Publications by authors named "Marije Oosting"

82 Publications

Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease.

Genome Biol 2021 07 6;22(1):198. Epub 2021 Jul 6.

Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, 3584, CT, Utrecht, the Netherlands.

Background: Recent studies highlight the role of metabolites in immune diseases, but it remains unknown how much of this effect is driven by genetic and non-genetic host factors.

Result: We systematically investigate circulating metabolites in a cohort of 500 healthy subjects (500FG) in whom immune function and activity are deeply measured and whose genetics are profiled. Our data reveal that several major metabolic pathways, including the alanine/glutamate pathway and the arachidonic acid pathway, have a strong impact on cytokine production in response to ex vivo stimulation. We also examine the genetic regulation of metabolites associated with immune phenotypes through genome-wide association analysis and identify 29 significant loci, including eight novel independent loci. Of these, one locus (rs174584-FADS2) associated with arachidonic acid metabolism is causally associated with Crohn's disease, suggesting it is a potential therapeutic target.

Conclusion: This study provides a comprehensive map of the integration between the blood metabolome and immune phenotypes, reveals novel genetic factors that regulate blood metabolite concentrations, and proposes an integrative approach for identifying new disease treatment targets.
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http://dx.doi.org/10.1186/s13059-021-02413-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259168PMC
July 2021

B. burgdorferi sensu lato-induced inhibition of antigen presentation is mediated by RIP1 signaling resulting in impaired functional T cell responses towards Candida albicans.

Ticks Tick Borne Dis 2021 03 23;12(2):101611. Epub 2020 Nov 23.

Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. Electronic address:

Antigen presentation is a crucial innate immune cell function that instructs adaptive immune cells. Loss of this pathway severely impairs the development of adaptive immune responses. To investigate whether B. burgdorferi sensu lato. spirochetes modulate the induction of an effective immune response, primary human PBMCs were isolated from healthy volunteers and stimulated with B. burgdorferi s.l. Through cell entry, TNF receptor I, and RIP1 signaling cascades, B. burgdorferi s.l. strongly downregulated genes and proteins involved in antigen presentation, specifically HLA-DM, MHC class II and CD74. Antigen presentation proteins were distinctively inhibited in monocyte subsets, monocyte-derived macrophages, and dendritic cells. When compared to a range of other pathogens, B. burgdorferi s.l.-induced suppression of antigen presentation appears to be specific. Inhibition of antigen presentation interfered with T-cell recognition of B. burgdorferi s.l., and memory T-cell responses against Candidaalbicans. Re-stimulation of PBMCs with the commensal microbe C.albicans following B. burgdorferi s.l. exposure resulted in significantly reduced IFN-γ, IL-17 and IL-22 production. These findings may explain why patients with Lyme borreliosis develop delayed adaptive immune responses. Unravelling the mechanism of B. burgdorferi s.l.-induced inhibition of antigen presentation, via cell entry, TNF receptor I, and RIP1 signaling cascades, explains the difficulty to diagnose the disease based on serology and to obtain an effective vaccine against Lyme borreliosis.
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http://dx.doi.org/10.1016/j.ttbdis.2020.101611DOI Listing
March 2021

Safety and COVID-19 Symptoms in Individuals Recently Vaccinated with BCG: a Retrospective Cohort Study.

Cell Rep Med 2020 Aug 5;1(5):100073. Epub 2020 Aug 5.

Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands.

Bacille Calmette-Guérin (BCG) induces long-term boosting of innate immunity, termed trained immunity, and decreases susceptibility to respiratory tract infections. BCG vaccination trials for reducing SARS-CoV-2 infection are underway, but concerns have been raised regarding the potential harm of strong innate immune responses. To investigate the safety of BCG vaccination, we retrospectively assessed coronavirus disease 2019 (COVID-19) and related symptoms in three cohorts of healthy volunteers who either received BCG in the last 5 years or did not. BCG vaccination is not associated with increased incidence of symptoms during the COVID-19 outbreak in the Netherlands. Our data suggest that BCG vaccination might be associated with a decrease in the incidence of sickness during the COVID-19 pandemic (adjusted odds ratio [AOR] 0.58, p < 0.05), and lower incidence of extreme fatigue. In conclusion, recent BCG vaccination is safe, and large randomized trials are needed to reveal if BCG reduces the incidence and/or severity of SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.xcrm.2020.100073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405881PMC
August 2020

Gut microbial co-abundance networks show specificity in inflammatory bowel disease and obesity.

Nat Commun 2020 08 11;11(1):4018. Epub 2020 Aug 11.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

The gut microbiome is an ecosystem that involves complex interactions. Currently, our knowledge about the role of the gut microbiome in health and disease relies mainly on differential microbial abundance, and little is known about the role of microbial interactions in the context of human disease. Here, we construct and compare microbial co-abundance networks using 2,379 metagenomes from four human cohorts: an inflammatory bowel disease (IBD) cohort, an obese cohort and two population-based cohorts. We find that the strengths of 38.6% of species co-abundances and 64.3% of pathway co-abundances vary significantly between cohorts, with 113 species and 1,050 pathway co-abundances showing IBD-specific effects and 281 pathway co-abundances showing obesity-specific effects. We can also replicate these IBD microbial co-abundances in longitudinal data from the IBD cohort of the integrative human microbiome (iHMP-IBD) project. Our study identifies several key species and pathways in IBD and obesity and provides evidence that altered microbial abundances in disease can influence their co-abundance relationship, which expands our current knowledge regarding microbial dysbiosis in disease.
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http://dx.doi.org/10.1038/s41467-020-17840-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419557PMC
August 2020

BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment.

Cell Host Microbe 2020 08 15;28(2):322-334.e5. Epub 2020 Jun 15.

Quantitative Systems Biology, Life & Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany; Single Cell Genomics and Epigenomics Unit at the German Center for Neurodegenerative Diseases and the University of Bonn, 53175 Bonn, Germany. Electronic address:

Induction of trained immunity by Bacille-Calmette-Guérin (BCG) vaccination mediates beneficial heterologous effects, but the mechanisms underlying its persistence and magnitude remain elusive. In this study, we show that BCG vaccination in healthy human volunteers induces a persistent transcriptional program connected to myeloid cell development and function within the hematopoietic stem and progenitor cell (HSPC) compartment in the bone marrow. We identify hepatic nuclear factor (HNF) family members 1a and b as crucial regulators of this transcriptional shift. These findings are corroborated by higher granulocyte numbers in BCG-vaccinated infants, HNF1 SNP variants that correlate with trained immunity, and elevated serum concentrations of the HNF1 target alpha-1 antitrypsin. Additionally, transcriptomic HSPC remodeling was epigenetically conveyed to peripheral CD14 monocytes, displaying an activated transcriptional signature three months after BCG vaccination. Taken together, transcriptomic, epigenomic, and functional reprogramming of HSPCs and peripheral monocytes is a hallmark of BCG-induced trained immunity in humans.
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http://dx.doi.org/10.1016/j.chom.2020.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295478PMC
August 2020

Platelet Integrin αIIbβ3 Activation is Associated with 25-Hydroxyvitamin D Concentrations in Healthy Adults.

Thromb Haemost 2020 May 5;120(5):768-775. Epub 2020 May 5.

Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.

Background:  Cardiovascular events are associated with low circulating vitamin D concentrations, although the underlying mechanisms are poorly understood. This study investigated associations between 25-hydroxyvitamin D concentrations, platelet function, and single-nucleotide polymorphisms (SNPs) in genes influencing vitamin D biology in the 500 Functional Genomics (500FG) cohort.

Methods:  In this observational study, platelet activation and function were measured by flow cytometry by binding of fibrinogen to the activated fibrinogen receptor integrin αIIbβ3 and expression of P-selectin, markers of platelet aggregation and degranulation, respectively. These parameters were correlated to serum 25-hydroxyvitamin D and genotyping was performed to investigate SNPs in genes important for vitamin D biology.

Results:  Circulating 25-hydroxyvitamin D concentrations correlated inversely with baseline platelet binding of fibrinogen to integrin αIIbβ3 (Pearson's = -0.172,  = 0.002) and platelet responses to platelet agonist cross-linked collagen-related peptide (CRP-XL) (Pearson's = -0.196, = 0.002). This effect was due to circulating vitamin D levels ≤50nmol/L, since no differences in platelet fibrinogen binding were observed between subjects with normal 25-hydroxyvitamin D concentrations (>75nmol/L) and a 25-hydroxyvitamin D insufficiency (50-75 nmol/L). No correlations between 25-hydroxyvitamin D concentrations and platelet P-selectin expression were found. Several SNPs in the GC region of the vitamin D binding proteingene were associated with platelet responses to CRP-XL.

Conclusion:  Low circulating vitamin D concentrations are associated with increased platelet fibrinogen binding to integrin αIIbβ3 in unstimulated samples and after stimulation with CRP-XL. These findings may contribute to the increased incidence of cardiovascular events in vitamin D deficient adults and its seasonal variation. Further studies are needed to investigate causality.
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http://dx.doi.org/10.1055/s-0040-1709523DOI Listing
May 2020

Rewiring of glucose metabolism defines trained immunity induced by oxidized low-density lipoprotein.

J Mol Med (Berl) 2020 06 30;98(6):819-831. Epub 2020 Apr 30.

Department of Internal Medicine (463), Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, the Netherlands.

Stimulation of monocytes with microbial and non-microbial products, including oxidized low-density lipoprotein (oxLDL), induces a protracted pro-inflammatory, atherogenic phenotype sustained by metabolic and epigenetic reprogramming via a process called trained immunity. We investigated the intracellular metabolic mechanisms driving oxLDL-induced trained immunity in human primary monocytes and observed concomitant upregulation of glycolytic activity and oxygen consumption. In two separate cohorts of healthy volunteers, we assessed the impact of genetic variation in glycolytic genes on the training capacity of monocytes and found that variants mapped to glycolytic enzymes PFKFB3 and PFKP influenced trained immunity by oxLDL. Subsequent functional validation with inhibitors of glycolytic metabolism revealed dose-dependent inhibition of trained immunity in vitro. Furthermore, in vivo administration of the glucose metabolism modulator metformin abrogated the ability for human monocytes to mount a trained response to oxLDL. These findings underscore the importance of cellular metabolism for oxLDL-induced trained immunity and highlight potential immunomodulatory strategies for clinical management of atherosclerosis. KEY MESSAGES: Brief stimulation of monocytes to oxLDL induces a prolonged inflammatory phenotype. This is due to upregulation of glycolytic metabolism. Genetic variation in glycolytic genes modulates oxLDL-induced trained immunity. Pharmacological inhibition of glycolysis prevents trained immunity.
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http://dx.doi.org/10.1007/s00109-020-01915-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297856PMC
June 2020

The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by β-Glucan.

Cell Rep 2020 04;31(3):107548

Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address:

Trained immunity confers a sustained augmented response of innate immune cells to a secondary challenge, via a process dependent on metabolic and transcriptional reprogramming. Because of its previous associations with metabolic and transcriptional memory, as well as the importance of H3 histone lysine 4 monomethylation (H3K4me1) to innate immune memory, we hypothesize that the Set7 methyltransferase has an important role in trained immunity induced by β-glucan. Using pharmacological studies of human primary monocytes, we identify trained immunity-specific immunometabolic pathways regulated by Set7, including a previously unreported H3K4me1-dependent plasticity in the induction of oxidative phosphorylation. Recapitulation of β-glucan training in vivo additionally identifies Set7-dependent changes in gene expression previously associated with the modulation of myelopoiesis progenitors in trained immunity. By revealing Set7 as a key regulator of trained immunity, these findings provide mechanistic insight into sustained metabolic changes and underscore the importance of characterizing regulatory circuits of innate immune memory.
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http://dx.doi.org/10.1016/j.celrep.2020.107548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184679PMC
April 2020

Genetic variation in Interleukin-32 influence the immune response against New World Leishmania species and susceptibility to American Tegumentary Leishmaniasis.

PLoS Negl Trop Dis 2020 02 5;14(2):e0008029. Epub 2020 Feb 5.

Radboud Institute for Molecular Sciences (RILMS), Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.

Interleukin-32 is a novel inflammatory mediator that has been described to be important in the immunopathogenesis and control of infections caused by Leishmania parasites. By performing experiments with primary human cells in vitro, we demonstrate that the expression of IL-32 isoforms is dependent on the time exposed to L. amazonensis and L. braziliensis antigens. Moreover, for the first time we show the functional consequences of three different genetic variations in the IL32 (rs4786370, rs4349147, rs1555001) modulating IL-32γ expression, influencing innate and adaptive cytokine production after Leishmania exposure. Using a Brazilian cohort of 107 American Tegumentary Leishmaniasis patients and a control cohort of 245 healthy individuals, the IL32 rs4786370 genetic variant was associated with protection against ATL, whereas the IL32 rs4349147 was associated with susceptibility to the development of localized cutaneous and mucosal leishmaniasis. These novel insights may help improve therapeutic strategies and lead to benefits for patients suffering from Leishmania infections.
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http://dx.doi.org/10.1371/journal.pntd.0008029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028298PMC
February 2020

The role of Toll-like receptor 10 in modulation of trained immunity.

Immunology 2020 03 26;159(3):289-297. Epub 2019 Nov 26.

Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.

Toll-like receptor 10 (TLR10) is the only member of the human Toll-like receptor family with an inhibitory function on the induction of innate immune responses and inflammation. However, its role in the modulation of trained immunity (innate immune memory) is unknown. In the present study, we assessed whether TLR10 modulates the induction of trained immunity induced by β-glucan or bacillus Calmette-Guérin (BCG). Interleukin 10 receptor antagonist production was increased upon activation of TLR10 ex vivo after BCG vaccination, and TLR10 protein expression on monocytes was increased after BCG vaccination, whereas anti-TLR10 antibodies did not significantly modulate β-glucan or BCG-induced trained immunity in vitro. A known immunomodulatory TLR10 missense single-nucleotide polymorphism (rs11096957) influenced trained immunity responses by β-glucan or BCG in vitro. However, the in vivo induction of trained immunity by BCG vaccination was not influenced by TLR10 polymorphisms. In conclusion, TLR10 has a limited, non-essential impact on the induction of trained immunity in humans.
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http://dx.doi.org/10.1111/imm.13145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011636PMC
March 2020

β-Glucan-Induced Trained Immunity Protects against Leishmania braziliensis Infection: a Crucial Role for IL-32.

Cell Rep 2019 Sep;28(10):2659-2672.e6

Radboud Institute for Molecular Sciences (RILMS), Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Goiás, Brazil. Electronic address:

American tegumentary leishmaniasis is a vector-borne parasitic disease caused by Leishmania protozoans. Innate immune cells undergo long-term functional reprogramming in response to infection or Bacillus Calmette-Guérin (BCG) vaccination via a process called trained immunity, conferring non-specific protection from secondary infections. Here, we demonstrate that monocytes trained with the fungal cell wall component β-glucan confer enhanced protection against infections caused by Leishmania braziliensis through the enhanced production of proinflammatory cytokines. Mechanistically, this augmented immunological response is dependent on increased expression of interleukin 32 (IL-32). Studies performed using a humanized IL-32 transgenic mouse highlight the clinical implications of these findings in vivo. This study represents a definitive characterization of the role of IL-32γ in the trained phenotype induced by β-glucan or BCG, the results of which improve our understanding of the molecular mechanisms governing trained immunity and Leishmania infection control.
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http://dx.doi.org/10.1016/j.celrep.2019.08.004DOI Listing
September 2019

Predicting bacterial infection outcomes using single cell RNA-sequencing analysis of human immune cells.

Nat Commun 2019 07 22;10(1):3266. Epub 2019 Jul 22.

Department of Biological Regulation, Weizmann Institute of Science, 7610001, Rehovot, Israel.

Complex interactions between different host immune cell types can determine the outcome of pathogen infections. Advances in single cell RNA-sequencing (scRNA-seq) allow probing of these immune interactions, such as cell-type compositions, which are then interpreted by deconvolution algorithms using bulk RNA-seq measurements. However, not all aspects of immune surveillance are represented by current algorithms. Here, using scRNA-seq of human peripheral blood cells infected with Salmonella, we develop a deconvolution algorithm for inferring cell-type specific infection responses from bulk measurements. We apply our dynamic deconvolution algorithm to a cohort of healthy individuals challenged ex vivo with Salmonella, and to three cohorts of tuberculosis patients during different stages of disease. We reveal cell-type specific immune responses associated not only with ex vivo infection phenotype but also with clinical disease stage. We propose that our approach provides a predictive power to identify risk for disease, and human infection outcomes.
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http://dx.doi.org/10.1038/s41467-019-11257-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646406PMC
July 2019

A Genome-Wide Functional Genomics Approach Identifies Susceptibility Pathways to Fungal Bloodstream Infection in Humans.

J Infect Dis 2019 07;220(5):862-872

Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.

Background: Candidemia, one of the most common causes of fungal bloodstream infection, leads to mortality rates up to 40% in affected patients. Understanding genetic mechanisms for differential susceptibility to candidemia may aid in designing host-directed therapies.

Methods: We performed the first genome-wide association study on candidemia, and we integrated these data with variants that affect cytokines in different cellular systems stimulated with Candida albicans.

Results: We observed strong association between candidemia and a variant, rs8028958, that significantly affects the expression levels of PLA2G4B in blood. We found that up to 35% of the susceptibility loci affect in vitro cytokine production in response to Candida. Furthermore, potential causal genes located within these loci are enriched for lipid and arachidonic acid metabolism. Using an independent cohort, we also showed that the numbers of risk alleles at these loci are negatively correlated with reactive oxygen species and interleukin-6 levels in response to Candida. Finally, there was a significant correlation between susceptibility and allelic scores based on 16 independent candidemia-associated single-nucleotide polymorphisms that affect monocyte-derived cytokines, but not with T cell-derived cytokines.

Conclusions: Our results prioritize the disturbed lipid homeostasis and oxidative stress as potential mechanisms that affect monocyte-derived cytokines to influence susceptibility to candidemia.
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http://dx.doi.org/10.1093/infdis/jiz206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667794PMC
July 2019

Increased proteinase 3 and neutrophil elastase plasma concentrations are associated with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes.

Mol Med 2019 05 2;25(1):16. Epub 2019 May 2.

Department of Internal Medicine, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Centre, Nijmegen, The Netherlands.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is becoming a major health problem worldwide. Inflammation plays an important role in disease pathogenesis and recent studies have shown a potential role for the neutrophil serine proteases (NSPs) proteinase-3 (PR3) and neutrophil elastase (NE) in NAFLD as well as an imbalance between NSPs and their natural inhibitor alpha-1 antitrypsin (AAT). The aim of this study was to investigate whether PR3 and NE plasma concentrations are associated with NAFLD and/or type 2 diabetes.

Methods: To explore this hypothesis we used several cohorts: a cohort of 271 obese individuals with liver steatosis, a cohort of 41 patients with biopsy-proven NAFLD, a cohort of 401 obese type 2 diabetes patients and a cohort of 205 lean healthy controls; and measured PR3 and NE plasma concentrations. In addition, we measured AAT plasma concentrations in order to investigate if the ratios between NSPs and their natural inhibitor were altered in NAFLD and type 2 diabetes when compared to healthy controls.

Results: Our data shows an increase in PR3 and NE concentrations and a decrease in AAT concentrations in obese patients when compared to controls. Moreover, PR3 plasma concentrations are increased in patients with liver steatosis. Furthermore, PR3 and NE concentrations in the liver are associated with the advanced stages of NAFLD characterized by NASH and/ or liver fibrosis. Additionally, PR3 and NE concentrations were up-regulated in patients with type 2 diabetes when compared to lean and obese controls.

Conclusion: We conclude that circulating levels of NSPs associate with obesity-related metabolic disorders. Further research is needed to clearly establish the role of these proteases and investigate whether they could be used as non-invasive markers for NAFLD and/or type 2 diabetes.
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http://dx.doi.org/10.1186/s10020-019-0084-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498541PMC
May 2019

Gut Microbial Associations to Plasma Metabolites Linked to Cardiovascular Phenotypes and Risk.

Circ Res 2019 06 11;124(12):1808-1820. Epub 2019 Apr 11.

From the Department of Genetics (A.K., L.C., M.J.B., S.S., C.W., A.Z., J.F.), University of Groningen, University Medical Center Groningen, the Netherlands.

Rationale: Altered gut microbial composition has been linked to cardiovascular diseases (CVDs), but its functional links to host metabolism and immunity in relation to CVD development remain unclear.

Objectives: To systematically assess functional links between the microbiome and the plasma metabolome, cardiometabolic phenotypes, and CVD risk and to identify diet-microbe-metabolism-immune interactions in well-documented cohorts.

Methods And Results: We assessed metagenomics-based microbial associations between 231 plasma metabolites and microbial species and pathways in the population-based LLD (Lifelines DEEP) cohort (n=978) and a clinical obesity cohort (n=297). After correcting for age, sex, and body mass index, the gut microbiome could explain ≤11.1% and 16.4% of the variation in plasma metabolites in the population-based and obesity cohorts, respectively. Obese-specific microbial associations were found for lipid compositions in the VLDL, IDL, and LDL lipoprotein subclasses. Bacterial L-methionine biosynthesis and a Ruminococcus species were associated to cardiovascular phenotypes in obese individuals, namely atherosclerosis and liver fat content, respectively. Integration of microbiome-diet-inflammation analysis in relation to metabolic risk score of CVD in the population cohort revealed 48 microbial pathways associated to CVD risk that were largely independent of diet and inflammation. Our data also showed that plasma levels rather than fecal levels of short-chain fatty acids were relevant to inflammation and CVD risk.

Conclusions: This study presents the largest metagenome-based association study on plasma metabolism and microbiome relevance to diet, inflammation, CVD risk, and cardiometabolic phenotypes in both population-based and clinical obesity cohorts. Our findings identified novel bacterial species and pathways that associated to specific lipoprotein subclasses and revealed functional links between the gut microbiome and host health that provide a basis for developing microbiome-targeted therapy for disease prevention and treatment.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.314642DOI Listing
June 2019

Antibody neutralization of microbiota-derived circulating peptidoglycan dampens inflammation and ameliorates autoimmunity.

Nat Microbiol 2019 05 4;4(5):766-773. Epub 2019 Mar 4.

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.

The human microbiota provides tonic signals that calibrate the host immune response, but their identity is unknown. Bacterial peptidoglycan (PGN) subunits are likely candidates since they are well-known immunity-enhancing adjuvants, released by most bacteria during growth, and have been found in the blood of healthy people. We developed a monoclonal antibody (mAb), 2E7, that targets muramyl-L-alanyl-D-isoglutamine (MDP), a conserved and minimal immunostimulatory structure of PGN. Using 2E7-based assays, we detected PGN ubiquitously in human blood at a broad range of concentrations that is relatively stable in each individual. We also detected PGN in the serum of several warm-blooded animals. However, PGN is barely detectable in the serum of germ-free mice, indicating that its origin is the host microbiota. Neutralization of circulating PGN via intraperitoneal administration of 2E7 suppressed the development of autoimmune arthritis and experimental autoimmune encephalomyelitis in mice. Arthritic NOD2 mice lacking the MDP sensor did not respond to 2E7, indicating that 2E7 dampens inflammation by blocking nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-mediated pathways. We propose that circulating PGN acts as a natural immune potentiator that tunes the host immune response; altering its level is a promising therapeutic strategy for immune-mediated diseases.
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http://dx.doi.org/10.1038/s41564-019-0381-1DOI Listing
May 2019

Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases.

Nat Genet 2019 04 18;51(4):600-605. Epub 2019 Feb 18.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

Microbiome-wide association studies on large population cohorts have highlighted associations between the gut microbiome and complex traits, including type 2 diabetes (T2D) and obesity. However, the causal relationships remain largely unresolved. We leveraged information from 952 normoglycemic individuals for whom genome-wide genotyping, gut metagenomic sequence and fecal short-chain fatty acid (SCFA) levels were available, then combined this information with genome-wide-association summary statistics for 17 metabolic and anthropometric traits. Using bidirectional Mendelian randomization (MR) analyses to assess causality, we found that the host-genetic-driven increase in gut production of the SCFA butyrate was associated with improved insulin response after an oral glucose-tolerance test (P = 9.8 × 10), whereas abnormalities in the production or absorption of another SCFA, propionate, were causally related to an increased risk of T2D (P = 0.004). These data provide evidence of a causal effect of the gut microbiome on metabolic traits and support the use of MR as a means to elucidate causal relationships from microbiome-wide association findings.
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http://dx.doi.org/10.1038/s41588-019-0350-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441384PMC
April 2019

Role of Glutamine Metabolism in Host Defense Against Mycobacterium tuberculosis Infection.

J Infect Dis 2019 04;219(10):1662-1670

Department of Internal Medicine, Radboud University Medical Center, Nijmegen.

Background: Rewiring cellular metabolism is important for activation of immune cells during host defense against Mycobacterium tuberculosis. Glutamine has been implicated as an immunomodulatory nutrient, but its role in the response to M. tuberculosis is unknown.

Methods: We assessed expression of glutamine pathway genes in M. tuberculosis-infected macrophages and blood transcriptomic profiles of individuals with latent M. tuberculosis infection or tuberculosis. Subsequently, we studied the effect of blocking glutaminolysis on M. tuberculosis-induced cytokines. Finally, we examined whether polymorphisms in genes involved in the glutamine pathway influence M. tuberculosis-induced cytokines in a cohort of 500 individuals.

Results: Glutamine pathway genes were differentially expressed in infected macrophages and patients with tuberculosis. Human peripheral blood mononuclear cells stimulated with M. tuberculosis displayed decreased cytokine (ie, interleukin 1β, interferon γ, and interleukin 17) responses when medium was devoid of glutamine. Specific inhibitors of the glutamine pathway led to decreased cytokine responses, especially T-cell cytokines (ie, interferon γ, interleukin 17, and interleukin 22). Finally, genetic polymorphisms in glutamine metabolism genes (including GLS2, SLC1A5, and SLC7A5) influenced ex vivo cytokine responses to M. tuberculosis, especially for T-cell cytokines.

Conclusions: Cellular glutamine metabolism is implicated in effective host responses against M. tuberculosis. Targeting immunometabolism may represent new strategies for tuberculosis prevention and/or treatment.
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http://dx.doi.org/10.1093/infdis/jiy709DOI Listing
April 2019

The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity.

Cell Metab 2019 01 4;29(1):211-220.e5. Epub 2018 Oct 4.

Department of Internal Medicine (463) and Radboud Center for Infectious Diseases (RCI), Radboud University Nijmegen Medical Centre, Geert Grooteplein 8, Nijmegen 6500 HB, the Netherlands; Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany; Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Craiova, Romania.

Sepsis involves simultaneous hyperactivation of the immune system and immune paralysis, leading to both organ dysfunction and increased susceptibility to secondary infections. Acute activation of myeloid cells induced itaconate synthesis, which subsequently mediated innate immune tolerance in human monocytes. In contrast, induction of trained immunity by β-glucan counteracted tolerance induced in a model of human endotoxemia by inhibiting the expression of immune-responsive gene 1 (IRG1), the enzyme that controls itaconate synthesis. β-Glucan also increased the expression of succinate dehydrogenase (SDH), contributing to the integrity of the TCA cycle and leading to an enhanced innate immune response after secondary stimulation. The role of itaconate was further validated by IRG1 and SDH polymorphisms that modulate induction of tolerance and trained immunity in human monocytes. These data demonstrate the importance of the IRG1-itaconate-SDH axis in the development of immune tolerance and training and highlight the potential of β-glucan-induced trained immunity to revert immunoparalysis.
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http://dx.doi.org/10.1016/j.cmet.2018.09.003DOI Listing
January 2019

Genetic deficiency of NOD2 confers resistance to invasive aspergillosis.

Nat Commun 2018 07 6;9(1):2636. Epub 2018 Jul 6.

Department of Experimental Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Geert Grooteplein zuid 8, 6525GA, Nijmegen, The Netherlands.

Invasive aspergillosis (IA) is a severe infection that can occur in severely immunocompromised patients. Efficient immune recognition of Aspergillus is crucial to protect against infection, and previous studies suggested a role for NOD2 in this process. However, thorough investigation of the impact of NOD2 on susceptibility to aspergillosis is lacking. Common genetic variations in NOD2 has been associated with Crohn's disease and here we investigated the influence of these  genetic variations on the anti-Aspergillus host response. A NOD2 polymorphism reduced the risk of IA after hematopoietic stem-cell transplantation. Mechanistically, absence of NOD2 in monocytes and macrophages increases phagocytosis leading to enhanced fungal killing, conversely, NOD2 activation reduces the antifungal potential of these cells. Crucially, Nod2 deficiency results in resistance to Aspergillus infection in an in vivo model of pulmonary aspergillosis. Collectively, our data demonstrate that genetic deficiency of NOD2 plays a protective role during Aspergillus infection.
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http://dx.doi.org/10.1038/s41467-018-04912-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035256PMC
July 2018

Integration of multi-omics data and deep phenotyping enables prediction of cytokine responses.

Nat Immunol 2018 07 21;19(7):776-786. Epub 2018 May 21.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

The immune response to pathogens varies substantially among people. Whereas both genetic and nongenetic factors contribute to interperson variation, their relative contributions and potential predictive power have remained largely unknown. By systematically correlating host factors in 534 healthy volunteers, including baseline immunological parameters and molecular profiles (genome, metabolome and gut microbiome), with cytokine production after stimulation with 20 pathogens, we identified distinct patterns of co-regulation. Among the 91 different cytokine-stimulus pairs, 11 categories of host factors together explained up to 67% of interindividual variation in cytokine production induced by stimulation. A computational model based on genetic data predicted the genetic component of stimulus-induced cytokine production (correlation 0.28-0.89), and nongenetic factors influenced cytokine production as well.
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http://dx.doi.org/10.1038/s41590-018-0121-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022810PMC
July 2018

Tissue Metabolic Changes Drive Cytokine Responses to Mycobacterium tuberculosis.

J Infect Dis 2018 06;218(1):165-170

Division of Infection and Immunity, University College London, United Kingdom.

Cellular metabolism can influence host immune responses to Mycobacterium tuberculosis. Using a systems biology approach, differential expression of 292 metabolic genes involved in glycolysis, glutathione, pyrimidine, and inositol phosphate pathways was evident at the site of a human tuberculin skin test challenge in patients with active tuberculosis infection. For 28 metabolic genes, we identified single nucleotide polymorphisms that were trans-acting for in vitro cytokine responses to M. tuberculosis stimulation, including glutathione and pyrimidine metabolism genes that alter production of Th1 and Th17 cytokines. Our findings identify novel therapeutic targets in host metabolism that may shape protective immunity to tuberculosis.
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http://dx.doi.org/10.1093/infdis/jiy173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989606PMC
June 2018

Role of glutathione metabolism in host defense against infection.

Proc Natl Acad Sci U S A 2018 03 14;115(10):E2320-E2328. Epub 2018 Feb 14.

Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands;

Pathogen-induced changes in host cell metabolism are known to be important for the immune response. In this study, we investigated how infection with the Lyme disease-causing bacterium () affects host metabolic pathways and how these metabolic pathways may impact host defense. First, metabolome analysis was performed on human primary monocytes from healthy volunteers, stimulated for 24 h with at low multiplicity of infection (MOI). Pathway analysis indicated that glutathione (GSH) metabolism was the pathway most significantly affected by Specifically, intracellular levels of GSH increased on average 10-fold in response to exposure. Furthermore, these changes were found to be specific, as they were not seen during stimulation with other pathogens. Next, metabolome analysis was performed on serum samples from patients with early-onset Lyme disease in comparison with patients with other infections. Supporting the in vitro analysis, we identified a cluster of GSH-related metabolites, the γ-glutamyl amino acids, specifically altered in patients with Lyme disease, and not in other infections. Lastly, we performed in vitro experiments to validate the role for GSH metabolism in host response against We found that the GSH pathway is essential for -induced cytokine production and identified glutathionylation as a potential mediating mechanism. Taken together, these data indicate a central role for the GSH pathway in the host response to GSH metabolism and glutathionylation may therefore be important factors in the pathogenesis of Lyme disease and potentially other inflammatory diseases as well.
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http://dx.doi.org/10.1073/pnas.1720833115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877983PMC
March 2018

Western Diet Triggers NLRP3-Dependent Innate Immune Reprogramming.

Cell 2018 01;172(1-2):162-175.e14

Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany; Department of Infectious Diseases & Immunology, UMass Medical School, Worcester, MA 01605, USA; Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, 7491 Trondheim, Norway; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany. Electronic address:

Long-term epigenetic reprogramming of innate immune cells in response to microbes, also termed "trained immunity," causes prolonged altered cellular functionality to protect from secondary infections. Here, we investigated whether sterile triggers of inflammation induce trained immunity and thereby influence innate immune responses. Western diet (WD) feeding of Ldlr mice induced systemic inflammation, which was undetectable in serum soon after mice were shifted back to a chow diet (CD). In contrast, myeloid cell responses toward innate stimuli remained broadly augmented. WD-induced transcriptomic and epigenomic reprogramming of myeloid progenitor cells led to increased proliferation and enhanced innate immune responses. Quantitative trait locus (QTL) analysis in human monocytes trained with oxidized low-density lipoprotein (oxLDL) and stimulated with lipopolysaccharide (LPS) suggested inflammasome-mediated trained immunity. Consistently, Nlrp3/Ldlr mice lacked WD-induced systemic inflammation, myeloid progenitor proliferation, and reprogramming. Hence, NLRP3 mediates trained immunity following WD and could thereby mediate the potentially deleterious effects of trained immunity in inflammatory diseases.
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http://dx.doi.org/10.1016/j.cell.2017.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324559PMC
January 2018

BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity.

Cell Host Microbe 2018 Jan;23(1):89-100.e5

Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany. Electronic address:

The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects against non-related infections. The basis of these effects has been poorly explored in humans. In a randomized placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide epigenetic reprograming of monocytes and protected against experimental infection with an attenuated yellow fever virus vaccine strain. Epigenetic reprogramming was accompanied by functional changes indicative of trained immunity. Reduction of viremia was highly correlated with the upregulation of IL-1β, a heterologous cytokine associated with the induction of trained immunity, but not with the specific IFNγ response. The importance of IL-1β for the induction of trained immunity was validated through genetic, epigenetic, and immunological studies. In conclusion, BCG induces epigenetic reprogramming in human monocytes in vivo, followed by functional reprogramming and protection against non-related viral infections, with a key role for IL-1β as a mediator of trained immunity responses.
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http://dx.doi.org/10.1016/j.chom.2017.12.010DOI Listing
January 2018

The NOD2 receptor is crucial for immune responses towards New World Leishmania species.

Sci Rep 2017 11 9;7(1):15219. Epub 2017 Nov 9.

Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.

American Tegumentary Leishmaniasis is a chronic infection caused by Leishmania protozoan. It is not known whether genetic variances in NOD-like receptor (NLR) family members influence the immune response towards Leishmania parasites and modulate intracellular killing. Using functional genomics, we investigated whether genetic variants in NOD1 or NOD2 influence the production of cytokines by human PBMCs exposed to Leishmania. In addition, we examined whether recognition of Leishmania by NOD2 contributes to intracellular killing. Polymorphisms in the NOD2 gene decreased monocyte- and lymphocyte-derived cytokine production after stimulation with L. amazonensis or L. braziliensis compared to individuals with a functional NOD2 receptor. The phagolysosome formation is important for Leishmania-induced cytokine production and upregulation of NOD2 mRNA expression. NOD2 is crucial to control intracellular infection caused by Leishmania spp. NOD2 receptor is important for Leishmania recognition, the control of intracellular killing, and the induction of innate and adaptive immune responses.
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http://dx.doi.org/10.1038/s41598-017-15412-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680260PMC
November 2017

The role of host immune cells and Borrelia burgdorferi antigens in the etiology of Lyme disease.

Eur Cytokine Netw 2017 Jun;28(2):70-84

Radboud University Medical Center, Radboud Center for Infectious Diseases (RCI), Department of Internal Medicine, Nijmegen, The Netherlands.

Lyme disease is a zoonosis caused by infection with bacteria belonging to the Borrelia burgdorferi species after the bite of an infected tick. Even though an infection by this bacterium can be effectively treated with antibiotics, when the infection stays unnoticed B. burgdorferi can persist and chronic post-treatment Lyme disease syndrome is able to develop. Although a cellular and humoral response is observed after an infection with the Borrelia bacteria, these pathogens are still capable to stay alive. Several immune evasive mechanisms have been revealed and explained and much work has been put into the understanding of the contribution of the innate and adaptive immune response. This review provides an overview with the latest findings regarding the cells of the innate and adaptive immune systems, how they recognize contribute and mediate in the killing of the B. burgdorferi spirochete. Moreover, this review also elaborates on the antigens that are expressed by on the spirochete. Since antigens drive the adaptive and, indirectly, the innate response, this review will discuss briefly the most important antigens that are described to date. Finally, there will be a brief elaboration on the escape mechanisms of B. burgdorferi with a focus on tick salivary proteins and spirochete antigens.
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http://dx.doi.org/10.1684/ecn.2017.0396DOI Listing
June 2017

An integrative genomics approach identifies novel pathways that influence candidaemia susceptibility.

PLoS One 2017 20;12(7):e0180824. Epub 2017 Jul 20.

Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.

Candidaemia is a bloodstream infection caused by Candida species that primarily affects specific groups of at-risk patients. Because only small candidaemia patient cohorts are available, classical genome wide association cannot be used to identify Candida susceptibility genes. Therefore, we have applied an integrative genomics approach to identify novel susceptibility genes and pathways for candidaemia. Candida-induced transcriptome changes in human primary leukocytes were assessed by RNA sequencing. Genetic susceptibility to candidaemia was assessed using the Illumina immunochip platform for genotyping of a cohort of 217 patients. We then integrated genetics data with gene-expression profiles, Candida-induced cytokine production capacity, and circulating concentrations of cytokines. Based on the intersection of transcriptome pathways and genomic data, we prioritized 31 candidate genes for candidaemia susceptibility. This group of genes was enriched with genes involved in inflammation, innate immunity, complement, and hemostasis. We then validated the role of MAP3K8 in cytokine regulation in response to Candida stimulation. Here, we present a new framework for the identification of susceptibility genes for infectious diseases that uses an unbiased, hypothesis-free, systems genetics approach. By applying this approach to candidaemia, we identified novel susceptibility genes and pathways for candidaemia, and future studies should assess their potential as therapeutic targets.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180824PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519064PMC
September 2017

Association of NF-κB polymorphisms with clinical outcome of non-medullary thyroid carcinoma.

Endocr Relat Cancer 2017 07 20;24(7):307-318. Epub 2017 Apr 20.

Department of EndocrinologyIuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania

The NF-κB inflammatory pathway plays a major role in cancer development and clinical progression. Activation of NF-κB signaling is promoted by NFKB1 and inhibited by NFKBIA. The present study aimed to determine the relevance of rs4648068 and rs2233406 genetic variants for non-medullary thyroid cancer (NMTC) susceptibility, progression and clinical outcome. This case-control and cohort study consists of a Romanian discovery cohort (157 patients and 258 controls) and a Dutch validation cohort (138 patients and 188 controls). In addition, patient cohorts were analyzed further for the association of genetic variants with clinical parameters. Functional studies were performed on human peripheral blood mononuclear cells. No associations were observed between the studied genetic variants and TC susceptibility. Although no statistically significant associations with clinical parameters were observed for rs4648068, the heterozygous genotype of rs2233406 was correlated with decreased radioactive iodide sensitivity requiring higher cumulative dosages to achieve clinical response. These findings were discovered in the Romanian cohort ( < 0.001) and confirmed in the Dutch cohort ( = 0.01). Functional studies revealed that this rs2233406 genotype was associated with elevated TLR4-mediated IL-1β production. In conclusion, genetic variation in , an inhibitor of NF-κB signaling, is associated with clinical response to RAI therapy and with increased production of the pro-inflammatory cytokine IL-1β, providing a potential mechanism for the observed clinical associations. These data suggest that NF-κB signaling is involved in NMTC pathogenesis and that the inflammatory tumor microenvironment could contribute to RAI resistance.
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http://dx.doi.org/10.1530/ERC-17-0033DOI Listing
July 2017
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