Biology subjects

Dubey, S.

Publications and source records attributed to Dubey, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Mitochondria-Targeted OGG1 remodels Alveolar Epithelial Transitional States and Immune-Epithelial Communication after Chlorine Lung Injury

Chlorine (Cl2) inhalation causes acute epithelial and endothelial injury, pulmonary edema, inflammation, and impaired gas exchange, yet no approved therapy directly targets the mechanisms that sustain lung injury after exposure. We recently showed that oxidative mitochondrial DNA (mtDNA) damage drives chlorine-induced lung injury and that post-exposure delivery of a fusion protein containing mitochondria-targeted 8-oxoguanine DNA glycosylase-1 (mOGG1) mitigates lung injury and improves survival. However, the cell populations and transcriptional states through which mtDNA injury shapes lung damage and repair remain unclear. Here, we used single-nucleus RNA sequencing to define early cellular responses to distinct epithelial and immune cell populations. C57BL/6 mice (4/group; 2 males and 2 females per group) were exposed to air or Cl2 (500 ppm, 30 min), returned them to room air and mOGG1 (1 mg/kg, intranasal) was administered 1 h after exposure; the mice were sacrifice and their lungs were collected at 24 h post exposure. Integrated analysis resolved 39 transcriptionally distinct epithelial, immune, endothelial, stromal, and vascular populations. Although the major cellular compartments remained broadly preserved, Cl2 induced marked remodeling of epithelial composition and transcriptional states. Subclustering of the AT1/AT2 transitional compartment identified four Differential Transcriptomic Adaptation Phases (DTAPs): an acute stress-response state (DTAP_D), a proliferative state (DTAP_P), a Krt8 damage-associated transitional state (DTAP_T), and an AT1-like resolution state (DTAP_A). Pseudotemporal analyses suggested that chlorine exposure increased heterogeneity in alveolar and airway epithelial states, with injury-associated transitional programs expanding along the inferred trajectories. Ligand-receptor analysis further predicted that Cl2 increased the complexity of IL-1 communication among neutrophils, macrophages, and epithelial populations. mOGG1 did not globally suppress this network but instead redistributed signaling interactions, including the participation of selected DTAP populations. Together, these findings identify heterogeneous epithelial transitional states associated with Cl2 injury and support a model in which mOGG1 promotes recovery by reshaping epithelial injury-repair programs and immune-epithelial communication. Keywords: Chlorine inhalation; mitochondrial DNA damage; mitoOGG1; single-nucleus RNA sequencing; alveolar epithelial repair; epithelial transitional states; epithelial-immune communication.

molecular biology↗

bioRxiv2026

FANCM restrains structural genome evolution and defines a synthetic lethal dependency in BRCA1-deficient breast cancer

BRCA1 deficient cancers experience persistent replication stress and structural genome instability yet retain the capacity for sustained proliferation, implying reliance on compensatory genome-maintenance mechanisms. Here, we establish BRCA1/FANCM synthetic lethality in human BRCA1 deficient breast cancer and exploit temporally controlled FANCM depletion to capture genome evolution over successive cell divisions before declining cellular fitness becomes limiting. We show that FANCM restrains genome wide structural variation in BRCA1 deficient breast cancer cells under endogenous replication stress. FANCM loss amplifies the characteristic BRCA1 associated short tandem duplication (TD) phenotype while permitting larger, including megabase-scale, TDs and diverse rearrangements to emerge. Newly emerged TDs preferentially associate with Pol II occupied regions, and FANCM depletion increases proximity between the replication machinery and elongating RNAPII in BRCA1 mutant breast cancer cells, linking FANCM-mediated genome protection to transcription replication encounters. BRCA1 altered human tumors with low FANCM expression recapitulate key features of this phenotype, while genome/transcriptome integration links newly emerged SVs to configuration dependent local transcriptional changes. Together, these findings establish FANCM as a replication stress safeguard coupling survival to restraint of structural genome evolution.

cancer biology↗

bioRxiv2026

Curvature-guided chiral collective organization of myoblast tissues

Surface curvature is a fundamental geometric cue in tissue morphogenesis, yet its role in guiding collective cell organization has remained elusive. Here, we show that curvature acts as a geometric control parameter that shapes supracellular alignment and chirality while modulating myogenic differentiation in myoblast tissues. Cells cultured on curved substrates self-organize into robust helical assemblies whose handedness is set, and can be reversed, by the sign of curvature: convex fibers produce right-handed helices, whereas concave channels invert the chirality. We identify a previously hidden clockwise bias in single-cell motion associated with the helical actin cytoskeleton. A minimal continuum theory coupling an effective chiral drive to curvature quantitatively captures the emergence and reversal of tissue-scale chiral alignment. On substrates with spatially varying curvature, local curvature gradients organize patterned multicellular architectures while preserving a global handedness. Curvature is also associated with myogenic state, with higher curvature linked to reduced or delayed differentiation. Together, these findings reveal how complex geometries shape the alignment, symmetry, and cellular state of living tissues.

biophysics↗

bioRxiv2026

Structure of the Type I-F3 CAST holo integration complex reveals licensing mechanisms during RNA-guided DNA integration

Precise genomic integration of large DNA cargo remains a central challenge in genome engineering. In this context, CRISPR-associated transposases (CASTs) offer a promising solution by coupling RNA-guided DNA recognition to transposon-mediated integration. Type I-F3 CASTs exhibit exceptional targeting fidelity, making them a leading focus for biotechnology and gene therapy applications. Yet, despite extensive characterization, the structural basis for RNA-guided DNA integration of type I-F3 CASTs has remained elusive. Here, using cryo-EM and functional assays, we report the structural licensing mechanism of the Vibrio cholerae CAST (VchCAST) holo integration complex (HIC). Our structures reveal that sequential conformational licensing events govern selective activation of the integration machinery at the on-target site. Different components, including Cascade-TniQ, TnsC, and TnsA/B, undergo conformational changes upon assembly into the HIC, and the catalytically competent state is stabilized only within the fully assembled complex. Finally, comparison with existing CAST integration complex structures reveals a set of conserved architectural features, suggesting a common molecular basis for RNA-guided transposition across CAST diversity.

biochemistry↗

bioRxiv2026

Cellular uptake of Micro and nano plastics Induces Mitochondrial Dysfunction

Micro and nano plastics (MNPs) have become ubiquitous contaminants in the environment with their occurrence being detected in air, water and food. They can cross biological barriers and slowly build up in different organs, including the placenta, raising concerns about possible impacts on maternal and fetal health. Placenta, a highly metabolically active organ composed primarily of trophoblast cells, requires substantial energy for proper development and function. However, the effects of MNPs exposure on trophoblast biology and mitochondrial health remain poorly understood. This study investigated the in vivo systemic accumulation of MNP in different organs of pregnant mice and their localization within various organelles in vitro. These effects influenced trophoblast energy metabolism and led to reduced migration. Mice received fluorescent polystyrene MNPs via their drinking water. Biodistribution was evaluated in vivo using IVIS whole-body imaging, while ex vivo fluorescence imaging confirmed accumulation of these particles in multiple organs and cells. In parallel, human HTR-8/SVneo trophoblast cells were exposed to MNPs, demonstrating rapid cellular uptake and mitochondrial and nuclear localization via fluorescence microscopy. TEM analysis uncovered mitochondrial structural alterations and the localization of MNPs. Seahorse analysis revealed impaired mitochondrial respiration and oxygen consumption rates, indicating compromised cellular bioenergetics in MNPs-treated cells, which led to inflammation, altered mtDNA copy number, and impaired trophoblast migration. Overall, these findings indicate that pregnant mice exposed to MNPs undergo systemic transfer, with trophoblast uptake marked by mitochondrial dysfunction, inflammation, and reduced migration. Our study identifies mitochondrial dysfunction as a central mechanism underlying MNP-mediated placental toxicity and underscores the potential role of environmental microplastic exposure in adverse pregnancy outcomes. HighlightsO_LICellular uptake of MNPs and their localization across various organelles. C_LIO_LIUptake of MNPs disrupts mitochondrial function and promotes inflammation. C_LIO_LICellular uptake of MNPs impairs cell migration. C_LI

physiology↗

bioRxiv2026

Programmable DNA integration with New-to-Nature tools using Computational Protein Design

Programmable integration of large DNA cargo ([≥] 2 kb), without inducing double-strand breaks, remains challenging for genome editing technologies. Current approaches have limitations in programmability, depend on co-delivery of multiple components, require multiple enzymatic steps, or have variable on-target editing outcomes. Here, we address this challenge using de novo protein design to create highly active, new-to-nature RNA-guided transposons. Our strategy exploits the modular architecture of CRISPR-associated transposons (CASTs), reconfiguring their conserved transposition machinery to interface with widely adopted Cas9. The resulting system, which we call NovoCAST, simplifies the CAST architecture from eight distinct proteins to four, establishing the simplest CAST described to date. NovoCAST exhibits sharply defined integration profiles, a 500-fold increase in activity relative to the parental PmcCAST, and general programmability. Using structural and biochemical analyses, we confirmed that the designed proteins fold and function as intended. Finally, we demonstrate robust programmable genomic integration in human cells highlighting its broad potential applications in research and therapeutics. Together, these results establish de novo protein design as a powerful strategy for engineering efficient genome-editing systems and for coupling CRISPR-mediated DNA recognition to heterologous functions through de novo designed protein interfaces.

biochemistry↗

bioRxiv2026

Conformational Diversity and Interaction Signatures of NADH across protein families

Nicotinamide adenine dinucleotide (NADH) is a ubiquitous redox cofactor that participates in a wide range of enzymatic and regulatory processes. These include metabolism, signalling, and diseases such as cancer and neurodegeneration. Despite the abundance of NADH-protein complex structures, general principles governing how proteins shape NADH conformation and interaction modes remain unclear, which limits our ability to rationally interpret cofactor specificity, catalytic efficiency, and off-target effects in inhibitors. Here, we present a comprehensive structural analysis of NADH recognition across protein families using 345 NADH-bound crystal structures from the Protein Data Bank. We adopted a descriptor-driven strategy that quantitatively captures the internal geometry of NADH using angles, dihedrals, and interatomic distances, enabling direct comparison of cofactor shapes independent of protein fold. These studies reveal that 65% of structures preferred conformers with a conserved adenine- nicotinamide separation while allowing limited flexibility in the pyrophosphate. The interaction profiles demonstrate that NADH recognition is dominated by hydrogen bonding and electrostatic interactions involving nearly all heteroatoms, while most carbon positions remain non-interacting. Residue and moiety level analyses further show that the nicotinamide region acts as the primary interaction hotspot across enzyme classes, while only a handful of structures exhibit adenine-centric recognition. Together, this study establishes a unified biophysical framework that links NADH shape, interaction signatures, and protein context, providing rational insights for cofactor engineering and the design of NADH-targeted inhibitors.

biochemistry↗

bioRxiv2025

Beyond Cell Cycle Control: CDKN2A Loss Orchestrates NAD⁺ Metabolic Plasticity and NAMPT Inhibitor Sensitivity in Glioblastoma

While CDKN2A loss is classically associated with cell cycle deregulation through the p16-Cdk4-Rb axis, our findings suggest an additional layer of metabolic vulnerability arising from altered NAD homeostasis in CDKN2A-deleted glioblastoma, revealing a previously unrecognized metabolic-genetic interface for rationally revisiting NAD+ targeting strategies, moving beyond the broad inhibition approaches.

cancer biology↗

bioRxiv2025

Heterotic Pooling Strategy for Enhanced Hybrid Performance in Bitter Gourd (Momordica charantia L.)

Bitter gourd (Momordica charantia L.), a crop of significant nutritional and medicinal renown, is experiencing a surge in global demand, particularly in Asia. To meet this demand amidst the challenge of limited agricultural land, enhancing productivity through innovative breeding is essential. Hybrid breeding, which harnesses the power of heterosis, offers a proven strategy for boosting crop yields. However, the success of any heterosis breeding program, especially in a naturally cross-pollinated and genetically variable crop like bitter gourd, is fundamentally dependent on robust methods for assessing and strategically utilizing the available genetic diversity. This study compared the efficacy of traditional morphological trait-based clustering with a modern breeding value-based method (Heterotic grouping based on Specific and General Combining Ability - HSGCA) for predicting heterosis. Eleven diverse bitter gourd inbred lines were crossed in a half-diallel fashion to generate 55 F1 hybrids. The hybrids and parents were evaluated for key yield-related traits. K-means clustering based on morphological data resulted in five groups but proved unreliable for predicting heterosis, as high heterosis was often observed within clusters. In contrast, HSGCA-based clustering organized the lines into three coherent groups, where crosses between the two main groups (Group 1 and Group 2) consistently exhibited significantly higher mid-parent (20.89%) and better-parent (7.5%) heterosis compared to intra-group crosses. The HSGCA method provides a far more reliable framework for defining heterotic groups in bitter gourd, enabling more efficient and predictive hybrid breeding programs.

plant biology↗

bioRxiv2025

Single-Assay Characterization of Ternary Complex Assembly and Activity in Targeted Protein Degradation

Targeted protein degradation (TPD) is a rapidly advancing therapeutic strategy that selectively eliminates disease-associated proteins by co-opting the cells protein degradation machinery. Covalent modification of proteins with ubiquitin is a critical event in TPD, yet the analytical tools for quantifying the ubiquitination kinetics have been limited. Here, we present a real-time, high-throughput fluorescent assay utilizing purified, FRET-active E2-Ub conjugates to monitor ubiquitin transfer. This assay is highly versatile, requiring no engineering of the target protein or ligase, thereby accelerating assay development and minimizing the risk of artifacts. The single-step, single-turnover nature of the monitored reaction enables rigorous and quantitative analysis of ubiquitination kinetics. We show that this assay can be used to measure key degrader characteristics such as degrader affinity for the target protein, degrader affinity for the ligase, affinity of ternary complex assembly, and catalytic efficiency of the ternary complex. The high sensitivity and accuracy of this comprehensive, single-assay approach to ternary complex characterization will empower the discovery and optimization of heterobifunctional degraders and molecular glues.

biochemistry↗

bioRxiv2025

Master control of protein secretion by Mycobacterium tuberculosis

Tuberculosis is the leading cause of death from a single infectious disease. Mycobacterium tuberculosis secretes proteins using five ESX systems with distinctive functions essential for its growth and virulence. Here we show that a non-canonical supercomplex of the EsxU-EsxT proteins, encoded in the esx-4 locus, with the orphan EsxE-EsxF proteins, encoded in the cpnT operon, is required for toxin secretion by M. tuberculosis. Surprisingly, the outer membrane localization of all Esx proteins and their secretion into the cytosol of infected macrophages also depend on the EsxEF-EsxUT supercomplex and ESX-4. These results not only demonstrate that the Esx proteins have dual functions as the long-sought outer membrane components of ESX systems and as secreted effector proteins, but also reveal a novel master control mechanism of protein secretion in M. tuberculosis. The mutual dependency of EsxEF and EsxUT on each other synchronizes ESX effector protein secretion, enabling M. tuberculosis to block phagosomal maturation and to permeabilize the phagosomal membrane only when it is capable of killing host cells by toxin secretion. The requirement of the ESX-4 system for general protein secretion is a critical vulnerability which could be targeted by drugs and/or vaccines to simultaneously block many virulence factors of M. tuberculosis.

microbiology↗

bioRxiv2025

Effect of perchlorate on biocementation capable bacteria and Martian bricks

With the recent discovery of perchlorate (0.5-1%) in Martian regolith, more experiments related to the impact of perchlorate on microbial life are crucial to understanding the possibility of earth life forms that could sustain on the Martian terrain. While we are familiar with the idea of bioconsolidated Martian bricks made via Microbially Induced Calcite Precipitation (MICP), studies on the effect of perchlorate on Martian bricks & biocementation capable microbes have been obscure. In this work, we investigated the effect of perchlorate (MgClO4- salt) on a lab-isolated biocementation capable bacteria & Martian bricks bioconsolidated by the same, with 1% perchlorate in Mars Global Simulant-1 (MGS-1). The screening of biocementation-capable bacteria involved phenol red assay for urease activity followed by Scanning Electron Microscopy (SEM) and X-ray diffraction (XRD) study of the precipitate formed through MICP via ureolytic pathway. The biocementation capable bacterium SI_IISc_isolate was found phylogenetically closest to Sporosarcina pasteurii strain S2135, its draft genome being approximately 3.69 Mb. To understand the effect of perchlorate on SI_IISc_isolate, we majorly relied on Gram-staining & SEM. The negative effect of perchlorate stress on the isolate was evident by its decreased growth in the presence of varying concentrations of perchlorate through plate assays, growth curve studies in broth & live-dead staining. Gram-staining study and SEM both revealed that perchlorate induces the release of extracellular matrix (ECM) and promotes clustering of cells by the bacteria, which we termed as multicellularity-like behavior. Further, we constructed Martian bricks with Martian Global Simulant (MGS-1) along with 1% perchlorate, utilizing the microbially induced calcite precipitation ability of the Sporosarcina sp. strain SI_IISc_isolate via ureolysis, following an established protocol at our lab. The bioconsolidation experiments showed that in the presence of a natural adhesive - guar gum, perchlorate tends to significantly improve the compressive strength of Martian bricks. However, the end result eventually relies on the overall effect of various additives in the regolith.

bioengineering↗

bioRxiv2024

High-Throughput Targeted Drug Screening for NF1-associated High-Grade Gliomas with ATRX Deficiency

Neurofibromatosis type 1 (NF1)-associated high-grade gliomas (HGGs) harboring ATRX mutations exhibit an aggressive clinical phenotype, driven by heightened genomic instability and metabolic reprogramming. Existing therapies, including chemotherapy and radiotherapy, are limited by resistance mechanisms and formation of secondary malignancy, underscoring the need for novel therapeutic strategies. Here, we report the results of a high-throughput screening of 10,000 small molecules aimed at identifying compounds selectively targeting vulnerabilities associated with concurrent ATRX and NF1 loss. Among the screened compounds, K784-6195 (ChemDiv ID) emerged as a promising candidate, exhibiting marked selective cytotoxicity in NF1-associated glioma cell lines with ATRX deficiency (IC50 = 4.84 {micro}M). In comparison, wild-type ATRX sporadic glioma cell lines (U251) exhibited significantly reduced sensitivity to K784-6195 (IC50 = 37.03 {micro}M). However, ATRX knockout U251 glioma cells recapitulating concurrent ATRX and NF1 loss exhibited heightened susceptibility to K784-6195 (IC50 = 20-23 {micro}M) compared to their wild-type counterpart. Metabolomic analysis revealed that K784-6195 treatment impairs metabolic pathways, including the pentose phosphate pathway, glutamine metabolism, and redox homeostasis, leading to oxidative stress and impaired cell survival. These findings highlight K784-6195 as a promising candidate for therapeutic development, offering a targeted approach for the treatment of NF-1 associated HGGs with ATRX deficiency.

cancer biology↗

bioRxiv2024

Oxidative Injury to Lung Mitochondrial DNA is a Key Contributorfor the Development of Chemical Lung Injury

The mechanisms and extent to which inhalation of oxidant gases damage the mitochondrial genome contributing to the development of acute and chronic lung injury have not been investigated. C57BL/6 mice exposed to chlorine (Cl2) gas and returned to room air, developed progressive loss of lung DNA glycosylase OGG1, significant oxidative injury to mtDNA, decreased intact lung mitochondrial (mt) DNA, generation of inflammatory pathway by DAMPs causing airway and alveolar injury with significant mortality. Global proteomics identified over 1400 lung proteins with alteration of key mitochondrial proteins at 24 h post Cl2 exposure. Intranasal instillation of a recombinant protein containing mitochondrial targeted OGG1 (mitoOGG1) post exposure, decreased oxidative injury to mtDNA, lung mitochondrial proteome, severity of the acute and chronic lung injury and increased survival. These data show that injury to the mt-genome is a key contributor to the development of acute and chronic lung injury.

physiology↗

bioRxiv2024

Mechanical stresses govern myoblast fusion and myotube growth

Myoblast fusion into multinucleated myotubes is essential for skeletal muscle development and repair, yet how tissue-scale mechanics contributes to this process remains poorly understood. Here, we show that primary myoblasts behave as an evolving active nematic system in which actomyosin-dependent stresses, extracellular-matrix (ECM) remodeling and fusion-driven myotube growth are dynamically coupled. As myoblasts fuse into elongated myotubes, orientational order increases and the nematic field is progressively reshaped. We identify a strong coupling between cellular and ECM nematic organization, whereby cytoskeleton-dependent ECM remodeling stabilizes topological defects and reinforces their associated stress patterns. Fusion events preferentially accumulate near comet-shaped +1/2 defects, which correspond to regions of high compressive stress predicted by our theoretical model. Our findings support a model in which the intrinsic fusion machinery provides fusion competence, while ECM-stabilized nematic stress patterns spatially bias the localization of fusion events. Fusion-driven myotube growth then feeds back on the mechanical landscape, increasing nematogen length and stress magnitude. Together, these results reveal a self-reinforcing biomechanical mechanism that contributes to the organization of myoblast fusion and myotube growth, with potential relevance for developmental and regenerative morphogenesis.

biophysics↗

bioRxiv2023

Hemopexin Reverses Activation of Lung eIF2a and Decreases Mitochondrial Injury in Chlorine Exposed Mice

We assessed the mechanisms by which non-encapsulated heme, released in the plasma of mice post exposure to chlorine (Cl2) gas, resulted in the initiation and propagation of acute lung injury. We exposed adult C57BL/6 male and female to Cl2 (500 ppm for 30 min) in environmental chambers and returned them to room air and injected them intramuscularly with a single dose of human hemopexin (hHPX; 5 {micro}g/ g BW), the most efficient scavenger of heme, 30-60 min post exposure. Concentrations of hHPX in plasma of air and Cl2 exposed mice were 9081{+/-}900 vs. 1879{+/-} 293 at 6 h and 2966{+/-}463 vs. 1555{+/-}250 at 50 h post injection (ng/ml; X{+/-}1 SEM=3; p<0.01). Cl2 exposed mice developed progressive acute lung injury post exposure characterized by increased concentrations of plasma heme, marked inflammatory response, respiratory acidosis and increased concentrations of plasma proteins in the alveolar space. Injection of hHPX decreased the onset of acute lung injury at 24 h post exposure; mean survival, for the saline and hHPX groups were 40 vs. 80% (P<0.001) at 15 d post exposure. Non-supervised global proteomics analysis of mouse lungs at 24 h post exposure, revealed the upregulation of 92 and downregulation of 145 lung proteins. Injection of hHPX at one h post exposure moderated the Cl2 induced changes in eighty-three of these 237 lung proteins. System biology analysis of the global proteomics data showed that hHPX reversed changes in mitochondrial dysfunction and elF2 and integrin signaling. Western blot analysis of lung tissue showed significant increase of phosphorylated elF2 at 24 h post exposure in vehicle treated mice but normal levels in those injected with hHPX. Similarly, RT-PCR analysis of lung tissue showed that hHPX reversed the onset of mtDNA lesions. A form of recombinant human hemopexin generated in tobacco plants was equally effective in reversing acute lung and mtDNA injury. The results of this study offer new insights as to the mechanisms by which exposure to Cl2 results in acute lung injury and to the therapeutic effects of hemopexin.

physiology↗

bioRxiv2023

Comparative Analysis of Molecular Pathogenic Mechanisms and Antiviral Development Targeting Old and New World Hantaviruses

BackgroundHantaviruses - dichotomized into New World (i.e. Andes virus, ANDV; Sin Nombre virus, SNV) and Old-World viruses (i.e. Hantaan virus, HTNV) - are zoonotic viruses transmitted from rodents to humans. Currently, no FDA-approved vaccines against hantaviruses exist. Given the recent breakthrough to human-human transmission by the ANDV, an essential step is to establish an effective pandemic preparedness infrastructure to rapidly identify cell tropism, infective potential, and effective therapeutic agents through systematic investigation. MethodsWe established human cell model systems in lung (airway and distal lung epithelial cells), heart (pluripotent stem cell-derived (PSC-) cardiomyocytes), and brain (PSC-astrocytes) cell types and subsequently evaluated ANDV, HTNV and SNV tropisms. Transcriptomic, lipidomic and bioinformatic data analyses were performed to identify the molecular pathogenic mechanisms of viruses in different cell types. This cell-based infection system was utilized to establish a drug testing platform and pharmacogenomic comparisons. ResultsANDV showed broad tropism for all cell types assessed. HTNV replication was predominantly observed in heart and brain cells. ANDV efficiently replicated in human and mouse 3D distal lung organoids. Transcriptomic analysis showed that ANDV infection resulted in pronounced inflammatory response and downregulation of cholesterol biosynthesis pathway in lung cells. Lipidomic profiling revealed that ANDV-infected cells showed reduced level of cholesterol esters and triglycerides. Further analysis of pathway-based molecular signatures showed that, compared to SNV and HTNV, ANDV infection caused drastic lung cell injury responses. A selective drug screening identified STING agonists, nucleoside analogues and plant-derived compounds that inhibited ANDV viral infection and rescued cellular metabolism. In line with experimental results, transcriptome data shows that the least number of total and unique differentially expressed genes were identified in urolithin B- and favipiravir-treated cells, confirming the higher efficiency of these two drugs in inhibiting ANDV, resulting in host cell ability to balance gene expression to establish proper cell functioning. ConclusionsOverall, our study describes advanced human PSC-derived model systems and systems-level transcriptomics and lipidomic data to better understand Old and New World hantaviral tropism, as well as drug candidates that can be further assessed for potential rapid deployment in the event of a pandemic.

microbiology↗

bioRxiv2023

SARS-CoV-2 variants of concern exhibit differential gastro-intestinal tropism and pathogenesis in the Syrian golden hamster model.

Severe Acute Respiratory Syndrome Virus-2 (SARS-CoV-2) is a respiratory virus that uses angiotensin-converting enzyme 2 (ACE2) protein as an entry receptor. Thus, ACE2 expression levels in different tissues should dictate viral tropism. Notably, human ACE2 mRNA and protein levels are most abundant in the gastrointestinal tract, a pattern mirrored in Syrian golden hamsters. This prompted us to investigate the gastrointestinal tropism of SARS-CoV-2 variants of concern, including the Wuhan-like Hong Kong strain, highly pathogenic Delta, and highly transmissible but mildly pathogenic Omicron variants in hamsters. Delta was the most pathogenic in the respiratory and gastrointestinal tracts, followed by ancestral Wuhan-like and Omicron strains. In the gastrointestinal tract, viral RNA load was significant in the proximal organs such as the oesophagus and stomach, highest in the SI, and minimal to undetectable in the colon. Additionally, all three variants reduced fecal microbial diversity, with the Delta causing the highest decrease in observed features and phylogenetic diversity. Our findings highlight Deltas stronger preference for the gastrointestinal tract, suggesting a link between high virulence and gastrointestinal tropism of SARS-CoV-2 variants of concern.

pathology↗