Search Results (185)

Long COVID (LC) is a heterogeneous post-infectious syndrome characterized by persistent symptoms, yet the biological basis underlying its interindividual variability remains poorly understood. Given the clinical overlap between LC and myalgic encephalomyelitis (ME), and prior demonstration that haptoglobin (Hp) phenotypes modulate symptom severity in ME, we investigated whether Hp phenotypes similarly stratify post-exertional cognitive dysfunction in LC. In this longitudinal observational study, 44 individuals with LC and 20 short-course COVID controls, who recovered rapidly from SARS-CoV-2 infection without persistent symptoms or sequelae, underwent Hp phenotyping alongside metabolomic and physiological profiling before and after a standardized 90 min passive post-exertional challenge. Hp phenotypes identified clinically distinct LC subgroups. Compared with Hp1-1 individuals, Hp2 allele carriers exhibited greater fatigue, poorer physical function, and more severe post-exertional symptoms. Immediately following the challenge, Hp2-2 participants with LC showed significant cognitive decline, whereas Hp1-1 individuals demonstrated cognitive resilience and more favorable longitudinal cognitive trajectories. This differential susceptibility was accompanied by higher post-exertional cerebral fractional tissue oxygen extraction in the right hemisphere in Hp1-1 individuals and by distinct metabolic signatures, with Hp2 allele carriers exhibiting lower post-exertional plasma concentrations of citric acid, isethionate, and glucosamine. Lower metabolite levels were associated with poorer cognitive performance. These findings support Hp phenotypes as promising candidate biomarkers for biological stratification in Long COVID, pending validation in larger independent cohorts. Full article

The human placenta is a temporary organ structured to optimize exchange between the maternal and fetal circulatory systems. Its fetal component consists of highly branched chorionic villi, which are anchored to the maternal uterine wall and project into the intervillous space. The outer surface of these villi is lined by a multinucleated, continuous layer called the syncytiotrophoblast, which is supported by an underlying layer of proliferative cytotrophoblast cells and the invasive extravillous trophoblast (EVT). This cellular bilayer forms a selective barrier that directly bathes in maternal blood, allowing for the efficient transfer of oxygen and nutrients while structurally preventing the direct mixing of maternal and fetal blood cells. Human placental studies have been stymied by ethical and accessibility constraints. Stem cell biology has now revolutionized the capacity to model human placental development, in particular with the derivation of human trophoblast stem cells (hTSCs) and organoids. Authentic, self-renewing human trophoblast stem cells (hTSCs) were first derived not from pluripotent stem cells but from primary tissue—first-trimester villous cytotrophoblasts and blastocysts. Derivation from human pluripotent stem cells (PSCs) followed only subsequently, along two principal routes: conversion of naive PSCs, which retain extraembryonic competence, and induction from primed PSCs, as well as by direct reprogramming of somatic cells to induced hTSCs. An important advance underlying these improvements is the mapping of a global reprogramming roadmap. Multi-omic and lineage-tracing experiments have mapped the stepwise transcriptional and epigenetic conversions of fibroblasts to hTSCs, including sequential chromatin reconfiguration, trophoblast gene network activation, and repression of somatic signatures. These results identify major regulatory bottlenecks and intermediate states, improving reprogramming fidelity. The derivation of stem-cell-based trophoblast organoids now enables complex modeling of placental architecture, function, and disease susceptibility in vitro. These organoids accurately recapitulate placental barrier functions and immunological features, allowing for examinations of maternal–fetal health, pregnancy disorders, and placental infection response to viruses like cytomegalovirus and SARS-CoV-2. Looking ahead, the integration of reprogramming and organoid technologies will propel patient-specific and tailor-made models for personalized diagnostics, drug screening, and mechanism studies. As we unravel the molecular ballet of trophoblast induction, such discoveries have the potential to bridge basic translational gaps in reproductive biology and maternal–fetal medicine. Full article

The COVID-19 pandemic underscored the need to better characterize immune and molecular responses following SARS-CoV-2 infection and vaccination. Beyond antibody and cellular immunity, COVID-19 involves oxidative stress and DNA damage, affecting repair mechanisms and metabolic adaptation linked to immune resilience. Here, we present a multidimensional analysis of 20 individuals who recovered from mild COVID-19, integrating clinical features with humoral and cellular immune responses, T cell and myeloid phenotypes, oxidative stress, DNA damage, and metabolomic and lipidomic profiles. Although most individual parameters fell within physiological ranges, network modeling revealed structured associations spanning multiple biological domains. A central finding was a coherent cluster organized around vaccine dose number, linking anti-Spike antibody titers, oxidative stress, bioenergetic signatures, and granulocyte activation. Higher vaccination was associated with stronger humoral responses, lower oxidative stress, and a more balanced myeloid–metabolic profile, suggesting a potential protective role extending beyond antibody induction. Additional associations linked symptom patterns to T cell differentiation states, anti-nucleocapsid responses to systemic inflammation, and anaerobic signatures to DNA damage markers, revealing interconnections between immunometabolism, clinical expression, and genomic stress. Despite the small sample size, these findings offer a preliminary systems-level perspective on mild COVID-19 recovery and illustrate the value of integrative exploratory frameworks in infectious disease research, laying the groundwork for validation in larger longitudinal cohorts. Full article

Background: SARS-CoV-2 infection has been linked to an increased risk of hypertensive disorders during pregnancy, particularly preeclampsia (PE). As both conditions involve vascular and endothelial dysfunction, a mechanistic overlap has been proposed. This study examines the relationship between maternal COVID-19 and preeclampsia by analyzing inflammatory, endothelial, and angiogenic biomarkers in pregnancies with and without these complications. Methods: A case–control study was conducted, including four groups: healthy pregnancies before 2020 (n = 10), preeclampsia cases before 2020 (n = 10), COVID-19 cases without preeclampsia (n = 10), and COVID-19 cases with preeclampsia (n = 10). The groups were selected to be comparable in terms of gestational age at blood sampling. Biomarkers related to endothelial, inflammatory, and angiogenic pathways were measured. Results: Significant differences in biomarker levels were detected among the four groups. Regarding endothelial damage, sICAM1 levels were significantly higher in the COVID-PE group compared with the COVID-noPE group (p = 0.002). Additionally, vWF (p = 0.006), END1 (p < 0.001), and sVCAM1 (p = 0.030) levels varied significantly across groups. IL8 levels showed significant differences (p < 0.001), and were particularly elevated in preeclampsia cases (preCOVID-PE and COVID-PE groups) compared with controls (p = 0.005 and p < 0.001, respectively). Angiogenic markers sFlt-1, PLGF, and sFlt-1/PLGF exhibited significant group differences (p < 0.001). In contrast, maternal SARS-CoV-2 infection in the absence of preeclampsia was not associated with a significant alteration of the sFlt-1/PlGF ratio. Discussion: PE associated with SARS-CoV-2 infection preserved the classical angiogenic signature of preeclampsia, but showed additional endothelial and inflammatory biomarker alterations. These findings support an association between SARS-CoV-2 infection and a distinct endothelial and inflammatory biomarker profile in PE, warranting confirmation in larger prospective studies. Full article

Airports are strategic targets for wastewater-based epidemiology because they concentrate highly mobile populations and may provide early signals of pathogen circulation. However, metagenomic investigations of airport wastewater remain limited, particularly in South America. Here, we present one of the first hybrid-capture target-enriched metagenomic investigations of airport wastewater in Brazil, integrating the detection of human-associated viruses and bacteriophage-derived host signatures to evaluate airports as sentinel surveillance sites. Seven untreated wastewater samples collected from a major Brazilian airport between December 2021 and March 2023 were concentrated, subjected to nucleic acid extraction, and analyzed using hybrid-capture target-enriched next-generation sequencing. Taxonomic analysis identified 615 viral and bacteriophage-associated taxa, including 440 viruses and 175 bacteriophages. Among the viral fraction, 21 human-associated viral taxa representing eight viral families were selected for detailed analysis. Norovirus GII was detected in all samples, while Mamastrovirus 1 and JC polyomavirus were detected in six of seven samples. SARS-CoV-2 and dengue virus type 1 were simultaneously detected in the March, 2023 sample. The bacteriophage fraction comprised 47 host-associated phage groups, with Streptococcus-associated phages predominating across samples. These findings demonstrate that airport wastewater can capture diverse human viral and bacteriophage-derived signatures associated with population mobility, supporting its application in environmental genomic surveillance and early-warning systems for emerging and circulating pathogens. Full article

There is no proven therapy for Long COVID, a post-acute condition characterized by persistent symptoms following SARS-CoV-2 infection. Extracellular vesicles (EVs) are emerging as mediators of disease pathogenesis through their molecular cargo. We investigated whether EV glycosylation is altered in Long COVID plasma and whether these vesicles can be selectively targeted using a glycan-binding affinity resin. Large (100–500 nm) and small (40–200 nm) EVs were isolated from post-acute COVID-19 plasma and analyzed by nanoparticle flow cytometry to assess surface glycosylation. Small EV capture assays were performed using Galanthus nivalis agglutinin (GNA) affinity resin. Plasma miRNA profiles before and after GNA treatment were evaluated using NanoString nCounter analysis, and potential downstream pathway effects were computationally inferred using validated miRNA–mRNA interactions and PROGENy. Mannose-positive large EVs were significantly increased in Long COVID compared to recovered controls (p < 0.05). GNA-mediated small EV capture correlated with mannose-positive EV abundance (r = 0.341, p < 0.05), and seven miRNAs were significantly reduced following treatment. Computational pathway analysis suggested modulation of key signaling pathways, including JAK-STAT, Estrogen, VEGF, and PI3K. These findings suggest a glycan-associated EV signature in Long COVID and support further investigation of lectin-based capture as a potential strategy to target vesicle-associated molecular cargo. Full article

Mitochondria are central hubs of antiviral immunity and cellular metabolism, yet the links between SARS-CoV-2–induced mitochondrial remodeling, antiviral gene regulation, and post-translational control remain incompletely understood. Here, we investigated mitochondrial–immune remodeling in SARS-CoV-2–infected lung-derived LC-HK2 cells at 48 and 96 h post-infection using confocal and high-content imaging, colocalization analysis, CellProfiler quantification, RT-qPCR, proteomics, cytokine profiling, and conditioned-medium analysis. Infection induced a time-dependent mitochondrial phenotype. At 48 hpi, cells displayed early mitochondrial stress and fission-associated signatures, including increased DRP1, transient upregulation of mitochondrial respiratory genes, and reduced MFN1/2. At 96 hpi, mitochondria shifted toward elongated perinuclear networks, accompanied by increased fusion/biogenesis markers and partial ISG15–MFN2 colocalization, indicating a spatial association between ISG15-related antiviral/stress responses and mitochondrial remodeling. Antiviral and ISG-related transcripts were consistently upregulated, but IFN-α2 secretion remained limited, suggesting partial uncoupling between antiviral transcriptional activation and downstream interferon output. SUMO2/3 was dynamically modulated and showed time-dependent colocalization with mitochondrial dynamics proteins and MAVS. Together, these data support a coordinated mitochondrial–immune regulatory axis involving mitochondrial remodeling, ISG15-associated responses, and SUMO-dependent regulation during SARS-CoV-2 infection. Full article

The primary route of SARS-CoV-2 entry is via respiratory epithelium. However, many COVID-19 patients developed dermatological lesions, and SARS-CoV-2 RNA has been detected in the patients’ skin. Inflammatory skin diseases, psoriasis and atopic dermatitis (AD), significantly increased the risk of COVID-19. To evaluate the potential role of skin in SARS-CoV-2 host interactions, we utilized 3D human skin organoids (HSO) generated from human epidermal keratinocytes, as well as neonatal skin explants. HSO were treated with cytokines involved in acute and chronic skin inflammation and cytokine storm in severe COVID-19 disease: TNF-α, IL-6, IL-1β, and IFN-γ, individually and in combination. HSO were also treated with Th1 (TNF-α + IL-17) and Th2 (IL-4 + IL-13) cocktails inducing pro-psoriasis and pro-AD HSO changes, respectively. All individual cytokines, and especially their combinations, elevated the expression of ACE2 and TMPRSS2 at mRNA/protein levels. The Th2 cocktail induced only TMPRSS2, the Th1 cocktail predominantly induced ACE2. Topically applied Spike-pseudotyped lentiviral Tomato reporter, which binds ACE2 similarly to SARS-CoV-2, successfully transduced control and cytokine-treated HSO as well as neonatal skin explants. Cytokine treatment, especially TNF-α + IL-6 + IL-1β + IFN-γ and the Th1 cocktail, significantly increased viral entry. Transcriptomic analysis further revealed partial overlap between gene expression signatures induced by Spike-mediated entry in inflamed HSO and those observed in lung tissue from COVID-19 patients, supporting the biological relevance of skin models. Together, these findings demonstrate that inflammation may transiently alter the permissiveness of human skin to SARS-CoV-2 entry, suggesting that the skin may represent a previously underappreciated, although likely limited, interface in viral- host interactions. Full article

Background/Objectives: Long COVID-19 (LC-19), also known as Post-Acute COVID-19 Syndrome (PACS), is a chronic condition some people experience after an initial SARS-CoV-2 infection. The etiology of this complex, multifactorial disease remains largely unknown, although various theories have been propounded. This study aims to profile and compare the metabolic activity of cells of normal and LC-19 patients. Methods: A cohort of 20 individuals, 10 with LC-19 and 10 without LC-19, was selected based on their post-COVID-19 symptomatology. Saliva was tested for opportunistic viruses like Epstein–Barr virus (EBV) and Human Herpesvirus 6 (HHV-6). Lymphoblastoid cell lines derived from blood were analyzed using the Biolog Phenotype Mammalian Microarrays (PM-M1, PM-M6, and PM-M7) to assess metabolic activity across a wide array of growth substrates and effector molecules. Results: Unique metabolic profiles emerged across the controls and LC-19 groups. The SARS-CoV-2 infection causes an over two-fold enhanced utilization of glycolytic and anaerobic substrates and a reduced response to growth factors and effectors. The increased energy source utilization assessed in PM-M1 is unsustainable, and the LC-19 groups demonstrate this with a clear correlation with the number of LC-19 symptoms, demonstrating a trend consistent with metabolic reprogramming. The infection also results in a reduced response to growth factors and effectors, assessed in PM-M6 and PM-M7, with the level of reduction commensurate with the symptom burden. Conclusions: The data from the patient groups were analyzed and compared to construct a metabolic profile unique to individuals who developed LC-19, which could, in the future, be used for diagnosis and to identify targets for therapeutic intervention. Our study identified an LC-19-specific metabolic profile indicative of adaptive responses to stress, cellular dysfunction, and prolonged inflammation, leading to the reprogramming of bioenergetic pathways. Full article

Evidence on hospitalised COVID-19 patients during the Omicron BA.5 wave from Eastern European, vaccine-heterogeneous cohorts remains limited. We conducted a retrospective single-centre cohort study of 395 consecutive adults admitted with laboratory-confirmed COVID-19 to a tertiary infectious-diseases unit in western Romania between 1 July and 31 October 2022. Median age was 72 years (IQR 65–81); 33.2% were unvaccinated, 42.8% had documented prior SARS-CoV-2 infection, and 41.3% were obese. Multivariable logistic regression identified independent predictors of in-hospital mortality and post-acute symptom burden. In-hospital mortality was 15.7% (62/395). Vaccination was independently associated with lower mortality (adjusted odds ratio [aOR] 0.55, 95% CI 0.30–0.99; p = 0.048), as was each 1% increase in admission SpO₂ (aOR 0.83, 95% CI 0.76–0.92; p < 0.001), whereas COPD independently increased mortality risk (aOR 2.42, 95% CI 1.15–5.10; p = 0.020). Interleukin-6 was the most discriminating admission biomarker for in-hospital mortality (AUROC 0.70). Bloodstream bacterial co-infection, detected in 22.5% of patients tested on clinical suspicion, was dominated by gut-derived organisms with case-fatality ≥30%. At discharge, 90.1% reported persistent symptoms, most commonly cognitive (24.6%). Prior SARS-CoV-2 infection independently predicted post-acute symptom burden (aOR 2.96, 95% CI 1.75–5.01; p < 0.001), with a specific cardiopulmonary signature. In this BA.5 cohort, vaccination remained protective; IL-6 was the most informative admission biomarker; bloodstream infections suggested gut translocation; and prior infection was an independent determinant of early post-acute symptom burden. Full article

SARS-CoV-2, the causative agent of COVID-19, emerged in late 2019 and rapidly developed into a global health crisis. In this study, we analysed 173,194 SARS-CoV-2 genomes from the GISAID database to explore the intra-continental dynamics and distribution of variants across Africa between 2020 and 2024. We have identified 1377 distinct lineages, which were classified by clade to assess associations with infection and mortality rate. So, we conducted a Shannon entropy analysis to confirm the diversity and we applied a Correspondence Analysis (CA). Our findings revealed that one of the deadliest in Africa during the Delta wave, lineage AY.45 predominated in the South Africa cluster, whereas AY.34.1 drove transmission in the Atlantic West Africa cluster, underscoring regional heterogeneity. Furthermore, early in the pandemic, men exhibited a 39% higher risk of infection compared to women (aOR: 1.39, 95% CI [1.34–1.45]), particularly in association with clade G. By contrast, later stages were dominated by clade GRA, which disproportionately affected the elderly (≥70 years; aOR: 1.39, 95% CI [1.33–1.45]) and children (0–9 years; aOR: 1.26, 95% CI [1.20–1.33]). Our analysis highlighted that the pandemic on the African continent unfolded as a mosaic of epidemics shaped by diverse variants and regional epidemiological contexts. These findings emphasize the importance of genomic surveillance to capture local epidemic signatures and inform region-specific public health strategies. Full article

The evolution and spatial dissemination of SARS-CoV-2 Omicron subvariants have been characterized by rapid lineage replacement and complex transmission dynamics influenced by regional connectivity. This study presents a comprehensive discrete phylogeographic analysis of 90,136 SARS-CoV-2 sequences collected in Poland from 2022 to 2024 to reconstruct the dispersal dynamics of major Omicron lineages, including BA.1, BA.2, BA.5, CH.1, XBB.1, and JN.1. Utilizing Bayesian statistical frameworks, we identified significant viral transitions between the 16 Polish voivodeships and established variant-specific dominance windows ranging from 2 to 4 months. Our findings reveal a highly dynamic epidemic landscape with shifting regional epicenters. The initial BA.1 wave was primarily driven by the Mazovian voivodeship, accounting for 36.1% of outward migration events. This pattern shifted dramatically with the rise in BA.2, which was centered in the industrial Silesian region in the south-west, a densely populated area with strong economic ties to neighboring countries, potentially reflecting a different introduction or transmission dynamic. Furthermore, the epidemic landscape continued to reconfigure during the BA.5 wave, marked by the emergence of new transmission hubs in eastern border regions such as Lublin. Subsequent lineages exhibited distinct geographic signatures: BA.5 spread broadly along the Baltic-central corridor, CH.1 was centered in the north-east, XBB.1 re-emerged in the west-central region of Greater Poland, and JN.1 was driven overwhelmingly by Lesser Poland. These transitions highlight that regional transmission hubs are transient and influenced by local factors such as population density, cross-border mobility, and socio-economic connectivity. This study underscores the critical value of dense genomic surveillance in identifying evolving dispersal routes to inform adaptive, region-specific public health interventions. Full article

Probiotics are widely used to support host health by modulating microbial communities and immune–metabolic homeostasis. Such interventions may be particularly relevant in long COVID syndrome, a condition characterized by persistent symptoms, low-grade inflammation, and microbiota alterations following SARS-CoV-2 infection. This study investigated the effects of a multi-strain probiotic on gut microbiota composition and predicted functional potential and biochemical parameters in individuals with long COVID and convalescent participants. Healthy individuals were included as reference controls. In an interventional study, 34 participants received a 12-week probiotic formulation containing Saccharomyces boulardii, Lacticaseibacillus rhamnosus GG, and two Lactiplantibacillus plantarum strains, while 40 served as non-supplemented controls. Fecal microbiota, assessed using 16S rRNA sequencing, and biochemical markers were measured at baseline and post-intervention. Probiotic supplementation induced selective compositional changes without significantly altering overall microbial diversity. Effects were more pronounced in long COVID participants and included enrichment of bacteria associated with metabolic and immune regulation, including Adlercreutzia, Coprococcus, and Eubacterium. Functional prediction analysis identified a probiotic-responsive signature in long-COVID-affected individuals, characterized by enrichment of pathways related to energy metabolism and redox balance. These microbial changes were accompanied by a consistent trend toward reduced inflammatory and hepatic markers. Overall, probiotic intervention demonstrated microbiota-status-dependent potential in long COVID recovery. Full article

Background: COVID-19, caused by SARS-CoV-2, exhibits highly variable severity, from mild symptoms to respiratory failure and multiorgan dysfunction. Traditional risk factors incompletely explain this heterogeneity, highlighting the potential role of gut microbiota and host metabolomics in modulating immune responses. Methods: Thus, this study investigates how gut microbiota variations are associated with plasma metabolite profiles in COVID-19, exploring relationships between microbial and metabolic signatures and disease severity and potential therapeutic targets. In a prospective cohort of 55 patients, stool and plasma samples were analyzed using 16S rRNA sequencing and untargeted LC-HRMS metabolomics. Results: Severe COVID-19 was associated with reduced microbial diversity and enrichment of pro-inflammatory taxa, including Prevotella, Alistipes, Dialister, and Lachnoclostridium, whereas mild cases showed higher abundance of protective commensals such as Bacteroides, Faecalibacterium, and Blautia. Metabolomic profiling revealed alterations in bile acids, unsaturated fatty acids, tryptophan, and inositol phosphate pathways. Notably, linoleate levels were elevated in severe cases, showing correlations with pro-inflammatory microbes, while acylcarnitines and inositol derivatives were enriched in mild disease. Predictive functional analysis suggested that severe-associated microbes showed enhanced amino acid catabolism, oxidative glucose metabolism, and xenobiotic degradation, which may be linked to host inflammation. Conclusions: These findings highlight associations between gut microbiota composition, microbial metabolism, and circulating metabolites in COVID-19 severity. Identified microbial and metabolomic signatures may represent potential candidates to be considered biomarkers and therapeutic targets to modulate disease progression. Full article

This prospective, single-center, case-control study investigated circulating autoantibodies (AAbs) targeting G protein-coupled receptors (GPCRs) in Long COVID (LC) patients to identify potential diagnostic biomarkers and therapeutic targets. Fifteen participants were enrolled at the LC clinic in Rome: eleven with severe LC—defined as >4 persistent symptoms (fatigue, cognitive impairment, poor exercise tolerance, dyspnea, arthralgia, or dysautonomic manifestations) >3 months post-infection—and four asymptomatic post-COVID (APC) individuals. Fatigue was assessed using the Fatigue Assessment Scale (FAS ≥ 22; severe ≥ 35). Auto-Abs against AT1R, endothelin receptor A, adrenergic (α1, α2, β1, β2), and muscarinic (M1–M5) receptors were quantified, along with blood cortisol and ACTH levels. SARS-CoV-2-specific T-cell responses to Spike and Nucleocapsid proteins were evaluated by ELISpot assay. In our small cohort, LC patients were younger, had fewer comorbidities (p = 0.03), fewer vaccine doses (p = 0.03), and higher FAS scores (33 vs. 12; p = 0.001). Mean GPCR AAbs levels were higher in LC than in APC (8.88 vs. 5.45 Units/mL; p = 0.17), indicating a coherent autoimmune signature in LC that correlates with symptom development. Morning cortisol was lower in LC (12.7 vs. 17 mg/dL; p = 0.01), and T-cell responses tended to be weaker. These findings suggest GPCR AAbs may serve as biomarkers and therapeutic targets for a subset of patients, guiding diagnosis and treatments with IV immunoglobulin or immunoadsorption. Full article