Biology subjects

Wang, J. Y.

Publications and source records attributed to Wang, J. Y..

At least 19 recordsLinked to original sources

bioRxiv2025

Proteogenomic profiling of soft tissue leiomyosarcoma reveals distinct molecular subtypes with divergent outcomes and therapeutic vulnerabilities

Soft tissue leiomyosarcoma (STLMS) is an aggressive malignancy for which robust molecular subclassification and mechanism-based therapeutic strategies still remain limited. We performed integrative proteogenomic analyses of primary and metastatic STLMS to define subtype-associated molecular programs. Joint analysis of the proteome and phosphoproteome identified 3 biologically distinct subtypes. P1 was characterized by relative genomic stability, low proliferative activity, and enrichment of FGFR2- and PDK-associated signaling. In contrast, P2 and P3 showed greater chromosomal instability and more aggressive clinical behavior, but with distinct molecular features. Notably, P2 was associated with inflammatory and RTK-RAS pathway programs, activation of CDK-AURKA/B-mTOR-ERK kinase networks, IGF1R/PDGFRA alterations, and the poorest outcomes. On the other hand, P3 showed strong cell cycle and DNA repair programs, elevated NCOR1 expression, and increased expression of nonhomologous end joining components, including PARP1. Homologous recombination deficiency analyses distinguished HRD-low P1 from HRD-high P2/P3, and paired analyses suggested increased HRD-related features in metastatic lesions within P3. Immune profiling identified an immune-hot yet potentially suppressive state in P2, marked by higher LGALS9 expression and M2-like macrophage infiltration. To support clinical translation, we developed a tissue microarray-based immunohistochemical classifier that enabled surrogate assignment of proteome-defined subtypes in an independent cohort and showed recurrence-free survival differences across inferred subtypes. These findings together establish a proteogenomic framework for STLMS heterogeneity and nominate subtype-associated biological vulnerabilities for future translational and clinical investigation.

cancer biology↗

bioRxiv2025

Uncovering Design and Assembly Rules for mRNA-DNA Origami

mRNA-DNA hybrid origami offers a powerful route to combine the structural programmability of DNA origami with the biological functionality of messenger RNA, but generalizable design and assembly rules for these hybrids remain poorly defined. Here we systematically investigate the design principles and synthesis conditions that govern high-yield formation of mRNA-DNA hybrid nanostructures. Using mature mRNAs encoding firefly luciferase, EGFP, and mCherry as scaffolds, we construct a series of five hybrid compact origamis with diverse sizes, shapes, crossover strategies, and packing densities. We identify key parameters that control folding fidelity, including asymmetric A-form crossovers, monovalent-cation concentrations, and moderate-temperature annealing protocols, which together mitigate RNA instability, reduce kinetic traps, and accommodate RNA-DNA helical geometry. Atomic force microscopy reveals monodisperse, well-folded structures consistent with design expectations across most architectures and confirms that optimized conditions produce nanoscale precision comparable to DNA origami. Our findings establish generalizable design rules and a standard synthesis protocol for mRNA-DNA hybrid origami, providing a framework for their use in gene delivery and other RNA-based nanotechnologies.

bioengineering↗

bioRxiv2024

Root Remodeling Mechanisms and Salt Tolerance Trade-Offs: The Roles of HKT1, TMAC2, and TIP2;2 in Arabidopsis

Plant responses to salt stress involve complex processes integrating short- and long-term adaptations, including changes in ion transport, systemic signaling, root architecture, and biomass distribution. A key adaptive mechanism involves the regulation of sodium (Na+) and potassium (K+) ion transport via Class 1 HKT1 transporters, which reduce Na+ accumulation in shoots, thereby enhancing salinity tolerance but at the expense of lateral root development. In this study, we identified differential roles of TMAC2 in modulating ABA accumulation and lateral root development under salt stress in two distinct Arabidopsis genotypes, Col-0 and C24. Overexpression of TMAC2 in the Col-0 background increased ABA accumulation, resulting in reduced lateral root development, suggesting a positive feedback loop involving HKT1, TMAC2, and ABA signaling. In contrast, TMAC2 overexpression in C24 reduced ABA accumulation in lines overexpressing HKT1, indicating genotype-specific differences in the TMAC2-HKT1 interaction. Additionally, we observed that the co-expression of TMAC2 and HKT1 in Col-0 induced ABI4 and ABI5 transcription factors, which are known to mediate salt sensitivity. These findings reveal a regulatory network where TMAC2 and HKT1 modulate salt stress responses through genotype-dependent feedback mechanisms. Our results highlight the complexity of root remodeling under salt stress and the crucial role of genetic background in shaping these adaptive responses.

plant biology↗

bioRxiv2024

Three Open Questions in Polygenic Score Portability

A major obstacle hindering the broad adoption of polygenic scores (PGS) is their lack of "portability" to people that differ--in genetic ancestry or other characteristics--from the GWAS samples in which genetic effects were estimated. Here, we use the UK Biobank to measure the change in PGS prediction accuracy as a continuous function of individuals genome-wide genetic dissimilarity to the GWAS sample ("genetic distance"). Our results highlight three gaps in our understanding of PGS portability. First, prediction accuracy is extremely noisy at the individual level and not well predicted by genetic distance. In fact, variance in prediction accuracy is explained comparably well by socioeconomic measures. Second, trends of portability vary across traits. For several immunity-related traits, prediction accuracy drops near zero quickly even at intermediate levels of genetic distance. This quick drop may reflect GWAS associations being more ancestry-specific in immunity-related traits than in other traits. Third, we show that even qualitative trends of portability can de pend on the measure of prediction accuracy used. For instance, for type 2 diabetes, precision stays roughly constant, while recall surprisingly increases, with genetic distance. Together, our results show that portability cannot be understood through global ancestry groupings alone. There are other, understudied factors influencing portability, such as the specifics of the evolution of the trait and its genetic architecture, social context, and the construction of the polygenic score. Addressing these gaps can aid in the development and application of PGS and inform more equitable genomic research.

genetics↗

bioRxiv2024

Computationally designed mRNA-launched protein nanoparticle vaccines

Both protein nanoparticle and mRNA vaccines were clinically de-risked during the COVID-19 pandemic1-6. These vaccine modalities have complementary strengths: antigen display on protein nanoparticles can enhance the magnitude, quality, and durability of antibody responses7-10, while mRNA vaccines can be rapidly manufactured11 and elicit antigen-specific CD4 and CD8 T cells12,13. Here we leverage a computationally designed icosahedral protein nanoparticle that was redesigned for optimal secretion from eukaryotic cells14 to develop an mRNA-launched nanoparticle vaccine for SARS-CoV-2. The nanoparticle, which displays 60 copies of a stabilized variant of the Wuhan-Hu-1 Spike receptor binding domain (RBD)15, formed monodisperse, antigenically intact assemblies upon secretion from transfected cells. An mRNA vaccine encoding the secreted RBD nanoparticle elicited 5- to 28-fold higher levels of neutralizing antibodies than an mRNA vaccine encoding membrane-anchored Spike, induced higher levels of CD8 T cells than the same immunogen when delivered as an adjuvanted protein nanoparticle, and protected mice from vaccine-matched and -mismatched SARS-CoV-2 challenge. Our data establish that delivering protein nanoparticle immunogens via mRNA vaccines can combine the benefits of each modality and, more broadly, highlight the utility of computational protein design in genetic immunization strategies.

immunology↗

bioRxiv2024

Chromosome-scale pearl millet genomes reveal a CARLACTONOIC ACID METHYL TRANSFERASE as key determinant of strigolactone pattern and Striga susceptibility

The yield of pearl millet, a resilient cereal crop crucial for African food security, is severely impacted by the root parasitic weed Striga hermonthica, which requires host-released strigolactones (SLs) for seed germination. Herein, we identified four SLs present in the Striga-susceptible line SOSAT-C88-P10 (P10), but absent in the resistant 29Aw (Aw). We generated chromosome-scale genome assemblies including four gapless chromosomes for each line. We found the Striga-resistant Aw lacks a 0.7 Mb genome segment containing two putative CARLACTONOIC ACID METHYL TRANSFERASE1 (CLAMT1) genes. Upon transient expression, P10CLAMT1b produced methyl carlactonoate (MeCLA), an intermediate in SL biosynthesis. Feeding Aw with MeCLA resulted in the production of two P10-specific SLs. Screening a diverse pearl millet panel confirmed the pivotal role of the CLAMT1 section for SL diversity and Striga susceptibility. Our results reveal a reason for Striga susceptibility in pearl millet and pave the way for generating resistant lines through marker-assisted breeding or direct genetic modification.

plant biology↗

bioRxiv2023

Local structural flexibility drives oligomorphism in computationally designed protein assemblies

Many naturally occurring protein assemblies have dynamic structures that allow them to perform specialized functions. For example, clathrin coats adopt a wide variety of architectures to adapt to vesicular cargos of various sizes. Although computational methods for designing novel self-assembling proteins have advanced substantially over the past decade, most existing methods focus on designing static structures with high accuracy. Here we characterize the structures of three distinct computationally designed protein assemblies that each form multiple unanticipated architectures, and identify flexibility in specific regions of the subunits of each assembly as the source of structural diversity. Cryo-EM single-particle reconstructions and native mass spectrometry showed that only two distinct architectures were observed in two of the three cases, while we obtained six cryo-EM reconstructions that likely represent a subset of the architectures present in solution in the third case. Structural modeling and molecular dynamics simulations indicated that the surprising observation of a defined range of architectures, instead of non-specific aggregation, can be explained by constrained flexibility within the building blocks. Our results suggest that deliberate use of structural flexibility as a design principle will allow exploration of previously inaccessible structural and functional space in designed protein assemblies.

bioengineering↗

bioRxiv2023

Zaxinone Synthase overexpression modulates rice physiology and metabolism, improving growth and productivity under normal and low phosphate supply

The rice Zaxinone Synthase (ZAS) gene encodes a carotenoid cleavage dioxygenase (CCD) that forms the apocarotenoid growth regulator zaxinone. Here, we generated and characterized constitutive ZAS-overexpressing rice lines, to better understand ZAS role in determining zaxinone content and regulating growth and architecture. ZAS overexpression enhanced endogenous zaxinone level, promoted root growth and meristem size, and increased the number of productive tillers, leading to an up to 30% higher grain yield per plant. Hormone analysis revealed a decrease in strigolactone (SL) content, which we confirmed by rescuing the high-tillering phenotype through application of a SL analog. Metabolomics analysis revealed that ZAS overexpressing plants accumulate higher amounts of monosaccharide sugars, in line with transcriptome analysis. Moreover, transgenic plants showed higher carbon (C) assimilation rate and elevated root phosphate, nitrate and sulfate level, enhancing the tolerance towards low phosphate (Pi) and indicating a generally better nutrient uptake. Our study shows that ZAS regulates hormone homeostasis and a combination of physiological processes to promote growth and grain yield, which makes this gene an excellent candidate for sustainable crop improvement. TeaserZaxinone Synthase overexpression modulates rice metabolism and physiology and improves growth and phosphate uptake.

plant biology↗

bioRxiv2023

Abscisic acid inhibits germination of Striga seeds and is released by them as a rhizospheric signal providing competitive advantage and supporting host infestation

O_LISeeds of the root parasitic plant Striga hermonthica undergo a conditioning process under humid and warm environments before germinating in response to host-released stimulants, particularly strigolactones (SLs). The plant hormone abscisic acid (ABA) regulates different growth and developmental processes, and stress response; however, its role during Striga seed germination and early interactions with host plants is under-investigated. C_LIO_LIHere, we show that ABA inhibited Striga seed germination and that hindering its biosynthesis induced conditioning and germination in unconditioned seeds, which was significantly enhanced by treatment with the SL analog rac-GR24. However, the inhibitory effect of ABA remarkably decreased during conditioning, confirming the loss of sensitivity towards ABA in later developmental stages. ABA measurement showed a significant reduction of its content during the early conditioning stage and a significant increase upon rac-GR24-triggered germination. We observed this increase also in released seed exudates, which was further confirmed by using the Arabidopsis ABA-reporter GUS marker line. C_LIO_LISeed exudates of germinated seeds, containing elevated levels of ABA, impaired the germination of surrounding Striga seeds in vitro and promoted root growth of a rice host towards germinated Striga seeds. Application of ABA as a positive control caused similar effects, indicating its function in Striga/Striga and Striga/host communications. C_LIO_LIIn summary, we show that ABA is an essential player during seed dormancy and germination processes in Striga and acts as a rhizospheric signal released by germinated parasitic seeds to provide a competitive advantage and support host infestation. C_LI Societal Impact StatementThe root parasitic plant Striga hermonthica is a severe threat to cereals yield, endangering global food security. Herein, we uncover a new role of the known plant hormone abscisic acid (ABA) as a rhizospheric signal released by germinated Striga seeds, allowing them to better compete with surrounding un-conditioned seeds and facilitating host infestation. Our findings can help in developing strategies to control this parasite and mitigate its negative impact on the food supply and income of smallholder farmers.

plant biology↗

bioRxiv2023

Dysregulated alveolar epithelial maintenance in Hermansky-Pudlak syndrome pulmonary fibrosis

Hermansky-Pudlak syndrome (HPS) is a genetic disorder of endosomal protein trafficking associated with pulmonary fibrosis in specific subtypes, including HPS-1 and HPS-2. Single mutant HPS1 and HPS2 mice display increased fibrotic sensitivity while double mutant HPS1/2 mice exhibit spontaneous fibrosis with aging, which has been attributed to HPS mutations in alveolar epithelial type II (AT2) cells. We utilized HPS mouse models and human lung tissue to investigate mechanisms of AT2 cell dysfunction driving fibrotic remodeling in HPS. Starting at 8 weeks of age, HPS mice exhibited progressive loss of AT2 cell numbers. HPS AT2 cell function was impaired ex vivo and in vivo. Incorporating AT2 cell lineage tracing in HPS mice, we observed aberrant differentiation with increased AT2-derived alveolar epithelial type I cells. Transcriptomic analysis of HPS AT2 cells revealed elevated expression of genes associated with aberrant differentiation and p53 activation. Lineage tracing and organoid modeling studies demonstrated that HPS AT2 cells were primed to persist in a Krt8+ reprogrammed transitional state, mediated by p53 activity. Intrinsic AT2 progenitor cell dysfunction and p53 pathway dysregulation are novel mechanisms of disease in HPS-related pulmonary fibrosis, with the potential for early targeted intervention before the onset of fibrotic lung disease.

cell biology↗

bioRxiv2023

Disruption of the rice 4-DEOXYOROBANCHOL HYDROXYLASE unravels specific functions of canonical strigolactones

Strigolactones (SLs) regulate many developmental processes, including shoot-branching/tillering, and mediate rhizospheric interactions. SLs are structurally diverse, divided into a canonical and a non-canonical sub-family. To better understand the biological function of particular SLs, we generated CRISPR/Cas9 mutants disrupted in OsMAX1-1400 or OsMAX1-1900, which encode cytochrome P450 enzymes (CYP711A clade) contributing to SL diversity. The disruption of OsMAX1-1900 did neither affect the SL pattern nor plant architecture, indicating a functional redundancy. In contrast, disruption of OsMAX1-1400 activity, a 4-deoxyorobanchol hydroxylase, led to a complete lack of orobanchol and an accumulation of its precursor 4-deoxyorobanchol (4DO), both of which are a canonical SLs common in different plant species, accompanied by higher levels of the non-canonical methyl 4-oxo-carlactonoate (4-oxo-MeCLA). Os1400 mutants showed also shorter plant height, panicle and panicle base length, but did not exhibit a tillering phenotype. Hormone quantification and transcriptome analysis revealed elevated auxin levels and changes in the expression of auxin-related, as well as of SL biosynthetic genes. Interestingly, the Os900/1400 double mutant lacking both orobanchol and 4DO did not show the observed Os1400 architectural phenotypes, indicating that they are a result of 4DO accumulation. A comparison of the mycorrhization and Striga seed germinating activity of Os900, Os900/1400, and Os1400 loss-of-function mutants demonstrates that the germination activity positively correlates with 4DO content while disrupting OsMAX1-1400 negatively impact mycorrhizal symbiosis. Taken together, our paper deciphers the biological function of canonical SLs in rice and depicts their particular contributions to establishing architecture and rhizospheric communications.

plant biology↗

bioRxiv2023

Integration of Apocarotenoid Profile and Expression Pattern of Carotenoid Cleavage Dioxygenases during Mycorrhization in Rice

Carotenoids are susceptible to degrading processes initiated by oxidative cleavage reactions mediated by Carotenoid Cleavage Dioxygenases that break their backbone, leading to products called apocarotenoids. These carotenoid-derived metabolites include the phytohormones abscisic acid and strigolactones, and different signaling molecules and growth regulators, which are utilized by plants to coordinate many aspects of their life. Several apocarotenoids have been recruited for the communication between plants and arbuscular mycorrhizal (AM) fungi and as regulators of the establishment of AM symbiosis. However, our knowledge on their biosynthetic pathways and the regulation of their pattern during AM symbiosis is still limited. In this study, we generated a qualitative and quantitative profile of apocarotenoids in roots and shoots of rice plants exposed to high/low phosphate concentrations, and upon AM symbiosis in a time course experiment covering different stages of growth and AM development. To get deeper insights in the biology of apocarotenoids during this plant-fungal symbiosis, we complemented the metabolic profiles by determining the expression pattern of CCD genes, taking advantage of chemometric tools. This analysis revealed the specific profiles of CCD genes and apocarotenoids across different stages of AM symbiosis and phosphate supply conditions, identifying novel markers at both local and systemic levels. HighlightOur study presents the profiles of CCD gene expression and apocarotenoids across different stages of AM symbiosis and Pi supply conditions and reveals novel AM markers at both local and systemic levels.

plant biology↗

bioRxiv2023

Genome expansion by a CRISPR trimmer-integrase

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

biochemistry↗

bioRxiv2022

Improving the secretion of designed protein assemblies through negative design of cryptic transmembrane domains

Computationally designed protein nanoparticles have recently emerged as a promising platform for the development of new vaccines and biologics. For many applications, secretion of designed nanoparticles from eukaryotic cells would be advantageous, but in practice they often secrete poorly. Here we show that designed hydrophobic interfaces that drive nanoparticle assembly are often predicted to form cryptic transmembrane domains, suggesting that interaction with the membrane insertion machinery could limit efficient secretion. We develop a general computational protocol, the Degreaser, to design away cryptic transmembrane domains without sacrificing protein stability. Retroactive application of the Degreaser to previously designed nanoparticle components and nanoparticles considerably improves secretion, and modular integration of the Degreaser into design pipelines results in new nanoparticles that secrete as robustly as naturally occurring protein assemblies. Both the Degreaser protocol and the novel nanoparticles we describe may be broadly useful in biotechnological applications.

biochemistry↗

bioRxiv2022

ZAXINONE SYNTHASE 2 regulates growth and arbuscular mycorrhizal symbiosis in rice

Carotenoid cleavage, catalyzed by CAROTENOID CLEAVAGE DIOXYGENASES (CCDs), provides signaling molecules and precursors of plant hormones. Recently, we showed that zaxinone, a novel apocarotenoid metabolite formed by the CCD Zaxinone Synthase (ZAS), is a growth regulator required for normal rice growth and development. The rice genome encodes three OsZAS homologs, called here OsZAS1b, OsZAS1c, and OsZAS2, with unknown functions. Here, we investigated the enzymatic activity, expression pattern, and subcellular localization of OsZAS2, and generated and characterized loss-of-function CRISPR/Cas9-Oszas2 mutants. We show that OsZAS2 formed zaxinone in vitro. OsZAS2 is a plastid-localized enzyme mainly expressed in the root cortex under phosphate starvation. Moreover, OsZAS2 expression increased during mycorrhization, specifically in arbuscule-containing cells. Oszas2 mutants contained lower zaxinone content in roots and exhibited reduced root and shoot biomass, less productive tiller, and higher strigolactone (SL) levels. Exogenous zaxinone application repressed SL biosynthesis and partially rescued the growth retardation of Oszas2 mutant. Consistent with the OsZAS2 expression pattern, Oszas2 mutants displayed a lower frequency of AM colonization. In conclusion, OsZAS2 encodes a further zaxinone-forming enzyme that determines rice growth and architecture and strigolactone content and is required for optimal mycorrhization.

plant biology↗

bioRxiv2022

The Arabidopsis D27like1 is a novel Isomerase that Contributes to SL Biosynthesis and Negatively Impacts ABA Level

The enzyme DWARF27 (D27) catalyzes the reversible isomerization of all-trans- into 9-cis-{beta}-carotene, initiating strigolactone (SL) biosynthesis. Genomes of higher plants encode two D27-homologs, D27-like1 and -like2, with unknown functions. Here, we investigated the enzymatic activity and biological function of the Arabidopsis D27-like1. In vitro enzymatic assays and Expression in Synechocystis sp. PCC6803 revealed a yet not reported 13-cis/15-cis/9-cis- and a 9-cis/all-trans-{beta}-carotene isomerization. Although disruption of AtD27-like1 did not cause SL deficiency phenotypes, overexpression of AtD27-like1 in the Atd27 mutant restored the more-branching phenotype, indicating a contribution of AtD27-like1 to SL biosynthesis. Accordingly, generated Atd27 Atd27like1 double mutants showed more pronounced branching phenotype, compared to Atd27. The contribution of AtD27-like1 to SL biosynthesis is likely due to its formation of 9-cis-{beta}-carotene that was present at higher levels in AtD27-like1 overexpressing lines. In contrast, AtD27-like1 expression correlated negatively with the content of 9-cis-violaxanthin, a precursor of abscisic acid (ABA), in shoots. Consistently, ABA levels were higher in shoots and also in dry seeds of the Atd27like1 and Atd27 Atd27like1 mutants. Transgenic lines expressing {beta}-glucuronidase (GUS) driven by the AtD27LIKE1 promoter and transcript analysis performed with hormone-treated Arabidopsis seedlings unraveled that AtD27LIKE1 is expressed in different tissues and regulated ABA and auxin. Taken together, our work revealed a cis/cis-{beta}-carotene isomerase activity that affects the content of both cis-carotenoid derived plant hormones ABA and SLs.

plant biology↗

bioRxiv2022

Canonical Strigolactones Are Not the Tillering-Inhibitory Hormone but Rhizospheric Signals in Rice

The plant hormones strigolactones (SLs) regulate shoot branching and mediate the communication with symbiotic mycorrhizal fungi, but also with noxious root parasitic weeds, such as Striga spp. SLs derive from carlactone (CL) and are divided structurally into canonical and non-canonical SLs. However, the questions about particular biological functions of the two groups and the identification of the SL that inhibits shoot branching are still unanswered, hampering targeted modification of SL pattern towards improving plant architecture and resistance against Striga. Here, we reported that 4-deoxyorobanchol (4DO) and orobanchol, the two canonical SLs in rice, do not have major role in determining rice shoot architecture. CRISPR/Cas9 mediated Osmax1-900 mutants, lacking these two SLs, do not show the high tillering and dwarf phenotype typical for SL-deficient plants. However, the absence of 4DO and orobanchol in root exudates significantly decreased their capability in inducing Striga seed germination, while caused only a delay in root colonization by mycorrhizal fungi. To confirm the genetic evidence, we used the SL-biosynthesis inhibitor TIS108. Our results showed that TIS108 is a MAX1-specific inhibitor that lowers 4DO and orobanchol synthesis, conferring a resistance to Striga without a severe impact on rice architecture. Hence, our work uncovers the specific function of canonical SLs as rhizospheric signals and paves the way for establishing chemical and genetic based approaches for combating the root parasitic weeds, by targeted depletion of their release.

plant biology↗

bioRxiv2022

Immunization with a self-assembling nanoparticle vaccine displaying EBV gH/gL protects humanized mice against lethal viral challenge

Summary/AbstractEpstein-Barr virus (EBV) is a cancer-associated pathogen responsible for 140,000 deaths per year. EBV is also the etiological agent of infectious mononucleosis and is associated with multiple sclerosis and rheumatoid arthritis. Thus, an EBV vaccine could alleviate significant morbidity and mortality. EBV is orally transmitted and has tropism for both epithelial cells and B cells which are present in the oral cavity. Therefore, a prophylactic vaccine would need to prevent infection of both cell types. Passive transfer neutralizing monoclonal antibodies targeting the viral gH/gL glycoprotein complex prevent experimental EBV infection in humanized mice and rhesus macaques, suggesting that gH/gL is an attractive vaccine candidate. Here, we produced and evaluated the immunogenicity of several nanoparticle immunogens displaying gH/gL with distinct valencies and geometries. After one or two immunizations, all nanoparticles elicited superior binding and neutralizing titers relative to monomeric gH/gL. Antibodies elicited by a computationally designed self-assembling nanoparticle that displays 60 copies of the gH/gL protein conferred protection against a lethal dose of EBV in a humanized mouse challenge model, whereas antibodies elicited by monomeric gH/gL did not. Taken together, these data motivate further development of gH/gL nanoparticle vaccine candidates for EBV.

immunology↗