts SARS-CoV-2 infection, which is critical considering emerging variants.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Longitudinal Antigenic Sequences and Sites from Intra-Host Evolution (LASSIE) identifies immune-selected HIV variants

Within-host genetic sequencing from samples collected over time provides a dynamic view of how viruses evade host immunity. Immune-driven mutations might stimulate neutralization breadth by selecting antibodies adapted to cycles of immune escape that generate within-subject epitope diversity. Comprehensive identification of immune-escape mutations is experimentally and computationally challenging. With current technology, many more viral sequences can readily be obtained than can be tested for binding and neutralization, making down-selection necessary. Typically, this is done manually, by picking variants that represent different time-points and branches on a phylogenetic tree. Such strategies are likely to miss many relevant mutations and combinations of mutations, and to be redundant for other mutations. Longitudinal Antigenic Sequences and Sites from Intrahost Evolution (LASSIE) uses transmitted founder loss to identify virus “hot-spots” under putative immune selection and chooses sequences that represent recurrent mutations in selected sites. LASSIE favors earliest sequences in which mutations arise. Here, with well-characterized longitudinal Env sequences, we confirmed selected sites were concentrated in antibody contacts and selected sequences represented diverse antigenic phenotypes. Finally, practical applications include rapidly identifying immune targets under selective pressure within a subject, selecting minimal sets of reagents for immunological assays that characterize evolving antibody responses, and for immunogens in polyvalent “cocktail” vaccines.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRSDate not supplied

Altered Immune Differentials Between Male and Female Mice Independent of Ionizing Irradiation

As upcoming exploratory missions to the Lunar surface and Mars during the Artemis Program will send both female and male crewmembers, studies identifying sex-specific effects are necessary. It is well-documented that the immune system engages different responses between females and males following exposures to infectious challenge, tumors surveillance, and autoimmune development. Yet, the immune effects of spaceflight-like exposures between the sexes are limited. Therefore, this study sought to address the effects of spaceflight-like conditions on immune differentials in female and male mice. We hypothesized that the spaceflight factor, ionizing radiation, will have sex-specific effects on immune differentials. To test this, singly-housed, 12-month old female and male wildtype (Wt) mice were exposed to acute ionizing gamma irradiation (50 cGy), followed by retro-orbital blood collections at 7-days post-irradiation. Leukocytes were analyzed by flow cytometry characterizing, granulocytes, monocytes, lymphocytes (cytotoxic/helper T cells and B cells), neutrophils, eosinophils, and NK/NKT cells. Briefly, minimal sex-specific effects were observed across the cell types listed at this time point, including changes in granulocyte and lymphocyte populations. The results revealed females displayed elevated granulocytes and reduced lymphocytes compared to their male counterparts, independent of irradiation exposure. These results suggest female mice may be more capable to produce innate inflammatory mediators but may be adaptively immune compromised. In brief, this study provides insight into the sex-specific immune risks following ionizing radiation that may be experienced during spaceflight, which is relevant for future countermeasure development.

spaceflight stressors↗

NASA NTRSDate not supplied

Altered Immune Differentials Between Male and Female Mice Independent of Ionizing Irradiation

spaceflight stressors↗

DOE OSTI2019

Flowering plant immune repertoires expand under mycorrhizal symbiosis

Immune perception in flowering plants is mediated by a repertoire of cytoplasmic and cell-surface receptors that detect invading microbes and their effects on cells. Here, we show that several large families of immune receptors exhibit size variations related to a plant's competence to host symbiotic root fungi (mycorrhiza). Plants that do not participate in mycorrhizal associations have significantly smaller immune repertoires, while the most promiscuous symbiotic hosts (ectomycorrhizal plant species) have significantly larger immune repertoires. By contrast, we find no significant increase in immune repertoire size among legumes competent to form a symbiosis with nitrogen-fixing bacteria (rhizobia). To explain these observations, we hypothesize that plant immune repertoire size expands with symbiote species diversity.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2018

Global stability of a diffusive and delayed virus infection model with general incidence function and adaptive immune response

In this paper, the dynamical behaviors for a five-dimensional virus infection model with diffusion and two delays which describes the interactions of antibody, cytotoxic T-lymphocyte (CTL) immune responses and a general incidence function are investigated. The reproduction numbers for virus infection, antibody immune response, CTL immune response, CTL immune competition and antibody immune competition, respectively, are calculated. By using the Lyapunov functionals and linearization methods, the threshold conditions on the global stability of the equilibria for infection-free, immune-free, antibody response, CTL response and antibody and CTL responses, respectively, are established if the space is assumed as homogeneous. When the space is inhomogeneous, the effects of diffusion, intracellular delay and production delay are obtained by the numerical simulations.

97 MATHEMATICS AND COMPUTING↗

DOE OSTI2018

MicroRNA-140 suppresses osteosarcoma tumor growth by enhancing anti-tumor immune response and blocking mTOR signaling

Highlights: • PD-L1 is directly regulated by miR-140 in osteosarcoma. • The tumor-suppressive role of miR-140 is immune mediated in osteosarcoma. • miR-140 enhances anti-tumor immunity in osteosarcoma. • Combined miR-140 overexpression with mTOR blockade inhibits xenograft growth in immune-competent mice. Immune checkpoint blockade is proved to be a promising therapeutic strategy against several human malignancies. MicroRNAs (miRNAs) are ∼22 nucleotide RNAs that play important roles in regulating gene expression, either suppressing its translation or speeding up its degradation. In this study, we demonstrated that miR-140 acts as a critical modulator of PD-L1 and is significantly reduced in osteosarcoma (OS). MiR-140 was inversely correlated with PD-L1 and luciferase reporter assay confirmed that miR-140 can direct regulate PD-L1 expression by binding to its 3′UTR. MiR-140 failed to influence tumor growth in nude mice, whereas markedly inhibited tumor growth in the immune-competent C57BL/6J mice. Mechanistically, the tumor-suppressive role of miR-140 was associated with the increased infiltrates of cytotoxic CD8{sup +} T cells and the decreased infiltrates of myeloid-derived suppressive cells and regulatory T cells. Moreover, miR-140 significantly inhibited mTOR signaling and combined miR-140 overexpression with pharmacological inhibition of mTOR signaling showed remarkable synergistic anti-tumor effect. Collectively, our findings indicate that miR-140 exerts anti-OS efficacy by targeting immune checkpoint molecule PD-L1 and can be developed as a novel immunotherapeutic agent for the treatment of OS.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Modeling the immune response to HIV infection

The interplay between immune response and HIV is intensely studied via mathematical modeling, with significant insights but few direct answers. Here in this short review, we highlight advances and knowledge gaps across different aspects of immunity. In particular, we identify the innate immune response and its role in priming the adaptive response as ripe for modeling. The latter have been the focus of most modeling studies, but we also synthesize key outstanding questions regarding effector mechanisms of cellular immunity and development of broadly neutralizing antibodies. Thus far, most modeling studies aimed to infer general immune mechanisms; we foresee that significant progress will be made next by detailed quantitative fitting of models to data, and prediction of immune responses.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

Virus-like particle vaccine primes immune responses preventing inactivated-virus vaccine-enhanced disease against respiratory syncytial virus

Formalin inactivated respiratory syncytial virus (FI-RSV) vaccination caused vaccine-enhanced respiratory disease (ERD) upon exposure to RSV in children. Virus-like particles presenting RSV F fusion protein (F VLP) are known to increase T helper type-1 (Th1) immune responses and avoid ERD in animal models. We hypothesized that F VLP would prime immune responses preventing ERD upon subsequent exposure to ERD-prone FI-RSV. Here, we demonstrated that heterologous F VLP priming and FI-RSV boosting of mice prevented FI-RSV vaccine-enhanced lung inflammation and eosinophilia upon RSV challenge. F VLP priming redirected pulmonary T cells toward effector CD8 T cells producing Th1 cytokines and significantly suppressed pulmonary Th2 cytokines. This study suggests that RSV F VLP priming would modulate and shift immune responses to subsequent exposure to ERD-prone FI-RSV vaccine and RSV infection, suppressing Th2 immune-mediated pulmonary histopathology and eosinophilia. - Highlights: • RSV F VLP priming dictates the type of subsequent immune responses to FI-RSV. • F VLP priming redirects pulmonary T cells toward effector CD8 T cells. • F VLP priming suppresses Th2 immune-mediated pulmonary histopathology.

60 APPLIED LIFE SCIENCES↗