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DOE OSTI2021

Formin nanoclustering-mediated actin assembly during plant flagellin and DSF signaling

Plants respond to bacterial infection acutely with actin remodeling during plant immune responses. The mechanisms by which bacterial virulence factors (VFs) modulate plant actin polymerization remain enigmatic. Here, we show that plant-type-I formin serves as the molecular sensor for actin remodeling in response to two bacterial VFs: Xanthomonas campestris pv. campestris (Xcc) diffusible signal factor (DSF), and pathogen-associated molecular pattern (PAMP) flagellin in pattern-triggered immunity (PTI). Both VFs regulate actin assembly by tuning the clustering and nucleation activity of formin on the plasma membrane (PM) at the nano-sized scale. By being integrated within the cell-wall-PM-actin cytoskeleton (CW-PM-AC) continuum, the dynamic behavior and function of formins are highly dependent on each scaffold layer’s composition within the CW-PM-AC continuum during both DSF and PTI signaling. Our results reveal a central mechanism for rapid actin remodeling during plant-bacteria interactions, in which bacterial signaling molecules fine tune plant formin nanoclustering in a host mechanical-structure-dependent manner.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

Structural basis and mode of action for two broadly neutralizing antibodies against SARS-CoV-2 emerging variants of concern

Emerging variants of concern for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit more efficiently and partially evade protective immune responses, thus necessitating continued refinement of antibody therapies and immunogen design. Here, we elucidate the structural basis and mode of action for two potent SARS-CoV-2 spike (S)-neutralizing monoclonal antibodies, CV3-1 and CV3-25, which remain effective against emerging variants of concern in vitro and in vivo. CV3-1 binds to the (485-GFN-487) loop within the receptor-binding domain (RBD) in the “RBD-up” position and triggers potent shedding of the S1 subunit. In contrast, CV3-25 inhibits membrane fusion by binding to an epitope in the stem helix region of the S2 subunit that is highly conserved among β-coronaviruses. Thus, vaccine immunogen designs that incorporate the conserved regions in the RBD and stem helix region are candidates to elicit pan-coronavirus protective immune responses.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

Modular adjuvant-free pan-HLA-DR-immunotargeting subunit vaccine against SARS-CoV-2 elicits broad sarbecovirus-neutralizing antibody responses

Subunit vaccines typically require co-administration with an adjuvant to elicit protective immunity, adding development hurdles that can impede rapid pandemic responses. To circumvent the need for adjuvant in a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subunit vaccine, we engineer a thermostable immunotargeting vaccine (ITV) that leverages the pan-HLA-DR monoclonal antibody 44H10 to deliver the viral spike protein receptor-binding domain (RBD) to antigen-presenting cells. X-ray crystallography shows that 44H10 binds to a conserved epitope on HLA-DR, providing the basis for its broad HLA-DR reactivity. Adjuvant-free ITV immunization in rabbits and ferrets induces robust anti-RBD antibody responses that neutralize SARS-CoV-2 variants of concern and protect recipients from SARS-CoV-2 challenge. We demonstrate that the modular nature of the ITV scaffold with respect to helper T cell epitopes and diverse RBD antigens facilitates broad sarbecovirus neutralization. Our findings support anti-HLA-DR immunotargeting as an effective means to induce strong antibody responses to subunit antigens without requiring an adjuvant.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

CVID enteropathy is characterized by exceeding low mucosal IgA levels and interferon-driven inflammation possibly related to the presence of a pathobiont

Common variable immunodeficiency (CVID), the most common symptomatic primary antibody deficiency, is accompanied in some patients by a duodenal inflammation and malabsorption syndrome known as CVID enteropathy (E-CVID).The goal of this study was to investigate the immunological abnormalities in CVID patients that lead to enteropathy as well as the contribution of intestinal microbiota to this process.We found that, in contrast to noE-CVID patients (without enteropathy), E-CVID patients have exceedingly low levels of IgA in duodenal tissues. In addition, using transkingdom network analysis of the duodenal microbiome, we identified Acinetobacter baumannii as a candidate pathobiont in E-CVID. Finally, we found that E-CVID patients exhibit a pronounced activation of immune genes and down-regulation of epithelial lipid metabolism genes. We conclude that in the virtual absence of mucosal IgA, pathobionts such as A. baumannii , may induce inflammation that re-directs intestinal molecular pathways from lipid metabolism to immune processes responsible for enteropathy.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

Structure-guided development of a high-affinity human Programmed Cell Death-1: Implications for tumor immunotherapy

Programmed Cell Death-1 (PD-1) is an inhibitory immune receptor, which plays critical roles in T cell co-inhibition and exhaustion upon binding to its ligands PD-L1 and PD-L2. We report the crystal structure of the human PD-1 ectodomain and the mapping of the PD-1 binding interface. Mutagenesis studies confirmed the crystallographic interface, and resulted in mutant PD-1 receptors with altered affinity and ligand-specificity. In particular, a high-affinity mutant PD-1 (HA PD-1) exhibited 45 and 30-fold increase in binding to PD-L1 and PD-L2, respectively, due to slower dissociation rates. This mutant (A132L) was used to engineer a soluble chimeric Ig fusion protein for cell-based and in vivo studies. HA PD-1 Ig showed enhanced binding to human dendritic cells, and increased T cell proliferation and cytokine production in a mixed lymphocyte reaction (MLR) assay. Moreover, in an experimental model of murine Lewis lung carcinoma, HA PD-1 Ig treatment synergized with radiation therapy to decrease local and metastatic tumor burden, as well as in the establishment of immunological memory responses. Our studies highlight the value of structural considerations in guiding the design of a high-affinity chimeric PD-1 Ig fusion protein with robust immune modulatory properties, and underscore the power of combination therapies to selectively manipulate the PD-1 pathway for tumor immunotherapy.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes

During early HIV-1 infection, immunodominant T cell responses to highly variable epitopes lead to the establishment of immune escape virus variants. Here we assessed a type 1-polarized monocyte-derived dendritic cell (MDC1)-based approach to selectively elicit cytotoxic T lymphocyte (CTL) responses against highly conserved and topologically important HIV-1 epitopes in HIV-1-infected individuals from the Thailand RV254/SEARCH 010 cohort who initiated antiretroviral therapy (ART) during early infection (Fiebig stages I-IV). Autologous MDC1 were used as antigen presenting cells to induce in vitro CTL responses against HIV-1 Gag, Pol, Env, and Nef as determined by flow cytometry and ELISpot assay. Ultra-conserved or topologically important antigens were respectively identified using the Epigraph tool and a structure-based network analysis approach and compared to overlapping peptides spanning the Gag proteome. MDC1 presenting either the overlapping Gag, Epigraph, or Network 14-21mer peptide pools consistently activated and expanded HIV-1-specific T cells to epitopes identified at the 9-13mer peptide level. Interestingly, some CTL responses occurred outside known or expected HLA associations, providing evidence of new HLA-associated CTL epitopes. Comparative analyses demonstrated more sequence conservation among Epigraph antigens but a higher magnitude of CTL responses to Network and Gag peptide groups. Importantly, CTL responses against topologically constrained Gag epitopes contained in both the Network and Gag peptide pools were selectively enhanced in the Network pool-initiated cultures. Our study supports the use of MDC1 as a therapeutic strategy to induce and focus CTL responses toward putative fitness-constrained regions of HIV-1 to prevent immune escape and control HIV-1 infection.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

Comparison of distribution and toxicity following repeated oral dosing of different vanadium oxide nanoparticles in mice

Vanadium is an important ultra-trace element derived from fuel product combustion. With the development of nanotechnology, vanadium oxide nanoparticles (VO NPs) have been considered for application in various fields, thus the possibility of release into the environment and human exposure is also increasing. Considering that verification of bioaccumulation and relevant biological responses are essential for safe application of products, in this study, we aimed to identify the physicochemical properties that determine their health effects by comparing the biological effects and tissue distribution of different types of VO NPs in mice. For this, we prepared five types of VO NPs, commercial (C)-VO{sub 2} and -V{sub 2}O{sub 5} NPs and synthetic (S)-VO{sub 2}, -V{sub 2}O{sub 3,} and -V{sub 2}O{sub 5} NPs. While the hydrodynamic diameter of the two types of C-VO NPs was irregular and impossible to measure, those of the three types of S-VO NPs was in the range of 125–170 nm. The S- and C-V{sub 2}O{sub 5} NPs showed higher dissolution rates compared to other VO NPs. We orally dosed the five types of VO NPs (70 and 210 μg/mouse, approximately 2 and 6 mg/kg) to mice for 28 days and compared their biodistribution and toxic effects. We found that S-V{sub 2}O{sub 5} and S-V{sub 2}O{sub 3} NPs more accumulated in tissues compared to other three types of VO NPs, and the accumulated level was in order of heart>liver>kidney>spleen. Additionally, tissue levels of redox reaction-related elements and electrolytes (Na{sup +}, K{sup +}, and Ca{sup 2+}) were most clearly altered in the heart of treated mice. Notably, all S- and C-VO NPs decreased the number of WBCs at the higher dose, while total protein and albumin levels were reduced at the higher dose of S-V{sub 2}O{sub 5} and S-V{sub 2}O{sub 3} NPs. Taken together, we conclude that the biodistribution and toxic effects of VO NPs depend on their dissolution rates and size (surface area). Additionally, we suggest that further studies are needed to clarify effects of VO NPs on functions of the heart and the immune system. - Highlights: • We used commercial (C)-VO{sub 2} and -V{sub 2}O{sub 5} and synthetic (S)-VO{sub 2}, -V{sub 2}O{sub 3,} and -V{sub 2}O{sub 5} NPs. • The S- and C-V{sub 2}O{sub 5} NPs showed higher dissolution rates compared to other VO NPs. • S-V{sub 2}O{sub 5} and S-V{sub 2}O{sub 3} NPs more accumulated in tissues compared to other types of VO NPs. • Redox reaction-related elements and electrolytes were clearly altered in the heart. • With decreased body weight, immune and blood-related factors influence by all VO NPs. • Biodistribution and toxicity of VO NPs depend on their dissolution rates and size.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

Interactions of cationic polystyrene nanoparticles with marine bivalve hemocytes in a physiological environment: Role of soluble hemolymph proteins

The bivalve Mytilus galloprovincialis has proven as a suitable model invertebrate for evaluating the potential impact of nanoparticles (NPs) in the marine environment. In particular, in mussels, the immune system represents a sensitive target for different types of NPs. In environmental conditions, both NP intrinsic properties and those of the receiving medium will affect particle behavior and consequent bioavailability/uptake/toxicity. However, the evaluation of the biological effects of NPs requires additional understanding of how, once within the organism, NPs interact at the molecular level with cells in a physiological environment. In mammalian systems, different NPs associate with serum soluble components, organized into a “protein corona”, which affects particle interactions with target cells. However, no information is available so far on the interactions of NPs with biological fluids of aquatic organisms. In this work, the influence of hemolymph serum (HS) on the in vitro effects of amino modified polystyrene NPs (PS-NH{sub 2}) on Mytilus hemocytes was investigated. Hemocytes were incubated with PS-NH{sub 2} suspensions in HS (1, 5 and 50 µg/mL) and the results were compared with those obtained in ASW medium. Cell functional parameters (lysosomal membrane stability, oxyradical production, phagocytosis) were evaluated, and morphological changes were investigated by TEM. The activation state of the signalling components involved in Mytilus immune response (p38 MAPK and PKC) was determined. The results show that in the presence of HS, PS-NH{sub 2} increased cellular damage and ROS production with respect to ASW medium. The effects were apparently mediated by disregulation of p38 MAPK signalling. The formation of a PS-NH{sub 2}-protein corona in HS was investigated by centrifugation, and 1D- gel electrophoresis and nano-HPLC-ESI-MS/MS. The results identified the Putative C1q domain containing protein (MgC1q6) as the only component of the PS-NH{sub 2} hard protein corona in Mytilus hemolymph. These data represent the first evidence for the formation of a NP bio-corona in aquatic organisms and underline the importance of the recognizable biological identity of NPs in physiological exposure medium when testing their potential impact environmental model organisms. Although the results obtained in vitro do not entirely reflect a realistic exposure scenario and the more complex formation of a bio-corona that is likely to occur in vivo, these data will contribute to a better understanding of the effects of NPs in marine invertebrates. - Highlights: • The effects of PS-NH2 NPs on Mytilus hemocytes were compared in serum-HS and ASW. • HS increased cellular/lysosomal damage, ROS production and p-p38MAPK levels. • NP-corona proteins in HS were isolated and identified by MS. • NP-protein coronas in biological fluids can affect NP impact in marine species.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

Immunomodulatory effects of exposure to polychlorinated biphenyls and perfluoroalkyl acids in East Greenland ringed seals (Pusa hispida)

To better elucidate the potential immune-related health effects of exposure to environmentally persistent organic pollutants (POP), such as polychlorinated biphenyls (PCBs) and perfluoroalkyl substances (PFASs), in ringed seals (Pusa hispida), a sentinel Arctic species, we assessed 1) associations between mitogen-induced lymphocyte proliferation and in vivo tissue contaminant burdens, and 2) the concentration-response effects of in vitro exposure to PFASs and PCB congeners on mitogen-induced lymphocyte proliferation. Upon in vitro contaminant exposure, the non-coplanar PCB congeners CB 138, 153, and 180, but not the coplanar CB 169, significantly reduced lymphocyte proliferation between 10 and 20 µg g{sup −1} ww. The respective in vitro EC{sub 50} values for these congeners were 13.3, 20.7, 20.8, and 54.6 µg g{sup −1} ww. No modulation of lymphocyte proliferation was observed upon in vitro exposure to two individual PFASs, perfluorooctane sulphonic acid (PFOS) and perfluorooctanoic acid (PFOA), at concentrations up to 1000 ng g-1. In addition, no significant correlations were found between lymphocyte proliferation and any blood or blubber contaminant measured. Taken together, these data suggest this population of ringed seals is not currently at high risk of altered lymphocyte proliferation from exposure to the POPs or PFASs in this study. - Highlights: • Assess relationships between tissue contaminants and changes in immune function. • Risk for contaminant-induced immunotoxicity in East Greenland ringed seal is low. • Weight of evidence suggest non-coplanar PCBs are immunotoxic at high concentrations.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2017

The acute effects of ultraviolet radiation on the blood transcriptome are independent of plasma 25OHD{sub 3}

The molecular basis of many health outcomes attributed to solar ultraviolet radiation (UVR) is unknown. We tested the hypothesis that they may originate from transcriptional changes in blood cells. This was determined by assessing the effect of fluorescent solar simulated radiation (FSSR) on the transcriptional profile of peripheral blood pre- and 6 h, 24 h and 48 h post-exposure in nine healthy volunteers. Expression of 20 genes was down-regulated and one was up-regulated at 6 h after FSSR. All recovered to baseline expression at 24 h or 48 h. These genes have been associated with immune regulation, cancer and blood pressure; health effects attributed to vitamin D via solar UVR exposure. Plasma 25-hydroxyvitamin D{sub 3} [25OHD{sub 3}] levels increased over time after FSSR and were maximal at 48 h. The increase was more pronounced in participants with low basal 25OHD{sub 3} levels. Mediation analyses suggested that changes in gene expression due to FSSR were independent of 25OHD{sub 3} and blood cell subpopulations. - Highlights: • Exposure to UVR induced transient changes in gene expression in blood cells. • Affected genes are related to immune regulation, cancer and blood pressure. • UVR increased 25OHD{sub 3} over time, especially in participants with low baseline levels. • The acute effects of UVR on the blood transcriptome are independent of 25OHD{sub 3}.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Lung health in era of climate change and dust storms

Highlights: • Dust storms provide a vital role on Earth. • The health impact of dust storms is principally determined by the particle size. • The immune system plays a vital role in dust exposure. • Association between dust and sarcoidosis has been proposed. • Prevention and reduction of particle exposure is of paramount importance. Dust storms are strong winds which lead to particle exposure over extensive areas. These storms influence air quality on both a local and global scale which lead to both short and long-term effects. The frequency of dust storms has been on the rise during the last decade. Forecasts suggest that their incidence will increase as a response to the effects of climate change and anthropogenic activities. Elderly people, young children, and individuals with chronic cardiopulmonary diseases are at the greatest risk for health effects of dust storms. A wide variety of infectious and non-infectious diseases have been associated with dust exposure. Influenza A virus, pulmonary coccidioidomycosis, bacterial pneumonia, and meningococcal meningitis are a few examples of dust-related infectious diseases. Among non-infectious diseases, chronic obstructive pulmonary disease, asthma, sarcoidosis and pulmonary fibrosis have been associated with dust contact. Here, we review two molecular mechanisms of dust induced lung disease for asthma and sarcoidosis. We can also then further understand the mechanisms by which dust particles disturb airway epithelial and immune cells.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2024

Preclinical characterization of Pan-NKG2D ligand-binding NKG2D receptor decoys

NKG2D and its ligands are critical regulators of protective immune responses controlling infections and cancer, defining a crucial immune signaling axis. Current therapeutic efforts targeting this axis almost exclusively aim at enhancing NKG2D-mediated effector functions. However, this axis can drive disease processes when dysregulated, in particular, driving stem-like cancer cell reprogramming and tumorigenesis through receptor/ligand self-stimulation on tumor cells. Despite complexities with its structure and biology, we developed multiple novel engineered proteins that functionally serve as axis-blocking NKG2D “decoys” and report biochemical, structural, in vitro , and in vivo evaluation of their functionality.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

Tumor Cells Surviving Exposure to Proton or Photon Radiation Share a Common Immunogenic Modulation Signature, Rendering Them More Sensitive to T Cell–Mediated Killing

Purpose: To provide the foundation for combining immunotherapy to induce tumor antigen–specific T cells with proton radiation therapy to exploit the activity of those T cells. Methods and Materials: Using cell lines of tumors frequently treated with proton radiation, such as prostate, breast, lung, and chordoma, we examined the effect of proton radiation on the viability and induction of immunogenic modulation in tumor cells by flow cytometric and immunofluorescent analysis of surface phenotype and the functional immune consequences. Results: These studies show for the first time that (1) proton and photon radiation induced comparable up-regulation of surface molecules involved in immune recognition (histocompatibility leukocyte antigen, intercellular adhesion molecule 1, and the tumor-associated antigens carcinoembryonic antigen and mucin 1); (2) proton radiation mediated calreticulin cell-surface expression, increasing sensitivity to cytotoxic T-lymphocyte killing of tumor cells; and (3) cancer stem cells, which are resistant to the direct cytolytic activity of proton radiation, nonetheless up-regulated calreticulin after radiation in a manner similar to non-cancer stem cells. Conclusions: These findings offer a rationale for the use of proton radiation in combination with immunotherapy, including for patients who have failed radiation therapy alone or have limited treatment options.