Biology subjects

Netea, M. G.

Publications and source records attributed to Netea, M. G..

At least 19 recordsLinked to original sources

bioRxiv2026

Multi-Omics Clustering Differentiates the Total and Intact HIV Reservoirs and Related Host Immune Mechanisms

HIV reservoirs are heterogeneous across individuals, yet host determinants of this variability remain unclear. Applying multi-omics clustering to 1,230 people with HIV, integrating omics and functional data from circulating immune cells (transcriptomics, DNA methylation, immune phenotyping, ex-vivo cytokine production capacity), plasma proteomics, and CD4+ T-cell reservoir measurements (total and intact HIV-DNA copies), revealed three immunologically distinct endotypes: All Low (low total/low intact reservoir size), All High (high total/high intact reservoir size) and Mixed (high total/low intact reservoir size). Per endotype, distinct immune landscapes were noticed in single-layer analyses as well as differences in clinical signatures. Applying non-linear machine learning across all layers, key predictors not captured by linear single-layer approaches showed IFN-{gamma} production and TCF7/AK5 expression across T-cell and NK-cell populations as well as IL-1{beta}/MCP-1 production after 24h stimulation and MAN1C1/EDAR expression on T-cell populations, linked to intact and total reservoir size, respectively. This host-virus integrative multi-omics framework provides a systems-level resource that may help to personalize reservoir-reducing intervention studies aiming for HIV cure and/or comorbidity reductions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/734029v4_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@16fded7org.highwire.dtl.DTLVardef@18f2e69org.highwire.dtl.DTLVardef@12ffc9borg.highwire.dtl.DTLVardef@17127cc_HPS_FORMAT_FIGEXP M_FIG a) Multi-omics clustering of 1,230 virally suppressed PLHIV identified three immunologically distinct endotypes: All Low (n=428), Mixed (n=483), and All High (n=280), with distinct total and intact HIV reservoir sizes. b) Single-layer analyses reveal characteristic immune landscapes: All Low Th1-skewed, naive T cells (immunophenotyping), high IFN-{gamma} production (7-day), downregulated Type I IFN pathways (bulk transcriptome); Mixed intermediate Th1/Th2, CD8 and CD4 effector memory T cells (immunophenotyping), IL-5 production (7-day), downregulated Type I IFN pathways (bulk transcriptome); All High Th2-skewed, CD4 effector memory T cells (immunophenotyping), high IL-5 production (7-day), upregulated Type I IFN pathways (bulk transcriptome). c) Endotypes carry distinct comorbidity burdens: All Low lower carotid plaque, AIDS-defining malignancies, and residual viremia; Mixed intermediate burden; All High highest carotid plaque, AIDS-defining malignancies, opportunistic infections, and residual viremia. d) Non-linear classification models (XGBoost) prioritize top host predictive markers: IFN-{gamma} response (7-day), TCF7 and AK5 expression in CD4/CD8 T-cells and NK-cells (characterize All Low; IL-1 response (24-hour), MAN1C1 and EDAR in CD4/CD8 T-cells, and MCP1 response (24-hour) characterize All High. Created in BioRender. C_FIG

immunology↗

bioRxiv2026

Genetic, intrinsic, and environmental determinants of innate immune cytokine responses in healthy four-year-old children

Abstract/SummaryInnate immune responses are crucial for host defence but vary markedly between individuals. Although determinants of this variation are well characterised in adults, data from healthy children remain scarce. We therefore profiled whole-blood cytokine responses to innate immune stimulation in 286 children aged approximately four years and examined genetic, host-intrinsic, and environmental correlates of response. Cytokine responses showed marked inter-individual heterogeneity and stimulus-specific patterns. The top 50 genetic variants explained a substantial proportion ([~]20-45%) of this variance across many stimulus conditions, including a biologically coherent association of the STING locus with cGAMP-induced cytokine production. In contrast, sex, age, adiposity, and perinatal variables showed limited or modest associations. Systemic inflammatory biomarkers of systemic inflammation (hsCRP, glycoprotein acetyls, granulocyte-to-lymphocyte ratio) were strongly positively associated with cytokine responses. Finally, seasonal population-level viral infection burden was positively associated with antiviral and inflammatory cytokine responses. Collectively, these findings advance our understanding of variation in early-life whole-blood cytokine responses, underscoring this developmental period as a critical window for understanding immune development trajectories relevant to long-term health.

immunology↗

bioRxiv2026

Viral persistence and antiretroviral therapy shape systemic immune aging in treated HIV infection

Chronic infections can reshape immune system homeostasis, yet how persistent viral infections influence immune aging remains poorly understood. People living with HIV provide a unique model to investigate how long-term viral persistence affects immune aging despite effective antiretroviral therapy. Here, we characterize immune aging by integrating plasma proteomics with epigenetic and transcriptional profiles of circulating immune cells across large cohorts of treated individuals with HIV. We find that immune aging is markedly accelerated compared with healthy individuals and parallels established DNA methylation-based aging clocks. Accelerated immune aging is strongly associated with signatures of immunosenescence and correlates with the size of the latent HIV reservoir, suggesting a persistent imprint of viral persistence on immune aging trajectories. Notably, exposure to specific antiretroviral agents, particularly nucleoside reverse transcriptase inhibitors, is associated with reduced immune aging and suppression of age-associated immune gene programs. Together, these findings identify chronic viral persistence as a driver of systemic immune aging and indicate that antiretroviral therapy can partially modulate immune aging programs.

immunology↗

bioRxiv2025

Neonatal BCG Vaccination Engages the Vasculature to Elicit γδ T Cell-Mediated Protection against Tuberculosis

The Bacillus Calmette-Guerin (BCG) vaccine remains the only approved vaccine against tuber-culosis (TB). Although its efficacy against pulmonary TB in adults is limited, BCG provides re-markable protection against miliary TB when administered during infancy. Despite more than 100 million infants worldwide receiving BCG annually, the mechanisms underlying its neonatal protective effects remain poorly defined. Here, we demonstrate that subcutaneous neonatal BCG vaccination (BCG-sc) induces a marked expansion of {gamma}{delta} T cells producing IL-17 and IL-22, which mediated protection against subsequent Mycobacterium tuberculosis (Mtb) experimental infection. A similar expansion of {gamma}{delta} T cells was observed in a longitudinal cohort of infants, from birth to three months of infants followed after intradermal BCG vaccination. Mechanistical-ly, BCG-mediated protection in neonates was linked to its early vascular dissemination through the distinct structure of neonatal skin, resembling the protective effects of intravenous BCG in adults. Moreover, neonatal BCG-sc vaccination generated a distinct BCG-induced microbiome signature, characterized by enrichment of Prevotellaceae, Tannerellaceae, and Bifidobacteriaceae, which was associated with protection. Together, these findings identify {gamma}{delta} T cells as key mediators of early-life BCG-induced immunity and highlight the role of the gut-lung axis in long-term protection against TB from infancy into adulthood.

immunology↗

bioRxiv2025

HDL-associated phosphatidylserine blunts myeloid activation and protects from atherosclerosis

Background and aimsLipids play a critical role in atherosclerosis. Low-density lipoprotein (LDL)-cholesterol and certain lipid classes like sphingomyelins are associated with inflammation and poor cardiovascular outcomes. Phosphatidylserine (PS), on the other hand, is a negatively charged anti-inflammatory phospholipid class involved in efferocytosis. In this study, we sought to investigate its anti-atherosclerotic properties through a combination of complementary human lipidomics analyses, in vitro assays and in vivo experiments in Apoe-/- mice. MethodsHuman lipidomics studies were performed on the 300OB cohort comprising 300 obese and overweight individuals at risk of cardiovascular disease. In vitro assays were carried out using human monocytes and macrophages, and in vivo experiments included histopathological, immunophenotyping and single-cell transcriptomic analyses. ResultsIn humans, we identified PS as an anti-inflammatory and atheroprotective biomarker. Hence, we developed a high-density lipoprotein (HDL)-like formulation enriched in PS to exploit its properties in a targeted fashion in mice. In vitro, this formulation potently inhibited inflammatory cytokine production on human myeloid cells. Our in-depth in vivo experiments provided evidence of the formulations potent plaque-stabilizing and anti-inflammatory actions. These effects were mediated by a shift in the monocyte/macrophage compartment toward homeostatic/repairing phenotypes. ConclusionsCollectively, our results demonstrate that HDL-associated PS potently suppresses inflammation and atheroprogression, and holds promise as a viable approach to improve immunomodulatory therapies.

immunology↗

bioRxiv2025

Transcription-based identification of uncharacterized genes in the human immune response

Host-pathogen interactions are shaped by the nature of the pathogen and by host-related factors. The human host responses can be characterized in microbe-stimulated immune cells using transcriptomics. We set out to characterize gene expression changes as a result of microbial in vitro stimulation in RPMI-cultured human primary immune cells, using four pathogen ligands representing bacteria (LPS and S. aureus), viruses (Poly(I:C)) and fungi (C. albicans) for 4 and 24 hours, resulting in a total of 52 samples for analysis. We analyze the transcriptional changes on gene- and pathway level, highlighting common and distinct effects of pathogen stimulation. We highlight genes without a known function that were differentially expressed as a common effect of pathogen stimulation. We find uncharacterized genes such as KIAA0040 and CYRIA to be co-expressed with genes involved in innate immunity and downstream signaling from the PRRs, respectively. We identify 901 variants in uncharacterized genes in a cohort of patients with rare immune disorders, prioritizing 5 candidate variants in 4 genes that could underly these diseases. Our results therefore indicate the potential role of these genes the human immune response and provides candidate variants with potential relevance in rare immune-mediated diseases.

genomics↗

bioRxiv2024

Early and Delayed STAT1-Dependent Responses Drive Local Trained Immunity of Macrophages in the Spleen

Trained immunity (TI) is the process wherein innate immune cells gain functional memory upon exposure to specific ligands or pathogens, leading to augmented inflammatory responses and pathogen clearance upon secondary exposure. While the differentiation of hematopoietic stem cells (HSCs) and reprogramming of bone marrow (BM) progenitors are well-established mechanisms underpinning durable TI protection, remodeling of the cellular architecture within the tissue during TI remains underexplored. Here, we study the effects of peritoneal Bacillus Calmette-Guerin (BCG) administration to find TI-mediated protection in the spleen against a subsequent heterologous infection by the Gram-negative pathogen Salmonella Typhimurium (S.Tm). Utilizing single cell RNA-sequencing and flow cytometry, we discerned STAT1-regulated genes in TI-associated resident and recruited splenic myeloid populations. The temporal dynamics of TI were further elucidated, revealing both early and delayed myeloid subsets with time-dependent, cell type-specific STAT1 signatures. Using lineage tracing, we find that tissue-resident red pulp macrophages (RPM), initially depleted by BCG exposure, are restored from both tissue-trained, self-renewing macrophages and from bone marrow-derived progenitors, fostering long lasting local defense. Early inhibition of STAT1 activation, using specific JAK-STAT inhibitors, reduces both RPM loss and recruitment of trained monocytes. Our study suggests a temporal window soon after BCG vaccination, in which STAT1-dependent activation of long-lived resident cells in the tissue mediates localized protection.

immunology↗

bioRxiv2024

Immune correlates of early clearance of Mycobacterium tuberculosis among tuberculosis household contacts in Indonesia

Some individuals, even when heavily exposed to an infectious tuberculosis patient, do not develop a specific T-cell response as measured by interferon-gamma release assay (IGRA). This could be explained by an IFN-{gamma}-independent adaptive immune response, or an effective innate host response clearing Mycobacterium tuberculosis (Mtb) without adaptive immunity. In heavily exposed Indonesian tuberculosis household contacts (n=1347), a persistently IGRA negative status was associated with presence of a BCG scar, and - especially among BCG-vaccinated individuals - with altered innate immune cells dynamics, higher heterologous (Escherichia coli-induced) proinflammatory cytokine production, and higher inflammatory proteins in the IGRA mitogen tube. Neither circulating concentrations of Mtb-specific antibodies nor functional antibody activity associated with IGRA status at baseline or follow-up. In a cohort of adults in a low tuberculosis incidence setting, BCG vaccination induced heterologous innate cytokine production, but only marginally affected Mtb-specific antibody profiles. Our findings suggest that a more efficient host innate immune response, rather than a humoral response, mediates early clearance of Mtb. The protective effect of BCG vaccination against Mtb infection may be linked to innate immune priming, also termed trained immunity.

immunology↗

bioRxiv2024

In vitro host transcriptomics during Cryptococcus neoformans, Cryptococcus gattii, and Candida albicans infection of South African volunteers

Cryptococcus neoformans, Cryptococcus gattii and Candida albicans are opportunistic fungal pathogens associated with infections in immunocompromised hosts. Cryptococcal meningitis (CM) is the leading fungal cause of HIV-related deaths globally, with the majority occurring in Africa. The human immune response to C. albicans infection has been studied extensively in large genomics studies whereas cryptococcal infections, despite their severity, are comparatively understudied. Here we investigated the transcriptional response of immune cells after in vitro stimulation with in vitro C. neoformans, C. gattii and C. albicans infection of peripheral blood mononuclear cells (PBMCs) collected from healthy South African volunteers. We found a lower transcriptional response to cryptococcal stimuli compared to C. albicans and unique expression signatures from all three fungal stimuli. This work provides a starting point for further studies comparing the transcriptional signature of CM in immunocompromised patients, with the goal of identifying biomarkers of disease severity and possible novel treatment targets.

genomics↗

bioRxiv2023

Fatty acid desaturation and lipoxygenase pathways support trained immunity

Infections and vaccinations can induce long-term enhanced responses of innate immune cells to heterologous stimuli, establishing a de facto innate immunological memory termed trained immunity. Monocytes exposed to the Bacillus Calmette-Guerin (BCG) vaccine, have a trained immunity phenotype, characterized by an increased biosynthesis of different lipid mediators (LMs) derived from long-chain polyunsaturated fatty acids (PUFAs). Pharmacological and genetic approaches showed that long-chain PUFA synthesis and lipoxygenase (LOX)-derived LMs are crucial for the BCG trained immunity responses of human monocytes. Furthermore, monocytes of healthy individuals vaccinated with BCG are enriched in 12-LOX products. The elucidation of the lipid metabolic pathways that promote innate immune memory contributes to our understanding of trained immunity and may help identify therapeutic tools and targets for the modulation of innate immune responses.

immunology↗

bioRxiv2022

MMR vaccination induces a trained immunity program characterized by functional and metabolic reprogramming of γδ T cells

The measles, mumps and rubella (MMR) vaccine protects against all-cause mortality in children, but the immunological mechanisms mediating these effects are poorly known. We systematically investigated whether MMR can induce long-term functional changes in innate immune cells, a process termed trained immunity, that could at least partially mediate this heterologous protection. In a randomized placebo-controlled trial, 39 healthy adults received either the MMR vaccine or a placebo. By using single-cell RNA-sequencing, we found that MMR caused transcriptomic changes in CD14-positive monocytes and NK cells, but most profoundly in {gamma}{delta} T cells. Surprisingly, monocyte function was not altered by MMR vaccination. In contrast, the function of {gamma}{delta} T cells was significantly enhanced by MMR vaccination, with higher production of TNF and IFN{gamma}, as well as upregulation of cellular metabolic pathways. In conclusion, we describe a new trained immunity program characterized by modulation of {gamma}{delta} T cell function induced by MMR vaccination. One-sentence summaryMMR vaccination induces cellular and metabolic reprogramming in {gamma}{delta} T cells towards a more active phenotype.

immunology↗

bioRxiv2022

Diversity and ecology of Caudoviricetes phages with genome terminal repeats in fecal metagenomes from four Dutch cohorts

The human gut harbors numerous viruses infecting the human host, microbes and other inhabitants of the gastrointestinal tract. Most of these viruses remain undiscovered, and their influence on human health is unknown. Here we characterize viral genomes in gut metagenomic data from 1,950 individuals from four population and patient cohorts. We focus on a subset of viruses that is highly abundant in the gut, remains largely uncharacterized, and allows confident complete genome identification - phages that belong to the class Caudoviricetes and possess genome terminal repeats. We detect 1,899 species-level units belonging to this subset, 19% of which do not have complete representative genomes in major public gut virome databases. These units display diverse genomic features, are predicted to infect a wide range of microbial hosts, and on average account for < 1% of metagenomic reads. Analysis of longitudinal data from 338 individuals shows that the composition of this fraction of the virome remained relatively stable over a period of 4 years. We also demonstrate that 54 species-level units are highly prevalent (detected in > 5% of individuals in a cohort). Finally, we find 34 associations between highly prevalent phages and human phenotypes, 24 of which can be explained by the relative abundance of potential hosts.

microbiology↗

bioRxiv2022

Differences in anti-viral immune responses in individuals of Indian and European origin: relevance for the COVID-19 pandemic

During the COVID-19 pandemic, large differences in susceptibility and mortality due to SARS-CoV-2 infection have been reported between populations in Europe and South Asia. While both host and environmental factors (including BCG vaccination) have been proposed to explain this, the potential biological substrate of these differences is unknown. We purified peripheral blood mononuclear cells from individuals living in India and the Netherlands at baseline and 10-12 weeks after BCG vaccination. We compared chromatin accessibility between the two populations at baseline, as well as gene transcription profiles and cytokine production capacities upon viral stimulation with influenza and SARS-CoV-2. The chromatin accessibility of genes important for adaptive immunity was higher in Indians compared to Europeans, while the latter had more accessible chromatin regions in genes of the innate immune system. At the transcriptional level, we observed that Indian volunteers displayed a more tolerant immune response to viral stimulation, in contrast to a more exaggerated response in Europeans. BCG vaccination strengthened the tolerance program in Indians, but not in Europeans. These differences may partly explain the different impact of COVID-19 on the two populations.

immunology↗

bioRxiv2022

Differences in the inflammatory proteome of East African and Western European adults and associations with environmental and dietary factors

Non-communicable diseases (NCDs) are rising rapidly in urbanizing populations in sub-Saharan Africa. Assessment of inflammatory and metabolic characterstics of an urbanizing African population and the comparison with populations outside Africa could provide insight in the pathophysiology of the rapidly increasing epidemic of NCDs, including the role of environmental and dietary changes. Using a proteomic plasma profiling approach comprising 92 inflammation-related molecules, we examined differences in the inflammatory proteome in healthy Tanzanian and healthy Dutch adults. We show that healthy Tanzanians display a pro-inflammatory phenotype compared to Dutch subjects, with enhanced activity of the Wnt/{beta}-catenin signalling pathway and higher concentrations of different metabolic regulators such as 4E-BP1 and fibroblast growth factor 21. Among the Tanzanian volunteers, food-derived metabolites were identified as an important driver of variation in inflammation-related molecules, emphasizing the potential importance of lifestyle changes. These findings endorse the importance of the current dietary transition in the NCDs epidemic in sub-Saharan Africa and the inclusion of underrepresented populations in systems immunology studies.

immunology↗

bioRxiv2022

Integration of Candida albicans-induced single-cell gene expression data and circulatory protein concentrations reveal genetic regulators of inflammation

Both gene expression and protein concentrations are regulated by genetic variants. Exploring the regulation of both eQTLs and pQTLs simultaneously in a context- and cell-type dependent manner may help to unravel mechanistic basis for genetic regulation of pQTLs. Here, we performed meta-analysis of Candida albicans-induced pQTLs from two population-based cohorts and intersected the results with Candida-induced cell-type specific expression association data (eQTL). This revealed systematic differences between the pQTLs and eQTL, with only 35% of common genetic variants modulating both intermediate molecular phenotypes. By taking advantage of the tightly co-regulated pattern of the proteins, we also identified SNPs affecting protein network upon Candida stimulations. Colocalization of pQTLs and eQTLs signals implicated several genomic loci including MMP-1 and AMZ1. Analysis of Candida-induced single cell gene expression data implicated specific cell types that exhibit significant expression QTLs upon stimulation. By highlighting the role of trans-regulatory networks in determining the abundance of proteins in blood, our study serve as a framework to gain insights into the mechanisms of genetic regulation of protein levels in a context-dependent manner.

genomics↗

bioRxiv2022

Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections

Bacillus Calmette-Guerin (BCG) is recommended as intravesical immunotherapy to reduce the risk of tumor recurrence in patients with non-muscle invasive bladder cancer (NMIBC). Currently, it is unknown whether intravesical BCG application induces trained immunity. Here, we found that intravesical BCG does induce trained immunity based on an increased production of TNF and IL-1{beta} after heterologous ex-vivo stimulation of circulating monocytes 6- 12 weeks after intravesical BCG treatment; and a 37% decreased risk (OR 0.63 (95% CI 0.40- 1.01)) for respiratory infections in BCG-treated versus non-BCG-treated NMIBC patients. An epigenomics approach combining ChIP-sequencing and RNA-sequencing with in-vitro trained immunity experiments identified enhanced inflammasome activity in BCG-treated individuals. Finally, germline variation in genes that affect trained immunity was associated with recurrence and progression after BCG therapy in NMIBC, suggesting a link between trained immunity and oncological outcome.

immunology↗

bioRxiv2022

Differential recognition and cytokine induction by the peptidorhamnomannan from Sporothrix brasiliensis and S. schenckii

Sporotrichosis is a deep mycosis caused by dimorphic species of the genus Sporothrix, with differences in pathogenicity between S. schenckii and S. brasiliensis species. Recently, it was discovered that the cell wall peptidorhamnomannan (PRM) of Sporothrix spp. is a pathogen associated molecular pattern (PAMP). Interestingly, S. brasiliensis PRM has additional unknown rhamnose residues. We hypothesize that the structural differences of Sporothrix spp PRMs impact the hosts immune response and may explain the severity of sporotrichosis caused by S. brasiliensis. Here we demonstrate that S. brasiliensis yeasts and its PRM (S.b PRM) induced a strong inflammatory response in human PBMCs, with high production of TNF-, IL-6 and IL-1{beta} and induction of T-helper cytokines IFN-{gamma}, IL-17 and IL-22. In contrast, S. schenckii yeasts and its PRM induced higher concentrations of interleukin-1 receptor antagonist (IL-1Ra), which resulted in low production of T-helper cytokines such as IL-17 and IL-22. CR3 and dectin-1 were required for cytokine induction by both PRMs, while TLR2 and TLR4 were required for the response of S.s PRM and S.b PRM, respectively. IL-1{beta} and IL-1 production induced by S. brasiliensis yeasts and S.b PRM were dependent on inflammasome and caspase-1 activation. S. schenckii and S.s PRM were able to induce IL-1{beta} independent of ROS. In conclusion, these findings improve our understanding of the pathogenesis of Sporothrix spp. by reporting differences of immunological responses induced by S. schenckii and S. brasiliensis. The study also opens the gateway for novel treatment strategies targeting local inflammation and tissue destruction induced by S. brasiliensis infection through IL-1 inhibition.

immunology↗

bioRxiv2021

Discovery, diversity and functional associations of crAss-like phages in human gut metagenomes from four Dutch cohorts

The crAss-like phages are a diverse group of related viruses that includes one of the most abundant viruses of the human gut. To explore their diversity and functional role in human population and clinical cohorts, we analyzed gut metagenomic data collected from more than 2000 individuals from the Netherlands. We discovered 125 novel species-level and 32 novel genus-level clusters of crAss-like phages, all belonging to five previously recognized groups associated with the human gut. Analysis of their genomic features revealed that closely related crAss-like phages can possess strikingly divergent regions responsible for transcription, presumably acquired through recombination. Prediction of crAss-like phage hosts pointed primarily to bacteria of the phylum Bacteroidetes, consistent with previous reports. Finally, we explored the temporal stability of crAss-like phages over a 4-year period and identified associations between the abundance of crAss-like phages and several human phenotypes, including depletion of crAss-like phages in inflammatory bowel disease patients. HighlightsO_LI125 tentative new species of crAss-like phages were discovered C_LIO_LIClosely related crAss-like phages often possess highly divergent transcription gene modules possibly acquired via recombination C_LIO_LICrAss-like fraction of the human gut virome remains relatively stable over the period of 4 years C_LIO_LIPrevalence of crAss-like phages in the human gut is associated with several metabolic, dietary and health phenotypes C_LIO_LIGut crAss-like phages are depleted in inflammatory bowel disease patients C_LI

microbiology↗