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Dive into the research topics where Ekta Lachmandas is active.

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Featured researches published by Ekta Lachmandas.


Nature Immunology | 2016

Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis

Shih-Chin Cheng; Brendon P. Scicluna; Rob J.W. Arts; Mark S. Gresnigt; Ekta Lachmandas; Evangelos J. Giamarellos-Bourboulis; Matthijs Kox; Ganesh R. Manjeri; Jori A.L. Wagenaars; Olaf L. Cremer; Jenneke Leentjens; Anne Jan van der Meer; Frank L. van de Veerdonk; Marc J. M. Bonten; Marcus J. Schultz; Peter H. G. M. Willems; Peter Pickkers; Leo A. B. Joosten; Tom van der Poll; Mihai G. Netea

The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in some patients, immunoparalysis may be encountered, which is associated with a poor outcome. By transcriptional and metabolic profiling of human patients with sepsis, we found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense. Blocking metabolic pathways with metformin diminished cytokine production and increased mortality in systemic fungal infection in mice. In contrast, in leukocytes rendered tolerant by exposure to lipopolysaccharide or after isolation from patients with sepsis and immunoparalysis, a generalized metabolic defect at the level of both glycolysis and oxidative metabolism was apparent, which was restored after recovery of the patients. Finally, the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-γ, which suggested that metabolic processes might represent a therapeutic target in sepsis.


Cell Metabolism | 2016

Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity

Rob J.W. Arts; Boris Novakovic; Rob ter Horst; Agostinho Carvalho; Siroon Bekkering; Ekta Lachmandas; Fernando Rodrigues; Ricardo Silvestre; Shih-Chin Cheng; Shuang-Yin Wang; Ehsan Habibi; Luís G. Gonçalves; Inês Mesquita; Cristina Cunha; Arjan van Laarhoven; Frank L. van de Veerdonk; David L. Williams; Jos W. M. van der Meer; Colin Logie; Luke A. J. O'Neill; Charles A. Dinarello; Niels P. Riksen; Reinout van Crevel; Clary B. Clish; Richard A. Notebaart; Leo A. B. Joosten; Hendrik G. Stunnenberg; Ramnik J. Xavier; Mihai G. Netea

Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by β-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to β-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by β-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues.


Cell Reports | 2016

Immunometabolic Pathways in BCG-Induced Trained Immunity

Rob J.W. Arts; Agostinho Carvalho; Claudia La Rocca; Fernando Rodrigues; Ricardo Silvestre; Johanneke Kleinnijenhuis; Ekta Lachmandas; Luís G. Gonçalves; Cristina Cunha; Marije Oosting; Leo A. B. Joosten; Giuseppe Matarese; Reinout van Crevel; Mihai G. Netea

Summary The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as monocytes, a process termed trained immunity. Here, we show that BCG induction of trained immunity in monocytes is accompanied by a strong increase in glycolysis and, to a lesser extent, glutamine metabolism, both in an in-vitro model and after vaccination of mice and humans. Pharmacological and genetic modulation of rate-limiting glycolysis enzymes inhibits trained immunity, changes that are reflected by the effects on the histone marks (H3K4me3 and H3K9me3) underlying BCG-induced trained immunity. These data demonstrate that a shift of the glucose metabolism toward glycolysis is crucial for the induction of the histone modifications and functional changes underlying BCG-induced trained immunity. The identification of these pathways may be a first step toward vaccines that combine immunological and metabolic stimulation.


Nature microbiology | 2017

Microbial stimulation of different Toll-like receptor signalling pathways induces diverse metabolic programmes in human monocytes

Ekta Lachmandas; Lily Boutens; Jacqueline M. Ratter; Anneke Hijmans; Guido Hooiveld; Leo A. B. Joosten; Richard J. Rodenburg; Jack A. M. Fransen; Riekelt H. Houtkooper; Reinout van Crevel; Mihai G. Netea; Rinke Stienstra

Microbial stimuli such as lipopolysaccharide (LPS) induce robust metabolic rewiring in immune cells known as the Warburg effect. It is unknown whether this increase in glycolysis and decrease in oxidative phosphorylation (OXPHOS) is a general characteristic of monocytes that have encountered a pathogen. Using CD14+ monocytes from healthy donors, we demonstrated that most microbial stimuli increased glycolysis, but that only stimulation of Toll-like receptor (TLR) 4 with LPS led to a decrease in OXPHOS. Instead, activation of other TLRs, such as TLR2 activation by Pam3CysSK4 (P3C), increased oxygen consumption and mitochondrial enzyme activity. Transcriptome and metabolome analysis of monocytes stimulated with P3C versus LPS confirmed the divergent metabolic responses between both stimuli, and revealed significant differences in the tricarboxylic acid cycle, OXPHOS and lipid metabolism pathways following stimulation of monocytes with P3C versus LPS. At a functional level, pharmacological inhibition of complex I of the mitochondrial electron transport chain diminished cytokine production and phagocytosis in P3C- but not LPS-stimulated monocytes. Thus, unlike LPS, complex microbial stimuli and the TLR2 ligand P3C induce a specific pattern of metabolic rewiring that involves upregulation of both glycolysis and OXPHOS, which enables activation of host defence mechanisms such as cytokine production and phagocytosis.


Infection and Immunity | 2013

Low Induction of Proinflammatory Cytokines Parallels Evolutionary Success of Modern Strains within the Mycobacterium tuberculosis Beijing Genotype

Arjan van Laarhoven; Jornt J. Mandemakers; Johanneke Kleinnijenhuis; M. Enaimi; Ekta Lachmandas; Leo A. B. Joosten; Tom H. M. Ottenhoff; Mihai G. Netea; Dick van Soolingen; Reinout van Crevel

ABSTRACT One of the most widespread clades of Mycobacterium tuberculosis worldwide, the Beijing genotype family, consists of ancient (atypical) and modern (typical) strains. Modern Beijing strains outcompete ancient strains in terms of prevalence, while reserving a higher degree of genetic conservation. We hypothesize that their selective advantage lies in eliciting a different host immune response. Bead-disrupted lysates of a collection of different M. tuberculosis strains of the modern (n = 7) or ancient (n = 7) Beijing genotype, as well as the Euro-American lineage (n = 6), were used for induction of ex vivo cytokine production in peripheral blood mononuclear cells (PBMCs) from 10 healthy individuals. Hierarchical clustering and multivariate regression analyses were used to study possible differences in production of nine cytokines. Modern and ancient M. tuberculosis Beijing genotypes induced different cytokine signatures. Overall induction of interleukin-1β (IL-1β), gamma interferon (IFN-γ), and IL-22 was 38 to 40% lower after stimulation with modern Beijing strains (corrected P values of <0.0001, 0.0288, and 0.0002, respectively). Euro-American reactivation strains induced 2-fold more TNF-α production than both types of Beijing strains. The observed differences in cytokine induction point to a reduction in proinflammatory cytokine response as a possible contributing factor to the evolutionary success of modern Beijing strains.


Experimental Diabetes Research | 2016

Diabetes Mellitus and Increased Tuberculosis Susceptibility: The Role of Short-Chain Fatty Acids

Ekta Lachmandas; Corina N. A. M. van den Heuvel; Michelle S.M.A. Damen; Mihai G. Netea; Reinout van Crevel

Type 2 diabetes mellitus confers a threefold increased risk for tuberculosis, but the underlying immunological mechanisms are still largely unknown. Possible mediators of this increased susceptibility are short-chain fatty acids, levels of which have been shown to be altered in individuals with diabetes. We examined the influence of physiological concentrations of butyrate on cytokine responses to Mycobacterium tuberculosis (Mtb) in human peripheral blood mononuclear cells (PBMCs). Butyrate decreased Mtb-induced proinflammatory cytokine responses, while it increased production of IL-10. This anti-inflammatory effect was independent of butyrates well-characterised inhibition of HDAC activity and was not accompanied by changes in Toll-like receptor signalling pathways, the eicosanoid pathway, or cellular metabolism. In contrast blocking IL-10 activity reversed the effects of butyrate on Mtb-induced inflammation. Alteration of the gut microbiota, thereby increasing butyrate concentrations, can reduce insulin resistance and obesity, but further studies are needed to determine how this affects susceptibility to tuberculosis.


European Journal of Immunology | 2016

Rewiring cellular metabolism via the AKT/mTOR pathway contributes to host defence against Mycobacterium tuberculosis in human and murine cells

Ekta Lachmandas; Macarena Beigier-Bompadre; Shih-Chin Cheng; Vinod Kumar; Arjan van Laarhoven; Xinhui Wang; Anne Ammerdorffer; Lily Boutens; Dirk J. de Jong; Thirumala-Devi Kanneganti; Mark S. Gresnigt; Tom H. M. Ottenhoff; Leo A. B. Joosten; Rinke Stienstra; Cisca Wijmenga; Stefan H. E. Kaufmann; Reinout van Crevel; Mihai G. Netea

Cells in homeostasis metabolize glucose mainly through the tricarboxylic acid cycle and oxidative phosphorylation, while activated cells switch their basal metabolism to aerobic glycolysis. In this study, we examined whether metabolic reprogramming toward aerobic glycolysis is important for the host response to Mycobacterium tuberculosis (Mtb). Through transcriptional and metabolite analysis we show that Mtb induces a switch in host cellular metabolism toward aerobic glycolysis in human peripheral blood mononuclear cells (PBMCs). The metabolic switch is TLR2 dependent but NOD2 independent, and is mediated in part through activation of the AKT‐mTOR (mammalian target of rapamycin) pathway. We show that pharmacological inhibition of the AKT/mTOR pathway inhibits cellular responses to Mtb both in vitro in human PBMCs, and in vivo in a model of murine tuberculosis. Our findings reveal a novel regulatory layer of host responses to Mtb that will aid understanding of host susceptibility to Mtb, and which may be exploited for host‐directed therapy.


PLOS ONE | 2015

The Effect of Hyperglycaemia on In Vitro Cytokine Production and Macrophage Infection with Mycobacterium tuberculosis

Ekta Lachmandas; Frank Vrieling; Louis Wilson; Simone A. Joosten; Mihai G. Netea; Tom H. M. Ottenhoff; Reinout van Crevel

Type 2 diabetes mellitus is an established risk factor for tuberculosis but the underlying mechanisms are largely unknown. We examined the effects of hyperglycaemia, a hallmark of diabetes, on the cytokine response to and macrophage infection with Mycobacterium tuberculosis. Increasing in vitro glucose concentrations from 5 to 25 mmol/L had marginal effects on cytokine production following stimulation of peripheral blood mononuclear cells (PBMCs) with M. tuberculosis lysate, LPS or Candida albicans, while 40 mmol/L glucose increased production of TNF-α, IL-1β, IL-6 and IL-10, but not of IFN-γ, IL-17A and IL-22. Macrophage differentiation under hyperglycaemic conditions of 25 mmol/L glucose was also associated with increased cytokine production upon stimulation with M. tuberculosis lysate and LPS but in infection experiments no differences in M. tuberculosis killing or outgrowth was observed. The phagocytic capacity of these hyperglycaemic macrophages also remained unaltered. The fact that only very high glucose concentrations were able to significantly influence cytokine production by macrophages suggests that hyperglycaemia alone cannot fully explain the increased susceptibility of diabetes mellitus patients to tuberculosis.


Clinical & Experimental Allergy | 2016

Th2 and Th9 responses in patients with chronic mucocutaneous candidiasis and hyper-IgE syndrome.

Katharina L. Becker; B. Rosler; Xiaowen Wang; Ekta Lachmandas; M. Kamsteeg; Cor W. M. Jacobs; Leo A. B. Joosten; Mihai G. Netea; F.L. van de Veerdonk

STAT1 mutations cause chronic mucocutaneous candidiasis (CMC), while STAT3 mutations cause hyper‐IgE syndrome (HIES). CMC and HIES patients have T helper (Th) 17 defects suffering from mucosal Candida infections, but only patients with HIES show an allergic phenotype with eczema, eosinophilia and high IgE levels.


The Journal of Infectious Diseases | 2018

Tissue Metabolic Changes Drive Cytokine Responses to Mycobacterium tuberculosis

Ekta Lachmandas; Ana B. Rios-Miguel; Valerie A.C.M. Koeken; Eva van der Pasch; Vinod Kumar; Vasiliki Matzaraki; Yang Li; Marije Oosting; Leo A. B. Joosten; Richard A. Notebaart; Mahdad Noursadeghi; Mihai G. Netea; Reinout van Crevel; Gabriele Pollara

Our study reveals that human tissue challenged with mycobacterial antigens induces differential expression of genes that regulate multiple metabolic pathways. We demonstrate that variable expression of these metabolic genes influences the cytokine response of immune cells stimulated by Mycobacterium tuberculosis.

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Mihai G. Netea

Radboud University Nijmegen

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Leo A. B. Joosten

Radboud University Nijmegen

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Reinout van Crevel

Radboud University Nijmegen Medical Centre

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Marije Oosting

Radboud University Nijmegen

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Anneke Hijmans

Radboud University Nijmegen

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Lily Boutens

Wageningen University and Research Centre

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Rinke Stienstra

Wageningen University and Research Centre

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Rob J.W. Arts

Radboud University Nijmegen

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Shih-Chin Cheng

Radboud University Nijmegen

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