Biology subjects

Van Weyenbergh, J.

Publications and source records attributed to Van Weyenbergh, J..

10 recordsLinked to original sources

bioRxiv2025

Pathogenic IgG from long COVID patients with neurological sequelae triggers sensitive but not cognitive impairments upon transfer into mice

Approximately 30% of long COVID patients still experience neurological symptoms (brain fog, pain, chronic fatigue) more than 4 months after the onset of COVID-19. This condition, known as neurological long COVID, remains poorly understood and might be explained by a persisting autoimmune response against nervous-derived self-antigens. The aim of this study is to determine whether IgG autoantibodies from long COVID patients with neurological sequelae can bind to central or peripheral nervous system epitopes and triggers neuropsychiatric symptoms upon passive transfer into mice, thereby mirroring patient-reported manifestations. Long COVID patients meeting the 2021 consensus WHO definition were included following a standardized neuropsychological assessment, while excluding patients with a medical history of autoimmune and neurological disorders. Age- and sex-matched asymptomatic individuals were used as healthy controls. Total IgGs were isolated using protein G purification and injected intraperitoneally into C57Bl6/J mice for four consecutive days. During the two weeks post-injections, behavioral tests assessed mechanical allodynia, thermal hyperalgesia, spatial working memory, depression, and anxiety. Mice injected with IgG from long COVID patients showed no difference with the control group in terms of anxiety or depression behaviors, as well as no impairment of short- or long-term spatial memories and thermal hyperalgesia. However, they displayed a transient decrease of paw withdrawal threshold during the first week. This effect was abolished when IgG-depleted serum or papain-digested IgGs were transferred. IgG from long COVID patients accumulated in the lumbar dorsal root ganglia of injected mice and colocalized with proprioceptive and nociceptive sensory neurons, without inducing local neuroinflammation or astrogliosis. These data demonstrate that IgGs from long COVID patients bind to peripheral sensory neurons and induce pain-related symptoms in mice. Our findings also support the hypothesis that autoantibodies mediate pain-related pathophysiology in the spectrum of long COVID symptoms.

neuroscience↗

bioRxiv2023

Tittle: An integrated analysis of the structural changes and gene expression of spleen in human visceral leishmaniasis with and without HIV coinfection

The spleen plays a pivotal role in the pathogenesis of visceral leishmaniasis. In severe forms of the disease, the spleen undergoes changes that can compromise its function in surveilling blood-circulating pathogens. In this study, we present an integrated analysis of the structural and gene expression alterations in the spleens of three patients with relapsing visceral leishmaniasis, two of whom were coinfected with HIV. Our findings reveal that the IL6 signaling pathway plays a significant role in the disorganization of the white pulp, while BCL10 and ICOSLG are associated with spleen organization. Patients coinfected with HIV and visceral leishmaniasis exhibited lower splenic CD4+ cell density and reduced expression of genes such as IL15. These effects may contribute to a compromised immune response against L. infantum in coinfected individuals, further impacting the structural organization of the spleen.

pathology↗

bioRxiv2023

TUMOR ENDOTHELIAL CELL AUTOPHAGY IS A KEY VASCULAR-IMMUNE CHECKPOINT IN MELANOMA

Tumor endothelial cells (TECs) actively repress inflammatory responses and maintain an immune-excluded tumor phenotype. However, the molecular mechanisms that sustain TEC-mediated immunosuppression remain largely elusive. Here, we show that autophagy ablation in TECs boosts antitumor immunity by supporting infiltration and effector function of T cells, thereby restricting melanoma growth. In melanoma-bearing mice, loss of TEC autophagy leads to the transcriptional expression of an immunostimulatory/inflammatory TEC phenotype driven by heightened NF-kB and STING signaling. In line, single-cell transcriptomic datasets from melanoma patients disclose an enriched InflammatoryHigh/AutophagyLow TEC phenotype in correlation with clinical responses to immunotherapy. Congruently, patients responding to immunotherapy exhibit an increased presence of inflamed vessels, interfacing with infiltrating CD8+ T cells. Mechanistically, STING-dependent immunity in TECs is not critical for the immunomodulatory effects of autophagy ablation, since NF-kB-driven inflammation remains functional in STING/ATG5 double knockout TECs. Hence, autophagy is a principal tumor vascular anti-inflammatory mechanism dampening melanoma antitumor immunity.

cancer biology↗

bioRxiv2021

Interactome and structural basis for targeting the human T-cell leukemia virus Tax oncoprotein

Human T-cell leukemia virus type-1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL). Although ATL is a well-characterized T-cell neoplasm, linked to intermittent expression of the viral Tax-1 protein, there is currently no strategy to target Tax-1 functions using small molecules. Here, we report a comprehensive interaction map between Tax-1 and human PDZ domain-containing proteins (hPDZome). We show that Tax-1 interacts with more than one-third of hPDZome components, including proteins involved in cell cycle, cell-cell junctions, cytoskeleton organization, and membrane complex assembly. Using nuclear magnetic resonance (NMR) spectroscopy, we have determined the structural basis of the interaction between the C-terminal PDZ binding motif (PBM) of Tax-1, and the PDZ domains of syntenin-1, an evolutionary conserved hub that controls exosome trafficking. Finally, we have used confocal imaging, molecular modelling, NMR and mammalian cell-based assays to demonstrate that the Tax-1/syntenin-1 interaction is amenable to small-molecule inhibition. Altogether, our study highlights the biological significance of Tax-PDZ interactome and its interplay with exosome formation. It shows a direct link between extracellular vesicles and HTLV-1 transmission, providing a novel framework for the design of targeted therapies for HTLV-1-induced diseases.

biochemistry↗

bioRxiv2021

The viral oncoproteins Tax and HBZ reprogram the cellular mRNA splicing landscape

While viral infections are known to hijack the transcription and translation of the host cell, the extent to which encoded viral proteins coordinate these perturbations remains unclear. Here we demonstrate that the oncoviral proteins Tax and HBZ interact with specific components of the spliceosome machinery, including the U2 auxiliary factor large subunit (U2AF2), and the complementary factor for APOBEC-1 (A1CF), respectively. Tax and HBZ perturb the splicing landscape in T-cells by altering cassette exons in opposing manners, with Tax inducing exon inclusion while HBZ induces exon exclusion. Among Tax- and HBZ-dependent splicing changes, we identify events that are also altered in Adult T cell leukemia (ATL) patients, and in well-known cancer census genes. Our interactome mapping approach, applicable to other viral oncogenes, has identified spliceosome perturbation as a novel mechanism coordinately used by Tax and HBZ to reprogram the transcriptome. HighlightsO_LITax and HBZ interact with RNA-binding proteins as well as transcription factors C_LIO_LIHTLV-1 encoded proteins Tax and HBZ alter the splicing landscape in T-cells C_LIO_LITax and HBZ expression affect alternative splicing of 33 and 63 cancer genes, respectively C_LIO_LIOpposing roles for Tax and HBZ in deregulation of gene expression C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=158 HEIGHT=200 SRC="FIGDIR/small/427104v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@b5f6f0org.highwire.dtl.DTLVardef@6725b3org.highwire.dtl.DTLVardef@1dc32fborg.highwire.dtl.DTLVardef@19728c6_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2020

STAT2 signaling as double-edged sword restricting viral dissemination but driving severe pneumonia in SARS-CoV-2 infected hamsters

Introductory paragraphSince the emergence of SARS-CoV-2 causing COVID-19, the world is being shaken to its core with numerous hospitalizations and hundreds of thousands of deaths. In search for key targets of effective therapeutics, robust animal models mimicking COVID-19 in humans are urgently needed. Here, we show that productive SARS-CoV-2 infection in the lungs of mice is limited and restricted by early type I interferon responses. In contrast, we show that Syrian hamsters are highly permissive to SARS- CoV-2 and develop bronchopneumonia and a strong inflammatory response in the lungs with neutrophil infiltration and edema. Moreover, we identify an exuberant innate immune response as a key player in pathogenesis, in which STAT2 signaling plays a dual role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Finally, we assess SARS-CoV- 2-induced lung pathology in hamsters by micro-CT alike used in clinical practice. Our results reveal the importance of STAT2-dependent interferon responses in the pathogenesis and virus control during SARS-CoV-2 infection and may help rationalizing new strategies for the treatment of COVID-19 patients.

microbiology↗

bioRxiv2018

Serum GlycA level is a candidate biomarker for disease activity in systemic lupus erythematosus and for proliferative status of lupus nephritis, independent of renal function impairment.

ObjectiveGlycoprotein acetylation (GlycA) is a novel biomarker for chronic inflammation, associated to cardiovascular risk. Serum GlycA levels are increased in several inflammatory diseases, including systemic lupus erythematosus (SLE). We investigated the relevance of serum GlycA measurement in SLE and lupus nephritis (LN).\n\nMethodsGlycA was measured by NMR in 194 serum samples from patients and controls. Comparisons were performed between groups. Clinical and biological parameters were tested for correlation with GlycA levels. The predictive value of GlycA to differentiate proliferative from non-proliferative LN was determined using logistic regression models.\n\nResultsGlycA was correlated to C-reactive protein (CRP), neutrophil count, proteinuria and the SLE disease activity index (SLEDAI), and inversely with serum albumin. GlycA was higher in active (n=105) than in quiescent (n=39) SLE patients, in healthy controls (n=29), and in patients with non-lupus nephritis (n=21), despite a more altered renal function in the latter. In patients with biopsy-proven active LN, GlycA was higher in proliferative (n=32) than non-proliferative (n=11) LN, independent of renal function and proteinuria level. Logistic regression models showed that, in univariate models, GlycA outperforms traditional biomarkers. A bivariate model using GlycA and BMI better predicted the proliferative status of LN than a model comprising CRP, renal function (eGFR), serum albumin, proteinuria, C3 consumption and the presence of anti-dsDNA antibodies.\n\nConclusionSerum GlycA is elevated in SLE, and correlates with disease activity and LN. Serum GlycA, which summarizes different inflammatory processes, could be a valuable biomarker to discriminate proliferative from non-proliferative LN and should be tested in large, prospective cohorts.

immunology↗

bioRxiv2018

Age but not disease progression defines CD4+ and CD8+ T stem cell memory levels in human retroviral infections: contrasting effects of HTLV-1 and HIV-1

BackgroundHuman CD4+ and CD8+ stem cell memory T cells (TSCM) represent a minor fraction of circulating lymphocytes characterized by stemness and long-term in vivo persistence. CD4+ TSCM are preferentially infected and constitute a reservoir for HIV-1, whereas CD8+ TSCM appear to play a protective role. However, little is known about CD4+ and CD8+ TSCM in the only other human pathogenic retroviral infection, human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 is the etiological agent of both Adult T-cell Leukemia (ATL) and HTLV-1 associated myelopathy/tropical spastic paraperesis (HAM/TSP), a neuroinflammatory disorder. In ATL, CD4+ TSCM cells were identified as the hierarchical leukemic stem cell, but data in HAM/TSP are lacking. Age is a major risk factor for both ATL and HAM/TSP, as both diseases generally manifest several decades after infection. Therefore, we explored a possible link between TSCM, age and disease status in human retroviral infections in a cross-sectional study, using multiparametric flow cytometry.\n\nResultsWe found that CD4+ or CD8+ TSCM levels (quantified as CD3+CD45RA+CD45RO- CD27+CCR7+Fashi) do not differ between healthy controls and untreated HTLV-1 infected individuals with and without neuroinflammatory disorder. However, we found both TSCM as well as CD8+ TSCM significantly accumulated with age, resulting in a >400% increase in elderly HTLV-1 infected individuals (>60 years). A significant correlation between age and TSCM signature genes was validated at the transcriptome level in an independent cohort. CD8+ but not CD4+ TSCM were significantly decreased in untreated HIV-1 infection. Unexpectedly, CD8+ TSCM recovery upon successful antiretroviral treatment was essentially complete (92.2{+/-}11.0%) in younger (<45 years) individuals, but significantly lower (37.3{+/-}6.1%) in older (>45 years) individuals (p=0.0003).\n\nConclusionIn HTLV-1 infection, an age-dependent accumulation of CD4+ and CD8+ TSCM points towards a possible protective role of CD8 TSCM in the elderly against leukemic but not neuroinflammatory disease. HIV-1-infected individuals lose their ability to restore CD8+ TSCM levels upon successful antiretroviral therapy at later age (>45 years), which might eventually lead to immunological failure and decreased vaccine efficacy.

immunology↗

bioRxiv2018

Decreased RORC expression and downstream signaling in HTLV-1-associated Adult T-cell Lymphoma/Leukemia uncovers an antiproliferative IL17 link: a potential target for immunotherapy?

Retinoic acid-related drugs have shown promising pre-clinical activity in Adult T-cell Leukemia/Lymphoma (ATL), but RORC (Retinoic acid Orphan Receptor C) signaling has not been explored. Therefore, we investigated transcriptome-wide interactions of the RORC pathway in Human T-cell Leukemia Virus-1 (HTLV-1) infection and ATL, using our own and publicly available gene expression data for ATL and other leukemias, HTLV-1-infected individuals and healthy controls. Gene expression data from ATL patients were analyzed using Weighted Gene Correlation Network Analysis (WGCNA) to determine gene modules and their correlation to clinical and molecular data. Both PBMCs and CD4+ T-cells showed decreased RORC expression in four different ATL cohorts. A small subset of RORChi ATL patients was identified with significantly lower pathognomonic CADM1 and HBZ levels but similar levels of other ATL markers (CD4/CD25/CCR4), hinting at a less aggressive ATL subtype. In addition, an age-dependent decrease in RORC expression was found in HTLV-1-infected individuals, but not in healthy controls, suggesting an early molecular event predisposing to leukemogenesis. Genes upstream of RORC signaling were members of a proliferative gene module (containing proliferation markers PCNA/MKI67), whereas downstream members clustered in an antiproliferative gene module. IL17C transcripts showed the strongest negative correlation to PCNA in both ATL cohorts, which was replicated in two large cohorts of T- and B-cell acute leukemias. In conclusion, decreased RORC expression and downstream signaling might represent an early event in ATL pathogenesis. An antiproliferative IL17C/PCNA link is shared between ATL, T-ALL and B-ALL, suggesting (immuno)therapeutic benefit of boosting RORC/IL17 signaling.\n\nAbbreviations

immunology↗

bioRxiv2017

ISG15 induces IL-10 production in human monocytes and is a biomarker of disease severity during active tuberculosis

Interferon stimulated gene 15 (ISG15) deficiency in humans leads to severe interferonopathies and mycobacterial disease, the latter being previously associated to its extracellular cytokine-like activity. Here, we demonstrate a novel role for secreted ISG15 as an IL-10 inducer, unique to human primary monocytes. Employing ex vivo systems analysis of human transcriptome datasets, we observed a significant correlation of ISG15-induced monocyte IL-10 and lymphocyte IFN{gamma} balanced expression. This effect was associated with p38 MAPK and PI3K signalling in healthy volunteers. The specificity and MAPK/PI3K-dependence of ISG15-induced monocyte IL-10 production was confirmed in vitro using CRISPR/Cas9 knockout and pharmacological inhibitors. Moreover, this ISG15/IL10 axis was amplified in leprosy but disrupted in human active tuberculosis (TB) patients. Importantly, ISG15 strongly correlated with inflammation and disease severity during active TB. In conclusion, this study identifies a novel anti-inflammatory ISG15/IL-10 myeloid axis that is disrupted in active TB, revealing a potential biomarker for disease severity in this major human disease.

immunology↗