Engineering Papers⌕ Search

SEARCH · Engineering Papers

Results for “immunization”

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.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 271 records · Page 15
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Virion glycosylation influences mycobacteriophage immune recognition

Glycosylation of eukaryotic virus particles is common and influences their uptake, trafficking, and immune recognition. In contrast, glycosylation of bacteriophage particles has not been reported; phage virions typically do not enter the cytoplasm upon infection, and they do not generally inhabit eukaryotic systems. We show here that several genomically distinct phages of Mycobacteria are modified with glycans attached to the C terminus of capsid and tail tube protein subunits. These O-linked glycans influence antibody production and recognition, shielding viral particles from antibody binding and reducing production of neutralizing antibodies. Glycosylation is mediated by phage-encoded glycosyltransferases, and genomic analysis suggests that they are relatively common among mycobacteriophages. Putative glycosyltransferases are also encoded by some Gordonia and Streptomyces phages, but there is little evidence of glycosylation among the broader phage population. The immune response to glycosylated phage virions in mice suggests that glycosylation may be an advantageous property for phage therapy of Mycobacterium infections.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Plasticizer, di(2-ethylhexyl)phthalate (DEHP) enhances cockroach allergen extract-driven airway inflammation by enhancing pulmonary Th2 as well as Th17 immune responses in mice

Highlights: • DEHP enhances CE-induced airway inflammation/mucus secretion in mice. • DEHP enhances expression of costimulatory molecules on dendritic cells. • DEHP enhances expression of pro-inflammatory cytokines in dendritic cells. • DEHP down regulates expression of E-cadherin in airway epithelial cells. In recent decades, there has been a gradual increase in the prevalence of asthma. Various factors including environmental pollutants have contributed to this phenomenon. Plasticizer, di(2-ethylhexyl)phthalate (DEHP) is one of the commonest environmental pollutants due to its association with plastic products. DEHP gets released from plastic products easily leading to respiratory exposure in humans. As a consequence, DEHP is associated with allergic asthma in humans and animals. DEHP is reported to act as an adjuvant in ovalbumin-induced mouse models of asthma at high doses. However, these studies mostly looked into the role of DEHP on Th2 cytokines/eosinophilic inflammation without investigating the role of airway epithelial cells (AECs)/dendritic cells (DCs)/Th17 cells. Its adjuvant activity with natural allergens such as cockroach allergens at tolerable daily intake needs to be explored. Cockroach allergens and DEHP may be inhaled together due to their coexistence in work place as well as household environments. Therefore, effect of DEHP was assessed in cockroach allergens extract (CE)-induced mouse model of asthma. Airway inflammation, histopathology, mucus secretion, and immune responses related to Th2/Th17/DCs and AECs were assessed in mice with DEHP exposure alone and in combination with CE. Our study shows that DEHP converts CE-induced eosinophilic inflammation into mixed granulocytic inflammation by promoting Th2 as well as Th17 immune responses. This was probably due to downregulation of E-cadherin in AECs, and enhancement of costimulatory molecules (MHCII/CD86/CD40)/pro-inflammatory cytokines (IL-6/MCP-1) in DCs by DEHP. This suggests that DEHP facilitates development of mixed granulocytic airway inflammation in the presence of a natural allergen.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2021

Melanoma Cell Intrinsic GABAA Receptor Enhancement Potentiates Radiation and Immune Checkpoint Inhibitor Response by Promoting Direct and T Cell-Mediated Antitumor Activity

Most patients with metastatic melanoma show variable responses to radiation therapy and do not benefit from immune checkpoint inhibitors. Improved strategies for combination therapy that leverage potential benefits from radiation therapy and immune checkpoint inhibitors are critical.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Electron-Microscopy-Based Epitope Mapping Defines Specificities of Polyclonal Antibodies Elicited during HIV-1 BG505 Envelope Trimer Immunization

Characterizing polyclonal antibody responses via currently available methods is inherently complex and difficult. Mapping epitopes in an immune response is typically incomplete, which creates a barrier to fully understanding the humoral response to antigens and hinders rational vaccine design efforts. Here, we describe a method of characterizing polyclonal responses by using electron microscopy, and we applied this method to the immunization of rabbits with an HIV-1 envelope glycoprotein vaccine candidate, BG505 SOSIP.664. We detected known epitopes within the polyclonal sera and revealed how antibody responses evolved during the prime-boosting strategy to ultimately result in a neutralizing antibody response. We uncovered previously unidentified epitopes, including an epitope proximal to one recognized by human broadly neutralizing antibodies as well as potentially distracting non-neutralizing epitopes. Our method provides an efficient and semiquantitative map of epitopes that are targeted in a polyclonal antibody response and should be of widespread utility in vaccine and infection studies.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Fortifying the frontier: cell wall modifications during plant immunity

The plant cell wall (CW) was long thought to be a rigid barrier encasing the plant cell and protecting it against biotic and abiotic stressors. Different CW polysaccharides interact with each other, and modifications of either the components or organization of these polysaccharides result in impaired growth or immunity. Emerging evidence suggests that the CW is dynamically modified and reorganized based on internal and external cues. Thus, the CW is both the first barrier that pathogens encounter and the critical final step in defense signaling that leads to fortification of the CW. Here, in this work, we review recent findings on how CW components are remodeled to fortify the CW upon pathogen attack and propose a novel concept: layered CW remodeling as an immune strategy. Within this framework, we categorize three interconnected layers of CW remodeling upon pathogen attack: (i) rapid and reversible CW depositions that provide immediate but transient protection; (ii) flexible modifications with plausible signaling functions that integrate defense and surveillance; and (iii) irreversible fortifications that encase pathogen, delimiting infected cells from uninfected cells. This layered framework provides a cohesive view of how different CW modifications are integrated into, and contribute to, plant defense. We also discuss the challenges in studying CW modifications during biotic stresses and highlight important questions that remain unanswered.

Bhandari, Deepak D. [Michigan State Univ., East La↗
DOE OSTI2021

Polymersomes Decorated with the SARS-CoV-2 Spike Protein Receptor-Binding Domain Elicit Robust Humoral and Cellular Immunity

The COVID-19 pandemic underscores the need for rapid, safe, and effective vaccines. In contrast to some traditional vaccines, nanoparticle-based subunit vaccines are particularly efficient in trafficking antigens to lymph nodes, where they induce potent immune cell activation. Here, we developed a strategy to decorate the surface of oxidation-sensitive polymersomes with multiple copies of the SARS-CoV-2 spike protein receptor-binding domain (RBD) to mimic the physical form of a virus particle. We evaluated the vaccination efficacy of these surface-decorated polymersomes (RBD surf ) in mice compared to RBD-encapsulated polymersomes (RBD encap ) and unformulated RBD (RBD free ), using monophosphoryl-lipid-A-encapsulated polymersomes (MPLA PS) as an adjuvant. While all three groups produced high titers of RBD-specific IgG, only RBD surf elicited a neutralizing antibody response to SARS-CoV-2 comparable to that of human convalescent plasma. Moreover, RBD surf was the only group to significantly increase the proportion of RBD-specific germinal center B cells in the vaccination-site draining lymph nodes. Both RBD surf and RBD encap drove similarly robust CD4 + and CD8 + T cell responses that produced multiple Th1-type cytokines. We conclude that a multivalent surface display of spike RBD on polymersomes promotes a potent neutralizing antibody response to SARS-CoV-2, while both antigen formulations promote robust T cell immunity.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2019

Salivary mycobiome dysbiosis and its potential impact on bacteriome shifts and host immunity in oral lichen planus

The biodiversity of the mycobiome, an important component of the oral microbial community, and the roles of fungal–bacterial and fungal–immune system interactions in the pathogenesis of oral lichen planus (OLP) remain largely uncharacterized. In this study, we sequenced the salivary mycobiome and bacteriome associated with OLP. First, we described the dysbiosis of the microbiome in OLP patients, which exhibits lower levels of fungi and higher levels of bacteria. Significantly higher abundances of the fungi Candida and Aspergillus in patients with reticular OLP and of Alternaria and Sclerotiniaceae_unidentified in patients with erosive OLP were observed compared to the healthy controls. Aspergillus was identified as an “OLP-associated” fungus because of its detection at a higher frequency than in the healthy controls. Second, the co-occurrence patterns of the salivary mycobiome–bacteriome demonstrated negative associations between specific fungal and bacterial taxa identified in the healthy controls, which diminished in the reticular OLP group and even became positive in the erosive OLP group. Moreover, the oral cavities of OLP patients were colonized by dysbiotic oral flora with lower ecological network complexity and decreased fungal–Firmicutes and increased fungal–Bacteroidetes sub-networks. Third, several keystone fungal genera (Bovista, Erysiphe, Psathyrella, etc.) demonstrated significant correlations with clinical scores and IL-17 levels. Thus, we established that fungal dysbiosis is associated with the aggravation of OLP. Fungal dysbiosis could alter the salivary bacteriome or may reflect a direct effect of host immunity, which participates in OLP pathogenesis.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Lipopolysaccharide O-antigen delays plant innate immune recognition of Xylella fastidiosa

Lipopolysaccharides (LPS) are among the known pathogen-associated molecular patterns (PAMPs). LPSs are potent elicitors of PAMP-triggered immunity (PTI), and bacteria have evolved intricate mechanisms to dampen PTI. Here we demonstrate that Xylella fastidiosa (Xf), a hemibiotrophic plant pathogenic bacterium, possesses a long chain O-antigen that enables it to delay initial plant recognition, thereby allowing it to effectively skirt initial elicitation of innate immunity and establish itself in the host. Lack of the O-antigen modifies plant perception of Xf and enables elicitation of hallmarks of PTI, such as ROS production specifically in the plant xylem tissue compartment, a tissue not traditionally considered a spatial location of PTI. To explore translational applications of our findings, we demonstrate that pre-treatment of plants with Xf LPS primes grapevine defenses to confer tolerance to Xf challenge.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Senescent cells evade immune clearance via HLA-E-mediated NK and CD8 + T cell inhibition

Senescent cells accumulate in human tissues during ageing and contribute to age-related pathologies. The mechanisms responsible for their accumulation are unclear. Here we show that senescent dermal fibroblasts express the non-classical MHC molecule HLA-E, which interacts with the inhibitory receptor NKG2A expressed by NK and highly differentiated CD8 + T cells to inhibit immune responses against senescent cells. HLA-E expression is induced by senescence-associated secretary phenotype-related pro-inflammatory cytokines, and is regulated by p38 MAP kinase signalling in vitro. Consistently, HLA-E expression is increased on senescent cells in human skin sections from old individuals, when compared with those from young, and in human melanocytic nevi relative to normal skin. Lastly, blocking the interaction between HLA-E and NKG2A boosts immune responses against senescent cells in vitro. We thus propose that increased HLA-E expression contributes to persistence of senescent cells in tissues, thereby suggesting a new strategy for eliminating senescent cells during ageing.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Epigraph hemagglutinin vaccine induces broad cross-reactive immunity against swine H3 influenza virus

Influenza A virus infection in swine impacts the agricultural industry in addition to its zoonotic potential. Here, we utilize epigraph, a computational algorithm, to design a universal swine H3 influenza vaccine. The epigraph hemagglutinin proteins are delivered using an Adenovirus type 5 vector and are compared to a wild type hemagglutinin and the commercial inactivated vaccine, FluSure. In mice, epigraph vaccination leads to significant cross-reactive antibody and T-cell responses against a diverse panel of swH3 isolates. Epigraph vaccination also reduces weight loss and lung viral titers in mice after challenge with three divergent swH3 viruses. Vaccination studies in swine, the target species for this vaccine, show stronger levels of cross-reactive antibodies and T-cell responses after immunization with the epigraph vaccine compared to the wild type and FluSure vaccines. In both murine and swine models, epigraph vaccination shows superior cross-reactive immunity that should be further investigated as a universal swH3 vaccine.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Neutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer

Broadly-neutralizing antibodies (bNAbs) against HIV-1 Env can protect from infection. We characterize Ab1303 and Ab1573, heterologously-neutralizing CD4-binding site (CD4bs) antibodies, isolated from sequentially-immunized macaques. Ab1303/Ab1573 binding is observed only when Env trimers are not constrained in the closed, prefusion conformation. Fab-Env cryo-EM structures show that both antibodies recognize the CD4bs on Env trimer with an ‘occluded-open’ conformation between closed, as targeted by bNAbs, and fully-open, as recognized by CD4. The occluded-open Env trimer conformation includes outwardly-rotated gp120 subunits, but unlike CD4-bound Envs, does not exhibit V1V2 displacement, 4-stranded gp120 bridging sheet, or co-receptor binding site exposure. Inter-protomer distances within trimers measured by double electron-electron resonance spectroscopy suggest an equilibrium between occluded-open and closed Env conformations, consistent with Ab1303/Ab1573 binding stabilizing an existing conformation. Studies of Ab1303/Ab1573 demonstrate that CD4bs neutralizing antibodies that bind open Env trimers can be raised by immunization, thereby informing immunogen design and antibody therapeutic efforts.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Limited cross-variant immunity from SARS-CoV-2 Omicron without vaccination

SARS-CoV-2 Delta and Omicron are globally relevant variants of concern. Although individuals infected with Delta are at risk of developing severe lung disease, infection with Omicron often causes milder symptoms, especially in vaccinated individuals. The question arises of whether widespread Omicron infections could lead to future cross-variant protection, accelerating the end of the pandemic. Here we show that without vaccination, infection with Omicron induces a limited humoral immune response in mice and humans. Sera from mice overexpressing the human ACE2 receptor and infected with Omicron neutralize only Omicron, but not other variants of concern, whereas broader cross-variant neutralization was observed after WA1 and Delta infections. Unlike WA1 and Delta, Omicron replicates to low levels in the lungs and brains of infected animals, leading to mild disease with reduced expression of pro-inflammatory cytokines and diminished activation of lung-resident T cells. Sera from individuals who were unvaccinated and infected with Omicron show the same limited neutralization of only Omicron itself. By contrast, Omicron breakthrough infections induce overall higher neutralization titres against all variants of concern. Our results demonstrate that Omicron infection enhances pre-existing immunity elicited by vaccines but, on its own, may not confer broad protection against non-Omicron variants in unvaccinated individuals.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Increased ß-cell proliferation before immune cell invasion prevents progression of type 1 diabetes

Type 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a near-total loss of ß-cells1. Restoration of insulin producing ß-cells coupled with immunomodulation to suppress the autoimmune attack has emerged as a potential approach to counter T1D2-4. Here we report that enhancing ß-cell mass early in life (prior to weaning) results in immunomodulation of T-cells, reduced islet infiltration and lower ß-cell apoptosis, in female NOD mice that together protect them from developing T1D. We observed that a model exhibiting ß-cell hyperplasia on the NOD background (NOD-LIRKO) displayed reduced ß-cell antigens, and islet transplantation studies showed prolonged graft survival of NOD-LIRKO islets even upon exposure to diabetogenic splenocytes in vivo. Adoptive transfer of splenocytes from the NOD-LIRKOs prevented diabetes development in pre-diabetic NOD mice, while conversely; similar protective outcomes were obtained when NOD-LIRKO splenocytes were adoptively transferred after mixing them with diabetogenic NOD splenocytes in a dose-dependent manner. A significant increase in splenic CD4+CD25+FoxP3+ regulatory T-cell (Treg) population in the NOD-LIRKO mice was observed to drive the protected phenotype since Treg depletion rendered NOD-LIRKO mice diabetic. The increase in Tregs coupled with downregulation of key mediators of cellular function, upregulation of apoptosis and activation of TGF-ß/SMAD3 signaling pathway in pathogenic T-cells favored reduced ability to kill ß-cells. These data provide novel evidence that initiating ß-cell proliferation prior to islet infiltration by immune cells alters the identity of ß-cells, improves pathologic self-reactivity of effector cells and increases Tregs to prevent progression of T1D.

Dirice, Ercument↗
DOE OSTI2019

The molecular mechanism of robust macrophage immune responses induced by PEGylated molybdenum disulfide

Molybdenum disulfide (MoS 2 ), a representative hexagonal transition metal dichalcogenide (TMD), has been extensively exploited in biomedical applications due to its unique physicochemical properties and biocompatibility. However, the lack of adequate data regarding how MoS 2 activates immunological responses of macrophages remains a key concern for its risk assessment. Here, we employ a combined theoretical and experimental approach to investigate the interactions of MoS 2 and PEGylated MoS 2 (MoS 2 -PEG) with macrophages. We first perform molecular dynamics simulations to examine the atomic-detailed interactions of MoS 2 and MoS 2 -PEG nanoflakes with a realistic model of the macrophage membrane. We show that a small MoS 2 nanoflake (edge length of 2.86 nm) is capable of penetrating the macrophage membrane independent of its concentration. We also demonstrate that when initiated with a corner point-on configuration, the surface-bound PEG chains of MoS 2 -PEG hinder its membrane insertion process, leading to a prolonged passage through the membrane. Moreover, when placed in a face-on arrangement initially, the MoS 2 -PEG exhibits a lower binding free energy than pristine MoS 2 after its adsorption on the membrane surface. The PEG chains can even insert and get buried in the outer leaflet of the membrane, providing additional contact for membrane adsorption. Our flow cytometric experiments then show that the responses of macrophages to either MoS 2 -PEG or MoS 2 are significantly higher than that of the control (no nanomaterial stimulus), with MoS 2 -PEG eliciting stronger cytokine secretion than the pristine MoS 2 . The characteristics of slower/prolonged membrane penetration and stronger membrane adsorption of MoS 2 -PEG compared to pristine MoS 2 explain why it triggers more sustained stimulation and higher cytokine secretion in macrophages as observed in our experiments. Our findings reveal the underlying molecular mechanism of how MoS 2 -PEG influences the immune responses and suggest its potential applications in nanomedicine involving immune stimulation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form

For cancer cells to survive and proliferate, they must escape normal immune destruction. One mechanism by which this is accomplished is through immune suppression effected by up-regulation of indoleamine 2,3-dioxygenase (IDO1), a heme enzyme that catalyzes the oxidation of tryptophan to N -formylkynurenine. On deformylation, kynurenine and downstream metabolites suppress T cell function. The importance of this immunosuppressive mechanism has spurred intense interest in the development of clinical IDO1 inhibitors. Herein, we describe the mechanism by which a class of compounds effectively and specifically inhibits IDO1 by targeting its apo-form. We show that the in vitro kinetics of inhibition coincide with an unusually high rate of intrinsic enzyme–heme dissociation, especially in the ferric form. X-ray crystal structures of the inhibitor–enzyme complexes show that heme is displaced from the enzyme and blocked from rebinding by these compounds. The results reveal that apo-IDO1 serves as a unique target for inhibition and that heme lability plays an important role in posttranslational regulation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Structure of SARS-CoV-2 ORF8, a rapidly evolving immune evasion protein

The molecular basis for the severity and rapid spread of the COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely unknown. ORF8 is a rapidly evolving accessory protein that has been proposed to interfere with immune responses. The crystal structure of SARS-CoV-2 ORF8 was determined at 2.04-Å resolution by X-ray crystallography. The structure reveals a ~60-residue core similar to SARS-CoV-2 ORF7a, with the addition of two dimerization interfaces unique to SARS-CoV-2 ORF8. A covalent disulfide-linked dimer is formed through an N-terminal sequence specific to SARS-CoV-2, while a separate noncovalent interface is formed by another SARS-CoV-2-specific sequence, 73 YIDI 76 . Together, the presence of these interfaces shows how SARS-CoV-2 ORF8 can form unique large-scale assemblies not possible for SARS-CoV, potentially mediating unique immune suppression and evasion activities.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

CasDinG is a 5′-3′ dsDNA and RNA/DNA helicase with three accessory domains essential for type IV CRISPR immunity

Abstract CRISPR-associated DinG protein (CasDinG) is essential to type IV-A CRISPR function. Here, we demonstrate that CasDinG from Pseudomonas aeruginosa strain 83 is an ATP-dependent 5′-3′ DNA translocase that unwinds double-stranded (ds)DNA and RNA/DNA hybrids. The crystal structure of CasDinG reveals a superfamily 2 helicase core of two RecA-like domains with three accessory domains (N-terminal, arch, and vestigial FeS). To examine the in vivo function of these domains, we identified the preferred PAM sequence for the type IV-A system (5′-GNAWN-3′ on the 5′-side of the target) with a plasmid library and performed plasmid clearance assays with domain deletion mutants. Plasmid clearance assays demonstrated that all three domains are essential for type IV-A immunity. Protein expression and biochemical assays suggested the vFeS domain is needed for protein stability and the arch for helicase activity. However, deletion of the N-terminal domain did not impair ATPase, ssDNA binding, or helicase activities, indicating a role distinct from canonical helicase activities that structure prediction tools suggest involves interaction with dsDNA. This work demonstrates CasDinG helicase activity is essential for type IV-A CRISPR immunity as well as the yet undetermined activity of the CasDinG N-terminal domain.

59 BASIC BIOLOGICAL SCIENCES↗