Tissue-specific Responses Research Articles

Worker Survival and Egg Production-But Not Transcriptional Activity-Respond to Queen Number in the Highly Polygynous, Invasive Ant Tapinoma magnum.

In social animals, reproductive activity and ageing are influenced by group composition. In monogynous (single-queen) insect societies, queen presence affects worker fecundity and longevity, but less is known about worker responses to queen number variation in polygynous (multi-queen) species or how queens age in these systems. We created queenless, one-queen and two-queen colonies of the invasive, polygynous ant Tapinoma magnum to examine the effect of queen number on worker survival, ovary and oocyte development, oxidative stress resistance and fat body gene expression. We also compared the fecundity and brain and fat body transcriptomes between young and old queens. Queenless workers experienced the highest mortality, contrasting with monogynous species, where queen removal typically extends lifespan. Workers lived longer and had more developing oocytes in their ovaries in single-queen than in two-queen colonies. Queen number did not directly affect oxidative stress resistance or fat body gene expression, though its effect on the latter differed between inside and outside workers. Furthermore, inside-likely younger-workers produced more oocytes, showed higher oxidative stress resistance and upregulated antioxidant genes compared to outside-likely older-workers. Minimal shifts in fecundity and gene expression of differently aged queens indicated their physiological stability. Our research highlights distinct caste- and tissue-specific responses to varying queen numbers in workers of a highly polygynous species.

Comprehensive Analysis of Class III Peroxidase Genes Revealed PePRX2 Enhanced Lignin Biosynthesis and Drought Tolerance in Phyllostachys edulis.

Class III peroxidase (PRX) is the key enzyme in lignin biosynthesis and critical for maintaining the redox balance in plants to respond to stress. In moso bamboo (Phyllostachys edulis), a globally significant non-timber forestry species, the potential roles of PRX genes remain largely unknown. In this research, a total of 179 PePRXs was identified on a genome-wide scale in moso bamboo. Phylogenic relationship, conserved motifs, gene structure, collinearity, and cis-acting elements were investigated. Analysis of gene expression indicated that PePRXs exhibited tissue-specific expression and different response patterns to hormones and abiotic stresses. Based on the transcriptome data, ten PePRXs with positive correlations between expression levels and lignification degree were screened out. Among them, PePRX2 was selected as a candidate gene according to the co-expression network. Y1H and Dual-Luc assays demonstrated that PeMYB61 could bind to the promoter of PePRX2 and enhance its transcription. The result of in situ hybridization showed that PePRX2 was specifically expressed in the vascular bundle sheath cells of bamboo shoot. As a secreted protein, PePRX2 was located on the cell wall. Overexpression of PePRX2 led to a significant increase in lignin content in transgenic poplar, indicating that PePRX2 could promote lignin polymerization. In comparison to the wild type, the PePRX2-OE poplar lines exhibited increased peroxidase activity and decreased levels of MDA, O2-, and H2O2 under drought stress, indicating enhanced drought resistance. This thorough analysis of the PRX family in moso bamboo provided new insight into the roles of PePRXs in lignin biosynthesis and drought adaptation.

Effects of functionalized nanoplastics on oxidative stress in the mussel Mytilus coruscus.

In the marine environment, various weathering effects on micro or nanoplastics lead to surface modifications, which in turn alter their toxic effects on aquatic organisms. This study investigated the impact of three types of nanoplastics (NPs, NPs-NH2, NPs-COOH) on the antioxidant capacity of Mytilus coruscus gills, mantle, and hemolymph over 28days. Analyzed key antioxidant stress indicators (CAT, SOD, GSH, GSH-Px, MDA, H2O2) and conducted IBR and PCA analyses to evaluate the toxic effects of modified nanoplastics. In particular, NPs-NH2 showed the most significant inhibition of antioxidant enzymes like CAT and GSH-Px in gills and mantle, while NPs-COOH affected a wider range of oxidative stress markers. Furthermore, tissue-specific responses were observed, with gills being the most sensitive to biomarker changes. Overall, NPs-NH2 emerged as the most toxic nanoplastic, highlighting the need to assess ecological risks associated with novel nanoparticles in marine environments and offering insights into tissue-specific toxicity in mussels.

Tissue-specific responses of the central carbon metabolism in tomato fruit to low oxygen stress.

Tomato (Solanum lycopersicum L.) is an important model plant whose fleshy fruit consists of well-differentiated tissues. Recently it was shown that these tissues develop hypoxia during fruit development and ripening. Therefore, we employed a combination of metabolomics and isotopic labeling to investigate the central carbon metabolic response of tomato fruit tissues (columella, septa and mesocarp) to low O2 stress. The concentration and 13C-label enrichment of intermediates from the central carbon metabolism were analyzed using gas chromatography-mass spectrometry. The results showed an increase in glycolytic activity and the initiation of fermentation in response to low O2 conditions. In addition, the up-regulation of the GABA shunt and accumulation of amino acids, alanine and glycine, were observed under low O2 conditions. Notably, tissue specificity was observed at the metabolite level, with concentrations of most metabolites being highest in columella tissue. In addition, there were tissue-specific differences in the central carbon metabolism with the columella exhibiting the highest metabolic activity and sensitivity to the changes in O2 concentration, followed by septa and mesocarp tissues. Our results are consistent with common plant responses and adaptive mechanisms to low O2 stress, while unravelling some tissue-specific differences, increasing our understanding of the intact fruit response to low O2 stress.

Transcriptomic atlas reveals organ-specific disease tolerance in sickle cell mice.

Sickle cell disease (SCD) is the most common genetic disease in the world and a societal challenge. SCD is characterized by multi-organ injury related to intravascular hemolysis. To understand tissue-specific responses to intravascular hemolysis and exposure to heme, we present a transcriptomic atlas in the primary target organs of HbSS vs HbAA transgenic SCD mice. We explored the transcriptomes of liver, kidney, heart, lung and bone marrow from HbAA and HbSS Townes littermates at resting state and their changes after injection of heme, assessed by RNA sequencing. Inflammation and myeloid cell signatures were omnipresent in resting HbSS organs, liver being the most affected. The injection of heme triggered a robust inflammatory response in HbAA mice. Signatures of exposure to heme in HbAA mice were downstream of TLR4 (sensor of LPS but also of heme), IL1b, IL6 and IFNg, similarly to HbSS mice at rest. Nevertheless, HbSS mice were strikingly unresponsive to heme administration, irrespective of the organ. This tolerance was driven by upregulation of the heme-detoxifying enzyme HO-1 and was abrogated by its specific inhibition. Therefore, HbSS mice develop robust protective mechanisms, which may explain how they and SCD patients survive bouts of severe hemolysis.

Role of Carrot (Daucus carota L.) Storage Roots in Drought Stress Adaptation: Hormonal Regulation and Metabolite Accumulation.

Background: Drought stress has become one of the biggest concerns in threating the growth and yield of carrots (Daucus carota L.). Recent studies have shed light on the physiological and molecular metabolisms in response to drought in the carrot plant; however, tissue-specific responses and regulations are still not fully understood. Methods: To answer this curiosity, this study investigated the interplay among carrot tissues, such as leaves (L); storage roots (SRs); and lateral roots (LRs) under drought conditions. This study revealed that the SRs played a crucial role in an early perception by upregulating key genes, including DcNCED3 (ABA biosynthesis) and DcYUCCA6 (auxin biosynthesis). The abundance of osmolytes (proline; GABA) and carbohydrates (sucrose; glucose; fructose; mannitol; and inositol) was also significantly increased in each tissue. In particular, LRs accumulated high levels of these metabolites and promoted growth under drought conditions. Conclusions: Our findings suggest that the SR acts as a central regulator in the drought response of carrots by synthesizing ABA and auxin, which modulate the accumulation of metabolites and growth of LRs. This study provides new insights into the mechanisms of tissue-specific carrot responses to drought tolerance, emphasizing that the SR plays a key role in improving drought resistance.

Transcriptomic Insights into Dual Temperature-Salinity Stress Response in "Shuike No. 1", a Pioneering Rainbow Trout Strain Bred in China.

Global warming poses a significant threat to aquaculture, particularly for cold-water species like rainbow trout (Oncorhynchus mykiss). Understanding the molecular mechanisms underlying stress responses is crucial for developing resilient strains. This study investigates the dual stress of salinity and temperature response of "Shuike No. 1" (SK), a pioneering commercially bred rainbow trout strain in China, using RNA-sequencing of gill, intestine, and liver tissues from fish exposed to four treatment combinations: freshwater at 16 °C, freshwater at 25 °C, saltwater (30‱) at 16 °C, and saltwater at 25 °C. Differential gene expression analysis identified a substantial number of DEGs, with the liver showing the most pronounced response and a clear synergistic effect observed under combined high-temperature and salinity stress. Weighted gene co-expression network analysis (WGCNA) revealed stress-responsive gene modules and identified hub genes, primarily associated with gene expression, endoplasmic reticulum (ER) function, disease immunity, energy metabolism, and substance transport. Key hub genes included klf9, fkbp5a, fkbp5b, ef2, cirbp, atp1b1, atp1b2, foxi3b, smoc1, and arf1. Functional enrichment analysis confirmed the prominent role of ER stress, particularly the pathway "protein processing in the endoplasmic reticulum." Our results reveal complex, tissue-specific responses to dual stress, with high temperature exerting a stronger influence than salinity. These findings provide valuable insights into the molecular mechanisms underpinning dual stress responses in SK, informing future breeding programs for enhanced resilience in the face of climate change.

Reprogramming of epidermal keratinocytes by PITX1 transforms the cutaneous cellular landscape and promotes wound healing.

Cutaneous wound healing is a slow process that often terminates with permanent scarring while oral wounds, in contrast, regenerate after damage faster. Unique molecular networks in epidermal and oral epithelial keratinocytes contribute to the tissue-specific response to wounding, but key factors that establish those networks and how the keratinocytes interact with their cellular environment remain to be elucidated. The transcription factor PITX1 is highly expressed in the oral epithelium but is undetectable in cutaneous keratinocytes. To delineate if PITX1 contributes to oral keratinocyte identity, cell-cell interactions, and the improved wound healing capabilities, we ectopically expressed PITX1 in the epidermis of murine skin. Using comparative analysis of murine skin and oral (buccal) mucosa with single-cell RNA-Seq and spatial transcriptomics, we found that PITX1 expression enhances epidermal keratinocyte migration and proliferation and alters differentiation to a quasi-oral keratinocyte state. PITX1+ keratinocytes reprogrammed intercellular communication between skin-resident cells to mirror buccal tissue while stimulating the influx of neutrophils that establish a pro-inflammatory environment. Furthermore, PITX1+ skin healed significantly faster than control skin via increased keratinocyte activation and migration and a tunable inflammatory environment. These results illustrate that PITX1 programs oral keratinocyte identity and cellular interactions while revealing critical downstream networks that promote wound closure.

Harnessing 2D and 3D human endometrial cell culture models to investigate SARS-CoV-2 infection in early pregnancy.

Vertical transmission of SARS-CoV-2 during human pregnancy remains highly controversial as most studies have focused on the third trimester or the peripartum period. Given the lack of early trimester data, determining the prevalence of vertical transmission during early pregnancy and assessing the potential risks for fetal morbidity and mortality poses a challenge. Therefore, we analyzed the impact of SARS-CoV-2 infection on an endometrial 3D spheroid model system. The 3D spheroids are capable of decidualization and express ACE2 as well as TMPRSS2, rendering them susceptible to SARS-CoV-2 infection. Employing this 3D cell model, we identified that SARS-CoV-2 can infect both non-decidualized and decidualized endometrial spheroids. Infection significantly increased the chemokine MCP-1 compared to non-infected spheroids. Decidualized spheroids exhibited upregulated chemokine IL-8 levels. Furthermore, RNA sequencing revealed dysregulation of several genes involved in tissue-specific immune response, Fc receptor signalling, angiotensin-activated signalling and actin function. Gene expression changes varied between SARS-CoV-2 infected non-decidualized and decidualized spheroids and genes associated with the innate immune system (CCL20, CD38, LCN2 and NR4A3) were dysregulated as a potential mechanism for immune evasion of SARS-CoV-2. Altogether, our study demonstrates that endometrial spheroids are a useful model to examine the clinical implications of SARS-CoV-2 vertical transmission, warranting further investigations.

Transcriptional and functional characterization in the terpenoid precursor pathway of the early land plant Physcomitrium patens.

Isoprenoids comprise the largest group of plant specialized metabolites. 1-deoxy-D-xylulose-5-phosphate synthase (DXS) is one of the major rate-limiting enzymes in their biosynthesis. The DXS family expanded structurally and functionally during evolution and is believed to have significantly contributed to metabolic complexity and diversity in plants. This family has not yet been studied in Physcomitrium patens or other bryophytes. Here, we assessed the degree of evolutionary expansion in the DXS family in bryophytes and, more specifically, in P. patens using phylogenetic analysis. Transcriptome profiling was applied to investigate tissue-specific, developmental, and environmental responses, such as salt stress, in the DXS family. Moreover, the effect of salt stress on terpenoid biosynthesis was monitored through metabolomics. The phylogenetic analysis of DXS revealed that a structural expansion occurred in bryophytes, but not in P. patens. Functional complementation assay revealed functional activity in all four copies. Comparative transcriptomics showed tissue- and condition-specific divergence in the expression profiles of DXS copies and demonstrated specific stress responses for PpDXS1D, particularly to salt stress. These findings coincide with increased flux in the pathway towards downstream metabolites under salt stress. Additionally, co-expression network analysis revealed significant differences between the co-expressed genes of the DXS copies and illustrated enrichment of stress-responsive genes in the PpDXS1D network. These results suggest that the DXS family in P. patens is conserved but undergoes differential transcriptional regulation, which might allow P. patens to fine-tune DXS levels under different conditions, such as abiotic stress.

Agrobacterium-Mediated Transient Expression Methods to Validate Gene Functions in Strawberry (F. × ananassa).

Understanding gene function is important for crop improvement and breeding efforts, especially in a genetically complex polyploid plant species such as the octoploid strawberry. Agrobacterium-mediated transient assays are a widely used tool for investigating gene functions and offer a reliable alternative to stable transformation. However, variability in tissue-specific responses and inconsistent applicability of Agrobacterium-mediated transient assay across diverse plant species can be challenging. In this study, we provide a method utilizing Agrobacterium-mediated transient expression to examine the function of genes in octoploid strawberry. Our approach encompasses leaf, root, and fruit tissues, providing a comprehensive strategy for validating gene functions in strawberries. Through meticulous optimization and validation in planta, this method offers valuable insights into gene function in strawberry functional genomics and genetics research. By addressing tissue-specific variability, our methodology serves as a valuable technical resource that could facilitate advancements in identifying gene functions in octoploid strawberry.

Please don’t go: retinoic acid ‘retains’ tissue-specific memory

Tissue-resident memory (TRM) T cells not only control infection and cancer, but also contribute to inflammatory disease. In a recent study, Obers et al. demonstrate that retinoic acid (RA) and TGF-β direct TRM residency in mice, with RA uniquely retaining cells in the intestine by limiting migration. This discovery highlights the potential for harnessing local residency cues to enhance tissue-specific TRM responses.

New genomic resources inform transcriptomic responses to heavy metal toxins in the common Eastern bumble bee Bombus impatiens.

The common Eastern bumble bee Bombus impatiens is native to North America and is the main commercially reared pollinator in the Americas. There has been extensive research on this species related to its social biology, applied pollination, and genetics. The genome of this species was previously sequenced using short-read technology, but recent technological advances provide an opportunity for substantial improvements. This species is common in agricultural and urban environments, and heavy metal contaminants produced by industrial processes can negatively impact it. To begin to identify possible mechanisms underlying responses to these toxins, we used RNA-sequencing to examine how exposure to a cocktail of four heavy metals at field-realistic levels from industrial areas affected B. impatiens worker gene expression. PacBio long-read sequencing resulted in 544x coverage of the genome, and HiC technology was used to map chromatin contacts. Using Juicer and manual curation, the genome was scaffolded into 18 main pseudomolecules, representing a high quality, chromosome-level assembly. The sequenced genome size is 266.6Mb and BRAKER3 annotation produced 13,938 annotated genes. The genome and annotation show high completeness, with ≥ 96% of conserved Eukaryota and Hymenoptera genes present in both the assembly and annotated genes. RNA sequencing of heavy metal exposed workers revealed 603 brain and 34 fat body differentially expressed genes. In the brain, differentially expressed genes had biological functions related to chaperone activity and protein folding. Our data represent a large improvement in genomic resources for this important model species-with 10% more genome coverage than previously available, and a high-quality assembly into 18 chromosomes, the expected karyotype for this species. The new gene annotation added 777 new genes. Altered gene expression in response to heavy metal exposure suggests a possible mechanism for how these urban toxins are negatively impacting bee health, specifically by altering protein folding in the brain. Overall, these data are useful as a general high quality genomic resource for this species, and provide insight into mechanisms underlying tissue-specific toxicological responses of bumble bees to heavy metals.

Time and tissue-specific responses of mitochondrial metabolism to hypoxia in fish.

Time and tissue-specific responses of mitochondrial metabolism to hypoxia in fish.

Abstract 4137414: Uncovering MLKL as a Novel Regulator of Endothelial Cells in the Splenic Niche to Repress Hematopoiesis During Atherosclerosis

Background: Atherosclerosis occurs as lipid and immune cell rich plaques deposit within the arterial wall of the heart. These immune cells are produced from hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) and spleen, a process known as hematopoiesis that is dictated by their microenvironment, including endothelial cells (ECs). Objective: While others have shown adverse remodeling of BM ECs during atherogenesis, whether splenic ECs show a similar dysfunction leading to exacerbated hematopoiesis has not been described. Methods: We analyzed RNA sequencing data from chow fed C57Bl/6 mice and high cholesterol diet (HCD) fed Apoe -/- mouse BM and splenic ECs obtained from published studies, as well as our own. In vivo studies were performed in mice on an atherogenic background ( Apoe -/-& Ldlr -/-) fed a HCD for 4 to 16 weeks. Knockdown of the mixed lineage kinase domain-like protein ( Mlkl KD) was achieved by weekly administration of antisense oligonucleotides (ASOs) or scrambled control (50mg/kg sc.). In vitro studies were performed in primary mouse splenic ECs transfected with siRNA. Results: Pathway analysis revealed remarkable tissue-specific responses to an atherogenic milieu, including dysregulation of Lipid Metabolism, Endocytosis and Cell Death pathways in splenic ECs. Interestingly, we previously showed that the mixed lineage kinase domain-like protein (MLKL) regulates the endocytic trafficking of lipids and cell death in macrophages. Indeed using Mlkl KD Apoe -/- mice, transplantation of Mlkl -/- BM into Ldlr -/- mice or EC-specific Mlkl -/- Apoe -/- mice, we show that loss of MLKL drives myelopoiesis and plaque development through regulation of splenic ECs. Both in vivo and in vitro , silencing Mlkl in splenic but not BM ECs potently increased lipid content and disrupted endocytosis by an accumulation of the multivesicular body marker CHMP4B, which mirror the dysregulated pathways we identified above. Furthermore, co-culture with Mlkl KD splenic ECs increased HSPC activation (pStat5) and myeloid colony formation, an effect that was lost when ECs were pre-treated with the upstream endocytosis inhibitor Dynasore. Conclusions: In conclusion, we establish a novel role for MLKL in regulating the balance of HSPCs, specifically through preservation of splenic, but not BM, ECs that repress hematopoiesis, highlighting the importance of splenic lipid metabolism and endocytosis and its impact on atherogenesis.

Maternal under-nutrition during pregnancy alters the molecular response to over-nutrition in multiple organs and tissues in nonhuman primate juvenile offspring.

Previous studies in rodents suggest that mismatch between fetal and postnatal nutrition predisposes individuals to metabolic diseases. We hypothesized that in nonhuman primates (NHP), fetal programming of maternal undernutrition (MUN) persists postnatally with a dietary mismatch altering metabolic molecular systems that precede standard clinical measures. We used unbiased molecular approaches to examine response to a high fat, high-carbohydrate diet plus sugar drink (HFCS) challenge in NHP juvenile offspring of MUN pregnancies compared with controls (CON). Pregnant baboons were fed ad libitum (CON) or 30% calorie reduction from 0.16 gestation through lactation; weaned offspring were fed chow ad libitum. MUN offspring were growth restricted at birth. Liver, omental fat, and skeletal muscle gene expression, and liver glycogen, muscle mitochondria, and fat cell size were quantified. Before challenge, MUN offspring had lower body mass index (BMI) and liver glycogen, and consumed more sugar drink than CON. After HFCS challenge, MUN and CON BMIs were similar. Molecular analyses showed HFCS response differences between CON and MUN for muscle and liver, including hepatic splicing and unfolded protein response. Altered liver signaling pathways and glycogen content between MUN and CON at baseline indicate in utero programming persists in MUN juveniles. MUN catchup growth during consumption of HFCS suggests increased risk of obesity, diabetes, and cardiovascular disease. Greater sugar drink consumption in MUN demonstrates altered appetitive drive due to programming. Differences in blood leptin, liver glycogen, and tissue-specific molecular response to HFCS suggest MUN significantly impacts juvenile offspring ability to manage an energy rich diet.

TORC1 Regulates Thermotolerance via Modulating Metabolic Rate and Antioxidant Capacity in Scallop Argopecten irradians irradians.

Target of rapamycin complex 1 (TORC1) is a key regulator of metabolism in eukaryotes across multiple pathways. Although TORC1 has been extensively studied in vertebrates and some invertebrates, research on this complex in scallops is limited. In this study, we identified the genes encoding TORC1 complex subunits in the scallop Argopecten irradians irradians through genome-wide in silico scanning. Five genes, including TOR, RAPTOR, LST8, DEPTOR, and PRAS40, that encode the subunits of TORC1 complex were identified in the bay scallop. We then conducted structural characterization and phylogenetic analysis of the A. i. irradians TORC1 (AiTORC1) subunits to determine their structural features and evolutionary relationships. Next, we analyzed the spatiotemporal expressions of AiTORC1-coding genes during various embryo/larvae developmental stages and across different tissues in healthy adult scallops. The results revealed stage- and tissue-specific expression patterns, suggesting diverse roles in development and growth. Furthermore, the regulation of AiTORC1-coding genes was examined in temperature-sensitive tissues (the mantle, gill, hemocyte, and heart) of bay scallops exposed to high-temperature (32 °C) stress over different durations (0 h, 6 h, 12 h, 24 h, 3 d, 6 d, and 10 d). The expression of AiTORC1-coding genes was predominantly suppressed in the hemocyte but was generally activated in the mantle, gill, and heart, indicating a tissue-specific response to heat stress. Finally, functional validation was performed using the TOR inhibitor rapamycin to suppress AiTORC1, leading to an enhanced catabolism, a decreased antioxidant capacity, and a significant reduction in thermotolerance in bay scallops. Collectively, this study elucidates the presence, structural features, evolutional relationships, expression profiles, and roles in antioxidant capacity and metabolism regulation of AiTORC1 in the bay scallop, providing a preliminary understanding of its versatile functions in response to high-temperature challenges in marine mollusks.

Tissue specific innate immune responses impact viral infection in Drosophila.

All organisms sense and respond to pathogenic challenge. Tissue-specific responses are required to combat pathogens infecting distinct cell types. Cyclic dinucleotides (CDNs) are produced endogenously downstream of pathogen recognition or by pathogens themselves which bind to STING to activate NF-kB-dependent antimicrobial gene expression programs. It remains unknown whether there are distinct immune responses to CDNs in Drosophila tissues. Here, we investigated tissue specific CDN-STING responses and uncovered differences in gene-induction patterns across tissues that play important roles in viral infections. Using tissue-and cell-specific genetic studies we found that dSTING in the fat body controls CDN-induced expression of dSTING-regulated gene 1 (Srg1) but not dSTING-regulated gene 2 (Srg2) or 3 (Srg3). In contrast, the gastrointestinal tract largely controls expression of Srg2 and Srg3. We found that Srg3 is antiviral against the natural fly pathogen Drosophila C virus and the human arthropod-borne Rift Valley Fever virus (RVFV), but not other arthropod-borne viruses including Sindbis virus and dengue virus. Furthermore, we found that Srg3 has an important role in controlling RVFV infection of the ovary which has important implications in understanding vertical transmission of viruses and RVFV in mosquitoes. Overall, our study underscores the importance of tissue-specific responses in antiviral immunity and highlights the complex tissue regulation of the CDN-STING pathway.

SARS-CoV-2 variants mediated tissue-specific metabolic reprogramming determines the disease pathophysiology in a hamster model

Despite significant effort, a clear understanding of host tissue-specific responses and their implications for immunopathogenicity against the severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) variant infection has remained poorly defined. To shed light on the interaction between tissues and SARS-CoV-2 variants, we sought to characterize the complex relationship among acute multisystem manifestations, dysbiosis of the gut microbiota, and the resulting implications for SARS-CoV-2 variant-specific immunopathogenesis in the Golden Syrian Hamster (GSH) model using multi-omics approaches. Our investigation revealed the presence of increased SARS-CoV-2 genomic RNA in diverse tissues of delta-infected GSH compared to the omicron variant. Multi-omics analyses uncovered distinctive metabolic responses between the delta and omicron variants, with the former demonstrating dysregulation in synaptic transmission proteins associated with neurocognitive disorders. Additionally, delta-infected GSH exhibited an altered fecal microbiota composition, marked by increased inflammation-associated taxa and reduced commensal bacteria compared to the omicron variant. These findings underscore the SARS-CoV-2-mediated tissue insult, characterized by modified host metabolites, neurological protein dysregulation, and gut dysbiosis, highlighting the compromised gut-lung-brain axis during acute infection.

Immune Dysregulation in the Oral Cavity during Early SARS-CoV-2 Infection

Tissue-specific immune responses are critical determinants of health-maintaining homeostasis and disease-related dysbiosis. In the context of COVID-19, oral immune responses reflect local host-pathogen dynamics near the site of infection and serve as important “windows to the body,” reflecting systemic responses to the invading SARS-CoV-2 virus. This study leveraged multiplex technology to characterize the salivary SARS-CoV-2–specific immunological landscape (37 cytokines/chemokines and 11 antibodies) during early infection. Cytokine/immune profiling was performed on unstimulated cleared whole saliva collected from 227 adult SARS-CoV-2+ participants and 37 controls. Statistical analysis and modeling revealed significant differential abundance of 25 cytokines (16 downregulated, 9 upregulated). Pathway analysis demonstrated early SARS-CoV-2 infection is associated with local suppression of oral type I/III interferon and blunted natural killer–/T-cell responses, reflecting a potential novel immune-evasion strategy enabling infection. This virus-associated immune suppression occurred concomitantly with significant upregulation of proinflammatory pathways including marked increases in the acute phase proteins pentraxin-3 and chitinase-3-like-1. Irrespective of SARS-CoV-2 infection, prior vaccination was associated with increased total α-SARS-CoV-2-spike (trimer), -S1 protein, -RBD, and -nucleocapsid salivary antibodies, highlighting the importance of COVID-19 vaccination in eliciting mucosal responses. Altogether, our findings highlight saliva as a stable and accessible biofluid for monitoring host responses to SARS-CoV-2 over time and suggest that oral-mucosal immune dysregulation is a hallmark of early SARS-CoV-2 infection, with possible implications for viral evasion mechanisms.