Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Plant Immunity: Thinking Outside and Inside the Box
Burgh, Aranka M. van der; Joosten, Matthieu H.A.J. - \ 2019
Trends in Plant Science 24 (2019)7. - ISSN 1360-1385 - p. 587 - 601.
danger signal - effector-triggered immunity - extracellular immunogenic pattern - intracellular immunogenic pattern - pattern-triggered immunity - plant immunity - spatial immunity model

Models are extensively used to describe the coevolution of plants and microbial attackers. Such models distinguish between different classes of plant immune responses, based on the type of danger signal that is recognized or on the strength of the defense response that the danger signal provokes. However, recent molecular and biochemical advances have shown that these dichotomies are blurred. With molecular proof in hand, we propose here to abandon the current classification of plant immune responses, and to define the different forms of plant immunity solely based on the site of microbe recognition – either extracellular or intracellular. Using this spatial partition, our ‘spatial immunity model’ facilitates a broadly inclusive, but clearly distinguishing nomenclature to describe immune signaling in plant–microbe interactions.

Distant Non-Obvious Mutations Influence the Activity of a Hyperthermophilic Pyrococcusfuriosus Phosphoglucose Isomerase
Subramanian, Kalyanasundaram ; Mitusińska, Karolina ; Raedts, John ; Almourfi, Feras ; Joosten, Henk Jan ; Hendriks, Sjon ; Sedelnikova, Svetlana E. ; Kengen, Servé W.M. ; Hagen, Wilfred R. ; Góra, Artur ; Martins Dos Santos, Vitor A.P. ; Baker, Patrick J. ; Oost, John van der; Schaap, Peter J. - \ 2019
Biomolecules 9 (2019)6.
Comulator - cupin phosphoglucose isomerase - Protein engineering - Pyrococcus furiosus - solvent access

The cupin-type phosphoglucose isomerase (PfPGI) from the hyperthermophilic archaeon Pyrococcus furiosus catalyzes the reversible isomerization of glucose-6-phosphate to fructose-6-phosphate. We investigated PfPGI using protein-engineering bioinformatics tools to select functionally-important residues based on correlated mutation analyses. A pair of amino acids in the periphery of PfPGI was found to be the dominant co-evolving mutation. The position of these selected residues was found to be non-obvious to conventional protein engineering methods. We designed a small smart library of variants by substituting the co-evolved pair and screened their biochemical activity, which revealed their functional relevance. Four mutants were further selected from the library for purification, measurement of their specific activity, crystal structure determination, and metal cofactor coordination analysis. Though the mutant structures and metal cofactor coordination were strikingly similar, variations in their activity correlated with their fine-tuned dynamics and solvent access regulation. Alternative, small smart libraries for enzyme optimization are suggested by our approach, which is able to identify non-obvious yet beneficial mutations.

An EFR-Cf-9 chimera confers enhanced resistance to bacterial pathogens by SOBIR1- and BAK1-dependent recognition of elf18
Wu, Jinbin ; Reca, Ida Barbara ; Spinelli, Francesco ; Lironi, Damiano ; Lorenzo, Giulia De; Poltronieri, Palmiro ; Cervone, Felice ; Joosten, Matthieu H.A.J. ; Ferrari, Simone ; Brutus, Alexandre - \ 2019
Molecular Plant Pathology 20 (2019)6. - ISSN 1464-6722 - p. 751 - 764.
BAK1 - Cf-9 - EFR - pattern recognition receptors - plant innate immunity - R genes - SOBIR1

The transfer of well-studied native and chimeric pattern recognition receptors (PRRs) to susceptible plants is a proven strategy to improve host resistance. In most cases, the ectodomain determines PRR recognition specificity, while the endodomain determines the intensity of the immune response. Here we report the generation and characterization of the chimeric receptor EFR-Cf-9, which carries the ectodomain of the Arabidopsis thaliana EF-Tu receptor (EFR) and the endodomain of the tomato Cf-9 resistance protein. Both transient and stable expression of EFR-Cf-9 triggered a robust hypersensitive response (HR) upon elf18 treatment in tobacco. Co-immunoprecipitation and virus-induced gene silencing studies showed that EFR-Cf-9 constitutively interacts with SUPPRESSOR OF BIR1-1 (SOBIR1) co-receptor, and requires both SOBIR1 and kinase-active BRI1-ASSOCIATED KINASE1 (BAK1) for its function. Transgenic plants expressing EFR-Cf-9 were more resistant to the (hemi)biotrophic bacterial pathogens Pseudomonas amygdali pv. tabaci (Pta) 11528 and Pseudomonas syringae pv. tomato DC3000, and mounted an HR in response to high doses of Pta 11528 and P. carotovorum. Taken together, these data indicate that the EFR-Cf-9 chimera is a valuable tool for both investigating the molecular mechanisms responsible for the activation of defence responses by PRRs, and for potential biotechnological use to improve crop disease resistance.

Effecten van ammoniak reducerende maatregelen in bedrijfsverband : Scenariostudie voor proeftuin Natura 2000 in veenweidegebied
Evers, Aart ; Haan, Michel de; Migchels, Gerard ; Joosten, Leo ; Leeuwen, Marieke van - \ 2019
Wageningen : Wageningen Livestock Research (Wageningen Livestock Research rapport 1161) - 32
Voor een intensief en extensief melkveebedrijf op veengrond zijn verschillende ammoniak reducerende maatregelen doorgerekend. Het uitkopen van bedrijven om de ammoniakuitstoot te verminderen brengt grote kosten met zich mee. Een andere mogelijkheid om de ammoniakuitstoot te verminderen is het aanpassen van de stal. Stalaanpassingen leiden over het algemeen tot een forse reductie van de ammoniakuitstoot, maar ook tot een aanzienlijke daling van het inkomen. Veelal zijn managementmaatregelen kosten-effectiever en in veel gevallen leiden ze zelfs tot een verbetering van het inkomen. Wanneer maatregelen gecombineerd worden, kan de ammoniakuitstoot verminderd worden met maximaal 40 tot 50% zonder dat dit grote negatieve gevolgen voor het inkomen heeft.
Quantitative and qualitative analysis of antimicrobial usage at farm and flock level on 181 broiler farms in nine European countries
Joosten, Philip ; Sarrazin, Steven ; Gompel, Liese Van; Luiken, Roosmarijn E.C. ; Mevius, Dik J. ; Wagenaar, Jaap A. ; Heederik, Dick J.J. ; Dewulf, Jeroen - \ 2019
Journal of Antimicrobial Chemotherapy 74 (2019)3. - ISSN 0305-7453 - p. 798 - 806.

OBJECTIVES: To control the emerging threat of antimicrobial resistance, international policy appeals for appropriate monitoring of antimicrobial usage (AMU) at supranational, species and farm level. The aim of this study was to quantify AMU in broilers at farm and flock level in nine European countries. METHODS: Antimicrobial treatment data of one flock and purchased antimicrobials over one year were collected at 181 European broiler farms. Afterwards AMU was quantified using treatment incidence (TI) per 100 days based on Defined Daily Dose (DDDvet), Defined Course Dose (DCDvet) or Used Daily Dose (UDDvet) values. Total AMU at flock level was obtained by summing the TIDDDvet of all treatments in the sampled flock (TIDDDvetFl*). RESULTS: The median TIDDDvetFl* was 9.0 (95% CI 5.5-10.8), meaning that broilers were treated with antimicrobials during 9% of their rearing period. TIDDDvetFl* varied considerably within and between countries. However, in every country at least one untreated flock was present. Average TIDDDvetFl* at country level ranged from 3.3 to 36.7. Polymyxins, extended-spectrum aminopenicillins and fluoroquinolones were the most used antimicrobials, accounting for 26%, 26% and 18% of total AMU, respectively. Twenty-six percent of the farms started a treatment on day 1 of production, and 49% of overall AMU was administered within the first week. CONCLUSIONS: Results show that rearing broilers without AMU is feasible. However, a huge variation in AMU in terms of amount, moment of administration and antimicrobial classes was observed. This shows that there is still ground to be covered when it comes to AMU on broiler farms.

Quantitative and qualitative analysis of antimicrobial usage patterns in 180 selected farrow-to-finish pig farms from nine European countries based on single batch and purchase data
Sarrazin, Steven ; Joosten, Philip ; Gompel, Liese Van; Luiken, Roosmarijn E.C. ; Mevius, Dik J. ; Wagenaar, Jaap A. ; Heederik, Dick J.J. ; Dewulf, Jeroen - \ 2019
Journal of Antimicrobial Chemotherapy 74 (2019)3. - ISSN 0305-7453 - p. 807 - 816.

OBJECTIVES: Farm-level quantification of antimicrobial usage (AMU) in pig farms. METHODS: In a cross-sectional study, AMU data on group treatments administered to a single batch of fattening pigs from birth to slaughter (group treatment data) and antimicrobials purchased during 1 year (purchase data) were collected at 180 pig farms in nine European countries. AMU was quantified using treatment incidence (TI) based on defined (DDDvet) and used (UDDvet) daily doses and defined (DCDvet) and used (UCDvet) course doses. RESULTS: The majority of antimicrobial group treatments were administered to weaners (69.5% of total TIDDDvet) followed by sucklers (22.5% of total TIDDDvet). AMU varied considerably between farms with a median TIDDDvet of 9.2 and 7.1 for a standardized rearing period of 200 days based on group treatment and purchase data, respectively. In general, UDDvet and UCDvet were higher than DDDvet and DCDvet, respectively, suggesting that either the defined doses were set too low or that group treatments were often dosed too high and/or administered for too long. Extended-spectrum penicillins (31.2%) and polymyxins (24.7%) were the active substances most often used in group treatments, with the majority administered through feed or water (82%). Higher AMU at a young age was associated with higher use in older pigs. CONCLUSIONS: Collecting farm-level AMU data of good quality is challenging and results differ based on how data are collected (group treatment data versus purchase data) and reported (defined versus used daily and course doses).

Unravelling the diversity and distribution of the soybean rust fungus Phakopsora pachyrhizi in East Africa
Murithi, Harun Muthuri - \ 2019
Wageningen University. Promotor(en): Bart Thomma, co-promotor(en): Matthieu Joosten; H.P. van Esse; G. Mahuku. - Wageningen : Wageningen University - ISBN 9789463434225 - 193
Kinase activity of SOBIR1 and BAK1 is required for immune signalling
Burgh, Aranka M. Van Der; Postma, Jelle ; Robatzek, Silke ; Joosten, Matthieu H.A.J. - \ 2019
Molecular Plant Pathology 20 (2019)3. - ISSN 1464-6722 - p. 410 - 422.
BAK1/SERK3 - Cf-4 - immunity - phosphorylation - RLK - RLP - SOBIR1

Leucine-rich repeat-receptor-like proteins (LRR-RLPs) and LRR-receptor-like kinases (LRR-RLKs) trigger immune signalling to promote plant resistance against pathogens. LRR-RLPs lack an intracellular kinase domain, and several of these receptors have been shown to constitutively interact with the LRR-RLK Suppressor of BIR1-1/EVERSHED (SOBIR1/EVR) to form signalling-competent receptor complexes. Ligand perception by LRR-RLPs initiates recruitment of the co-receptor BRI1-Associated Kinase 1/Somatic Embryogenesis Receptor Kinase 3 (BAK1/SERK3) to the LRR-RLP/SOBIR1 complex, thereby activating LRR-RLP-mediated immunity. We employed phosphorylation analysis of in planta-produced proteins, live cell imaging, gene silencing and co-immunoprecipitation to investigate the roles of SOBIR1 and BAK1 in immune signalling. We show that Arabidopsis thaliana (At) SOBIR1, which constitutively activates immune responses when overexpressed in planta, is highly phosphorylated. Moreover, in addition to the kinase activity of SOBIR1 itself, kinase-active BAK1 is essential for AtSOBIR1-induced constitutive immunity and for the phosphorylation of AtSOBIR1. Furthermore, the defence response triggered by the tomato LRR-RLP Cf-4 on perception of Avr4 from the extracellular pathogenic fungus Cladosporium fulvum is dependent on kinase-active BAK1. We argue that, in addition to the trans-autophosphorylation of SOBIR1, it is likely that SOBIR1 and BAK1 transphosphorylate, and thereby activate the receptor complex. The signalling-competent cell surface receptor complex subsequently activates downstream cytoplasmic signalling partners to initiate RLP-mediated immunity.

Effects of oral butyrate supplementation on inflammatory potential of circulating peripheral blood mononuclear cells in healthy and obese males
Cleophas, Maartje C.P. ; Ratter, Jacqueline M. ; Bekkering, Siroon ; Quintin, Jessica ; Schraa, Kiki ; Stroes, Erik S. ; Netea, Mihai G. ; Joosten, Leo A.B. - \ 2019
Scientific Reports 9 (2019). - ISSN 2045-2322

Sodium butyrate is well-known for its immune-modulatory properties. Studies until now only focused on the in vitro effects of butyrate or assessed local effects in the gut upon butyrate administration. In this trial, we studied the systemic anti-inflammatory effects induced by sodium butyrate supplementation in humans. Nine healthy (Lean) and ten obese (metabolic syndrome group, MetSyn) males were given 4 grams sodium butyrate daily for 4 weeks. PBMCs were isolated before and after supplementation for direct stimulation experiments and induction of trained immunity by oxidized low-density lipoprotein (oxLDL), β-glucan, or Bacillus Calmette-Guérin vaccine (BCG). Butyrate supplementation moderately affected some of the cytokine responses in the MetSyn group. In the direct stimulation setup, effects of butyrate supplementation were limited. Interestingly, butyrate supplementation decreased oxLDL-induced trained immunity in the MetSyn group for LPS-induced IL-6 responses and Pam3CSK4-induced TNF-α responses. Induction of trained immunity by β-glucan was decreased by butyrate in the MetSyn group for Pam3CSK4-induced IL-10 production. In this study, while having only limited effects on the direct stimulation of cytokine production, butyrate supplementation significantly affected trained immunity in monocytes of obese individuals with metabolic complications. Therefore, oral butyrate supplementation may be beneficial in reducing the overall inflammatory status of circulating monocytes in patients with metabolic syndrome.

Referenties en maatlatten voor natuurlijke watertypen voor de Kaderrichtlijn Water 2021-2027
Altenburg, W. ; Arts, G. ; Baretta-Bekker, J.G. ; Berg, M.S. van den; Broek Broek, T. van den; Buskens, R. ; Bijkerk, R. ; Coops, H.C. ; Dam, H. van; Ee, G. van; Evers, C.H.M. ; Franken, R. ; Higler, B. ; Ietswaart, T. ; Jaarsma, N. ; Jong, D.J. de; Joosten, A.M.T. ; Klinge, M. ; Knoben, R.A.E. ; Kranenbarg, J. ; Loon, W.M.G.M. van; Noordhuis, R. ; Pot, R. ; Twisk, F. ; Verdonschot, P.F.M. ; Vlek, H. ; Backx, J.J.G.M. ; Beers, M. ; Buijse, A.D. ; Duursema, G. ; Fagel, M. ; Leeuw, J. de; Molen, J. van der; Nijboer, R.C. ; Postma, J. ; Vriese, T. ; Duijts, R. ; Hartholt, J.G. ; Jager, Z. ; Stikvoort, E.C. ; Walvoort, D. - \ 2018
Amersfoort : Stowa (Stowa rapport 2018-49) - ISBN 9789057738135 - 481
Viable coxiella burnetii induces differential cytokine responses in chronic Q fever patients compared to Heat-Killed Coxiella burnetii
Jansen, Anne F.M. ; Dinkla, Annemieke ; Roest, Hendrik Jan ; Bleeker-Rovers, Chantal P. ; Schoffelen, Teske ; Joosten, Leo A.B. ; Wever, Peter C. ; Deuren, Marcel van; Koets, Ad P. - \ 2018
Infection and Immunity 86 (2018)10. - ISSN 0019-9567
Chronic Q fever - Coxiella burnetii - Cytokines - Immune response

Cytokine responses of chronic Q fever patients to the intracellular bacterium Coxiella burnetii have mostly been studied using ex vivo stimulation of immune cells with heat-killed C. burnetii due to the extensive measures needed to work with viable biosafety level 3 agents. Whether research with heat-killed C. burnetii can be translated to immune responses to viable C. burnetii is imperative for the interpretation of previous and future studies with heat-killed C. burnetii. Peripheral blood mononuclear cells (PBMCs) of chronic Q fever patients (n = 10) and healthy controls (n = 10) were stimulated with heat-killed or viable C. burnetii of two strains, Nine Mile and the Dutch outbreak strain 3262, for 24 h, 48 h, and 7 days in the absence or presence of serum containing anti-C. burnetii antibodies. When stimulated with viable C. burnetii, PBMCs of chronic Q fever patients and controls produced fewer proinflammatory cytokines (interleukin-6 [IL-6], tumor necrosis factor alpha, and IL-1β) after 24 h than after stimulation with heat-killed C. burnetii. In the presence of Q fever seronegative serum, IL-10 production was higher after stimulation with viable rather than heat-killed C. burnetii; however, when incubating with anti-C. burnetii antibody serum, the effect on IL-10 production was reduced. Levels of adaptive, merely T-cell-derived cytokine (gamma interferon, IL-17, and IL-22) and CXCL9 production were not different between heat-killed and viable C. burnetii stimulatory conditions. Results from previous and future research with heat-killed C. burnetii should be interpreted with caution for innate cytokines, but heat-killed C. burnetii-induced adaptive cytokine production is representative of stimulation with viable bacteria.

Distinct Roles of Non-Overlapping Surface Regions of the Coiled-Coil Domain in the Potato Immune Receptor Rx1
Slootweg, Erik J. ; Spiridon, Laurentiu N. ; Martin, Eliza C. ; Tameling, Wladimir I.L. ; Townsend, Philip D. ; Pomp, Rikus ; Roosien, Jan ; Drawska, Olga ; Sukarta, Octavina C.A. ; Schots, Arjen ; Borst, Jan Willem ; Joosten, Matthieu H.A.J. ; Bakker, Jaap ; Smant, Geert ; Cann, Martin J. ; Petrescu, Andrei-Jose ; Goverse, Aska - \ 2018
Plant Physiology 178 (2018)3. - ISSN 0032-0889 - p. 1310 - 1331.
The intracellular immune receptor Rx1 of potato (Solanum tuberosum), which confers effector-triggered immunity to Potato virus X, consists of a central nucleotide-binding domain (NB-ARC) flanked by a carboxyl-terminal leucine-rich repeat (LRR) domain and an amino-terminal coiled-coil (CC) domain. Rx1 activity is strictly regulated by interdomain interactions between the NB-ARC and LRR, but the contribution of the CC domain in regulating Rx1 activity or immune signaling is not fully understood. Therefore, we used a structure-informed approach to investigate the role of the CC domain in Rx1 functionality.
Targeted mutagenesis of CC surface residues revealed separate regions required for the intramolecular and intermolecular interaction of the CC with the NB-ARC-LRR and the cofactor Ran GTPase-activating protein2 (RanGAP2), respectively. None of the mutant Rx1 proteins was constitutively active, indicating that the CC does not contribute to the autoinhibition of Rx1 activity. Instead, the CC domain acted as a modulator of downstream responses involved in effector-triggered immunity. Systematic disruption of the hydrophobic interface between the four helices of the CC enabled the uncoupling of cell death and disease resistance responses. Moreover, a strong dominant negative effect on Rx1-mediated resistance and cell death was observed upon coexpression of the CC alone with full-length Rx1 protein, which depended on the RanGAP2-binding surface of the CC. Surprisingly, coexpression of the N-terminal half of the CC enhanced Rx1-mediated resistance, which further indicated that the CC functions as a scaffold for downstream components involved in the modulation of disease resistance or cell death signaling.
Induction of trained innate immunity in human monocytes by bovine milk and milk-derived immunoglobulin G
Splunter, Marloes van; Osch, Thijs L.J. van; Brugman, Sylvia ; Savelkoul, Huub F.J. ; Joosten, Leo A.B. ; Netea, Mihai G. ; Neerven, R.J.J. van - \ 2018
Nutrients 10 (2018)10. - ISSN 2072-6643
Bovine IgG - Bovine lactoferrin - Dietary compounds - Innate immune memory - Monocytes - Raw bovine milk - Trained immunity

Innate immune memory, also termed “trained immunity” in vertebrates, has been recently described in a large variety of plants and animals. In most cases, trained innate immunity is induced by pathogens or pathogen-associated molecular patterns (PAMPs), and is associated with long-term epigenetic, metabolic, and functional reprogramming. Interestingly, recent findings indicate that food components can mimic PAMPs effects and induce trained immunity. The aim of this study was to investigate whether bovine milk or its components can induce trained immunity in human monocytes. To this aim, monocytes were exposed for 24 h to β-glucan, Toll-like receptor (TLR)-ligands, bovine milk, milk fractions, bovine lactoferrin (bLF), and bovine Immunoglobulin G (bIgG). After washing away the stimulus and a resting period of five days, the cells were re-stimulated with TLR ligands and Tumor necrosis factor (TNF-) and interleukin (IL)-6 production was measured. Training with β-glucan resulted in higher cytokine production after TLR1/2, TLR4, and TLR7/8 stimulation. When monocytes trained with raw milk were re-stimulated with TLR1/2 ligand Pam3CSK4, trained cells produced more IL-6 compared to non-trained cells. Training with bIgG resulted in higher cytokine production after TLR4 and TLR7/8 stimulation. These results show that bovine milk and bIgG can induce trained immunity in human monocytes. This confirms the hypothesis that diet components can influence the long-term responsiveness of the innate immune system.

SOBIR1-containing immune complexes at the plant cell surface: partners and signalling
Burgh, Aranka Margrethe van der - \ 2018
Wageningen University. Promotor(en): Bart Thomma, co-promotor(en): Matthieu Joosten. - Wageningen : Wageningen University - ISBN 9789463433136 - 247
Towards microbial safety of fresh vegetables in Rwanda
Ssemanda, James Noah - \ 2018
Wageningen University. Promotor(en): Marcel Zwietering; Han Joosten, co-promotor(en): Martine Reij. - Wageningen : Wageningen University - ISBN 9789463437936 - 213
The ELR-SOBIR1 complex functions as a two-component receptor-like Kinase to mount defense against phytophthora infestans
Domazakis, Emmanouil ; Wouters, Doret ; Visser, Richard G.F. ; Kamoun, Sophien ; Joosten, Matthieu H.A.J. ; Vleeshouwers, Vivianne G.A.A. - \ 2018
Molecular Plant-Microbe Interactions 31 (2018)8. - ISSN 0894-0282 - p. 795 - 802.

The ELICITIN RESPONSE protein (ELR) from Solanum microdontum can recognize INF1 elicitin of Phytophthora infestans and trigger defense responses. ELR is a receptor-like protein (RLP) that lacks a cytoplasmic signaling domain and is anticipated to require interaction with a signaling-competent receptor-like kinase. SUPPRESSOR OF BIR1-1 (SOBIR1) has been proposed as a general interactor for RLPs involved in immunity and, as such, is a potential interactor for ELR. Here, we investigate whether SOBIR1 is required for response to INF1 and resistance to P. infestans and whether it associates with ELR. Our results show that virus-induced gene silencing of SOBIR1 in Nicotiana benthamiana leads to loss of INF1-triggered cell death and increased susceptibility to P. infestans. Using genetic complementation, we found that the kinase activity of SOBIR1 is required for INF1-triggered cell death. Coimmunoprecipitation experiments showed that ELR constitutively associates with potato SOBIR1 in planta, forming a bipartite receptor complex. Upon INF1 elicitation, this ELR-SOBIR1 complex recruits SERK3 (SOMATIC EMBRYOGENESIS RECEPTOR KINASE 3) leading to downstream signaling activation. Overall, our study shows that SOBIR1 is required for basal resistance to P. infestans and for INF1-triggered cell death and functions as an adaptor kinase for ELR.

Tissue Metabolic Changes Drive Cytokine Responses to Mycobacterium tuberculosis
Lachmandas, Ekta ; Rios-Miguel, Ana B. ; Koeken, Valerie A.C.M. ; Pasch, Eva van der; Kumar, Vinod ; Matzaraki, Vasiliki ; Li, Yang ; Oosting, Marije ; Joosten, Leo A.B. ; Notebaart, Richard A. ; Noursadeghi, Mahdad ; Netea, Mihai G. ; Crevel, Reinout van; Pollara, Gabriele - \ 2018
The Journal of Infectious Diseases 218 (2018)1. - ISSN 0022-1899 - p. 165 - 170.
cytokines - functional genomics - human challenge model - immune response - immunometabolism - metabolism - microarrays - transcriptomics - tuberculosis

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.

A role for TLR10 in obesity and adipose tissue morphology
Boutens, Lily ; Mirea, Andreea Manuela ; Munckhof, Inge van den; Doppenberg-Oosting, Marije ; Jaeger, Martin ; Hijmans, Anneke ; Netea, Mihai G. ; Joosten, Leo A.B. ; Stienstra, Rinke - \ 2018
Cytokine 108 (2018). - ISSN 1043-4666 - p. 205 - 212.
Adipose tissue - Inflammation - Obesity - SNPs - TLR10
Toll like receptors (TLRs) are expressed in adipose tissue and promote adipose tissue inflammation during obesity. Recently, anti-inflammatory properties have been attributed to TLR10 in myeloid cells, the only member of the TLR family with inhibitory activity. In order to assess whether TLR10-induced inhibition of inflammation may be protective during the development of obesity and metabolic abnormalities we used transgenic human TLR10 mice (hTLR10tg) and wild type (WT) controls on a C57B6J background. HFD-feeding enhanced TLR10 expression in the adipose tissue, and HFD-fed hTLR10tg mice displayed reduced adipocyte size, adipose tissue weight, and a trend toward lower plasma insulin levels compared to WT mice. In humans, obese individuals with polymorphisms in the TLR10 gene displayed reduced macrophage infiltration in the adipose tissue accompanied by a trend to lower leptin levels and higher adiponectin levels in plasma. In healthy individuals with the same polymorphisms in the TLR10 gene we did not observe any difference in plasma concentrations of leptin and adiponectin. We conclude that TLR10 impacts adipose tissue morphology in obesity. Larger studies in humans are warranted to assess its potential value as therapeutic target in metabolic syndrome and type 2 diabetes.
Estimates of the burden of illnesses related to foodborne pathogens as from the syndromic surveillance data of 2013 in Rwanda
Ssemanda, James Noah ; Reij, Martine W. ; Bagabe, Mark Cyubahiro ; Muvunyi, Claude Mambo ; Nyamusore, José ; Joosten, Han ; Zwietering, Marcel H. - \ 2018
Microbial Risk Analysis 9 (2018). - ISSN 2352-3522 - p. 55 - 63.
DALY - Developing countries - Foodborne diseases - Rwanda - Syndromic surveillance
Food related illnesses contribute significantly to the global burden of disease and the estimates of these illnesses are important to develop evidence based food safety policies. However estimating the burden of these illnesses is complex. There is paucity of input data, and developing and sustaining disease surveillance systems that provide the input data is resource-intensive. In most developing countries with relative peace, the initial, faster and cheaper kind of health data is generated through syndromic surveillance. In this study, we estimated the burden of food related clinical features and illnesses (watery diarrhea, bloody diarrhea, suspected cases of cholera and typhoid fever) by making use of various syndromic surveillance data sources in Rwanda. Data sources were the reported cases as by the notifiable surveillance system, an opinion survey with health care providers about the prevalence of clinical features related to foodborne pathogens and over the counter prescription of drugs associated with foodborne illnesses. Study findings indicate that for the year 2013, watery diarrhea occurred all year round as by the surveillance system data, resulting to an estimated 672 (95% credible interval [CrI] 424-932) DALY per million inhabitants, bloody diarrhea was seasonal coinciding with the rainy months and caused an estimated 213 (95% CrI 50-475) DALY per million, typhoid and cholera cases were sporadic with an estimated 73 (95% CrI 57-91) and 1 (95% CrI 0-2) DALY per million respectively. Our DALY estimates from the different data sources were in the same range for combined cases of watery diarrhea, bloody diarrhea and cholera, but significantly different for typhoid fever. The methodology applied in this study can be adopted in resource-scarce settings where most data is from syndromic surveillance (a common phenomenon in most developing countries) other than the desired integrated food chain and laboratory-based surveillance systems, to pave way for future improved estimates of the burden of foodborne illnesses.
Effect of vegan fecal microbiota transplantation on carnitine- and choline-derived trimethylamine-N-oxide production and vascular inflammation in patients with metabolic syndrome
Smits, Loek P. ; Kootte, Ruud S. ; Levin, Evgeni ; Prodan, Andrei ; Fuentes, Susana ; Zoetendal, Erwin G. ; Wang, Zeneng ; Levison, Bruce S. ; Cleophas, Maartje C.P. ; Kemper, E.M. ; Dallinga-Thie, Geesje M. ; Groen, Albert K. ; Joosten, Leo A.B. ; Netea, Mihai G. ; Stroes, Erik S.G. ; Vos, Willem M. de; Hazen, Stanley L. ; Nieuwdorp, Max - \ 2018
Journal of the American Heart Association 7 (2018)7. - ISSN 2047-9980
Atherosclerosis - Cardiovascular disease - Cardiovascular imaging - Inflammation - Metabolism
Background--Intestinal microbiota have been found to be linked to cardiovascular disease via conversion of the dietary compounds choline and carnitine to the atherogenic metabolite TMAO (trimethylamine-N-oxide). Specifically, a vegan diet was associated with decreased plasma TMAO levels and nearly absent TMAO production on carnitine challenge. Methods and Results--We performed a double-blind randomized controlled pilot study in which 20 male metabolic syndrome patients were randomized to single lean vegan-donor or autologous fecal microbiota transplantation. At baseline and 2 weeks thereafter, we determined the ability to produce TMAO from d6-choline and d3-carnitine (eg, labeled and unlabeled TMAO in plasma and 24-hour urine after oral ingestion of 250 mg of both isotope-labeled precursor nutrients), and fecal samples were collected for analysis of microbiota composition. 18F-fluorodeoxyglucose positron emission tomography/computed tomography scans of the abdominal aorta, as well as ex vivo peripheral blood mononuclear cell cytokine production assays, were performed. At baseline, fecal microbiota composition differed significantly between vegans and metabolic syndrome patients. With vegan-donor fecal microbiota transplantation, intestinal microbiota composition in metabolic syndrome patients, as monitored by global fecal microbial community structure, changed toward a vegan profile in some of the patients; however, no functional effects from vegan-donor fecal microbiota transplantation were seen on TMAO production, abdominal aortic 18Ffluorodeoxyglucose uptake, or ex vivo cytokine production from peripheral blood mononuclear cells. Conclusions--Single lean vegan-donor fecal microbiota transplantation in metabolic syndrome patients resulted in detectable changes in intestinal microbiota composition but failed to elicit changes in TMAO production capacity or parameters related to vascular inflammation.
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