ORCID Profile
0000-0002-9878-0863
Current Organisation
Leiden University Medical Center
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Publisher: Cold Spring Harbor Laboratory
Date: 08-02-2022
DOI: 10.1101/2022.02.07.22269422
Abstract: People with diabetes are more likely to develop tuberculosis (TB) and to have poor TB treatment outcomes than those without. We previously showed that blood transcriptomes in people with TB-diabetes (TB-DM) co-morbidity have excessive inflammatory and reduced interferon responses at TB diagnosis. It is unknown whether this persists through treatment, potentially underlying adverse outcomes. Pulmonary TB patients were recruited in South Africa, Indonesia and Romania, and classified as having TB-DM, TB with prediabetes, TB-related hyperglycaemia or uncomplicated TB, based on glycated haemoglobin (HbA1c) concentration at TB diagnosis and after 6 months of TB treatment. Gene expression in blood s les collected at diagnosis and at regular intervals throughout treatment was measured by unbiased RNA-Seq and targeted Multiplex Ligation-dependent Probe Amplification. Gene expression was modulated by TB treatment in all groups but to different extents, such that differences remained in people with TB-DM relative to TB-only throughout, including genes involved in innate responses, anti-microbial immunity and the inflammasome. People with prediabetes or with TB-related hyperglycaemia had gene expression more similar to people with TB-DM than TB-only throughout treatment. The overall pattern of change was similar across clinical groups irrespective of glycaemic index, permitting models predictive of TB treatment to be developed. The exacerbated transcriptome changes seen in TB-DM take longer to resolve during TB treatment, indicating that prolonged treatment or host-directed therapy may be needed to improve TB treatment outcomes. Development of transcriptome-based biomarker signatures of TB-treatment response should include people with diabetes to be useful across populations. Host blood transcriptomes are altered in tuberculosis, and further altered with diabetes co-morbidity. We have shown that there is similar resolution of transcriptomes through treatment, but with differing magnitude and kinetics in TB patients with or without diabetes.
Publisher: European Respiratory Society
Date: 09-2023
Publisher: Cold Spring Harbor Laboratory
Date: 04-12-2014
Publisher: Oxford University Press (OUP)
Date: 13-06-2020
DOI: 10.1093/CID/CIAA751
Abstract: People with diabetes have an increased risk of developing active tuberculosis (TB) and are more likely to have poor TB-treatment outcomes, which may impact on control of TB as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in patients with active TB relative to healthy in iduals. The effects of diabetes and intermediate hyperglycemia (IH) on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-TB comorbidity. Whole blood s les were collected from active TB patients with diabetes (glycated hemoglobin [HbA1c] ≥6.5%) or IH (HbA1c = 5.7% to & .5%), TB-only patients, and healthy controls in 4 countries: South Africa, Romania, Indonesia, and Peru. Differential blood gene expression was determined by RNA-seq (n = 249). Diabetes increased the magnitude of gene expression change in the host transcriptome in TB, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with IH and TB exhibited blood transcriptomes much more similar to patients with diabetes-TB than to patients with only TB. Both diabetes-TB and IH-TB patients had a decreased type I interferon response relative to TB-only patients. Comorbidity in in iduals with both TB and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type I interferon responses in comorbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in in iduals with IH, showing that altered immunity to TB may also be present in this group. The TB disease outcomes in in iduals with IH diagnosed with TB should be investigated further.
Publisher: American Thoracic Society
Date: 05-2018
Publisher: Elsevier BV
Date: 04-2020
Publisher: Springer Science and Business Media LLC
Date: 25-05-2020
DOI: 10.1038/S41598-020-65043-8
Abstract: Improved tuberculosis diagnostics and tools for monitoring treatment response are urgently needed. We developed a robust and simple, PCR-based host-blood transcriptomic signature, RISK6, for multiple applications: identifying in iduals at risk of incident disease, as a screening test for subclinical or clinical tuberculosis, and for monitoring tuberculosis treatment. RISK6 utility was validated by blind prediction using quantitative real-time (qRT) PCR in seven independent cohorts. Prognostic performance significantly exceeded that of previous signatures discovered in the same cohort. Performance for diagnosing subclinical and clinical disease in HIV-uninfected and HIV-infected persons, assessed by area under the receiver-operating characteristic curve, exceeded 85%. As a screening test for tuberculosis, the sensitivity at 90% specificity met or approached the benchmarks set out in World Health Organization target product profiles for non-sputum-based tests. RISK6 scores correlated with lung immunopathology activity, measured by positron emission tomography, and tracked treatment response, demonstrating utility as treatment response biomarker, while predicting treatment failure prior to treatment initiation. Performance of the test in capillary blood s les collected by finger-prick was noninferior to venous blood collected in PAXgene tubes. These results support incorporation of RISK6 into rapid, capillary blood-based point-of-care PCR devices for prospective assessment in field studies.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Wiley
Date: 17-02-2015
Abstract: CD8 T cells contribute to protective immunity against Mycobacterium tuberculosis . In humans, M. tuberculosis reactive CD8 T cells typically recognize peptides associated to classical MHC class Ia molecules, but little information is available on CD8 T cells recognizing M. tuberculosis Ags presented by nonclassical MHC class Ib molecules. We show here that CD8 T cells from tuberculosis (TB) patients recognize HLA‐E‐binding M. tuberculosis peptides in a CD3/TCR αβ mediated and CD8‐dependent manner, and represent an additional type of effector cells playing a role in immune response to M. tuberculosis during active infection. HLA‐E‐restricted recognition of M. tuberculosis peptides is detectable by a significant enhanced ex vivo frequency of tetramer‐specific circulating CD8 T cells during active TB. These CD8 T cells produce type 2 cytokines upon antigenic in vitro stimulation, help B cells for Ab production, and mediate limited TRAIL‐dependent cytolytic and microbicidal activity toward M. tuberculosis infected target cells. Our results, together with the finding that HLA‐E/ M. tuberculosis peptide specific CD8 T cells are detected in TB patients with or without HIV coinfection, suggest that this is a new human T‐cell population that participates in immune response in TB.
Publisher: Frontiers Media SA
Date: 22-03-2019
Publisher: Hindawi Limited
Date: 2016
DOI: 10.1155/2016/2695396
Abstract: Human HLA-E can, in addition to self-antigens, also present pathogen-derived sequences, which elicit specific T-cell responses. T-cells recognize their antigen presented by HLA-E highly specifically and have unique functional and phenotypical properties. Pathogen specific HLA-E restricted CD8 + T-cells are an interesting new player in the field of immunology. Future work should address their exact roles and relative contributions in the immune response against infectious diseases.
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.ATHEROSCLEROSIS.2016.05.031
Abstract: Bacille-Calmette-Guérin (BCG), prepared from attenuated live Mycobacterium bovis, modulates atherosclerosis development as currently explained by immunomodulatory mechanisms. However, whether BCG is pro- or anti-atherogenic remains inconclusive as the effect of BCG on cholesterol metabolism, the main driver of atherosclerosis development, has remained underexposed in previous studies. Therefore, we aimed to elucidate the effect of BCG on cholesterol metabolism in addition to inflammation and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established model of human-like lipoprotein metabolism. Hyperlipidemic APOE*3-Leiden.CETP mice were fed a Western-type diet containing 0.1% cholesterol and were terminated 6 weeks after a single intravenous injection with BCG (0.75 mg 5 × 10(6) CFU). BCG-treated mice exhibited hepatic mycobacterial infection and hepatomegaly. The enlarged liver (+53%, p = 0.001) coincided with severe immune cell infiltration and a higher cholesterol content (+31%, p = 0.03). Moreover, BCG reduced plasma total cholesterol levels (-34%, p = 0.003), which was confined to reduced nonHDL-cholesterol levels (-36%, p = 0.002). This was due to accelerated plasma clearance of cholesterol from intravenously injected [(14)C]cholesteryl oleate-labelled VLDL-like particles (t½ -41%, p = 0.002) as a result of elevated hepatic uptake (+25%, p = 0.05) as well as reduced intestinal cholestanol and plant sterol absorption (up to -37%, p = 0.003). Ultimately, BCG decreased foam cell formation of peritoneal macrophages (-18%, p = 0.02) and delayed atherosclerotic lesion progression in the aortic root of the heart. BCG tended to decrease atherosclerotic lesion area (-59%, p = 0.08) and reduced lesion severity. BCG reduces plasma nonHDL-cholesterol levels and delays atherosclerotic lesion formation in hyperlipidemic mice.
Publisher: Cold Spring Harbor Laboratory
Date: 09-02-2022
DOI: 10.1101/2022.02.08.22269796
Abstract: Globally, the anti-tuberculosis (TB) treatment success rate is approximately 85%, with treatment failure, relapse and death occurring in a significant proportion of pulmonary TB patients. Treatment success is lower among people with diabetes mellitus (DM). Predicting treatment failure early after diagnosis would allow early treatment adaptation and may improve global TB control. S les were collected in a longitudinal cohort study of adult TB patients with or without concomitant DM from South Africa and Indonesia to characterize whole blood transcriptional profiles before and during anti-TB treatment, using unbiased RNA-Seq and targeted gene dcRT-MLPA. We report differences in whole blood transcriptome profiles, which were observed before initiation of treatment and throughout treatment, between patients with a good versus poor anti- TB treatment outcome. An eight-gene and a 22-gene blood transcriptional signature distinguished patients with a good treatment outcome from patients with a poor treatment outcome at diagnosis (AUC=0·815) or two weeks (AUC=0·834) after initiation of anti-TB treatment, respectively. High accuracy was obtained by cross-validating this signature in an external cohort (AUC=0·749). These findings suggest that transcriptional profiles can be used as a prognostic biomarker for treatment failure and success, even in patients with concomitant DM. The research leading to these results, as part of the TANDEM Consortium, received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013 Grant Agreement No. 305279) and the Netherlands Organization for Scientific Research (NWO-TOP Grant Agreement No. 91214038).
Publisher: Public Library of Science (PLoS)
Date: 16-04-2019
Publisher: Frontiers Media SA
Date: 2017
Publisher: Frontiers Media SA
Date: 23-10-2018
Publisher: Frontiers Media SA
Date: 13-04-2018
Publisher: Wiley
Date: 20-02-2015
DOI: 10.1111/IMR.12257
Abstract: The spread of human immunodeficiency virus (HIV) infection within Africa led to marked increases in numbers of cases of tuberculosis (TB), and although the epidemic peaked in 2006, there were still 1.8 million new cases in 2013, with 29.2 million prevalent cases. Half of all TB cases in Africa are in those with HIV co-infection. A brief review of the well-documented main immunological mechanisms of HIV-associated increased susceptibility to TB is presented. However, a new threat is facing TB control, which presents itself in the form of a rapid increase in the number of people living with type II diabetes mellitus (T2DM), particularly in areas that are already hardest hit by the TB epidemic. T2DM increases susceptibility to TB threefold, and the TB burden attributable to T2DM is 15%. This review addresses the much smaller body of research information available on T2DM-TB, compared to HIV-TB comorbidity. We discuss the altered clinical presentation of TB in the context of T2DM comorbidity, changes in innate and adaptive immune responses, including lymphocyte subsets and T-cell phenotypes, the effect of treatment of the different comorbidities, changes in biomarker expression and genetic predisposition to the respective morbidities, and other factors affecting the comorbidity. Although significant gains have been made in improving our understanding of the underlying mechanisms of T2DM-associated increased susceptibility, knowledge gaps still exist that require urgent attention.
Publisher: Elsevier BV
Date: 06-2018
Publisher: Springer Science and Business Media LLC
Date: 29-09-2011
DOI: 10.1038/GENE.2011.64
Abstract: Owing to our lack of understanding of the factors that constitute protective immunity during natural infection with Mycobacterium tuberculosis (Mtb), there is an urgent need to identify host biomarkers that predict long-term outcome of infection in the absence of therapy. Moreover, the identification of host biomarkers that predict (in)adequate response to tuberculosis (TB) treatment would similarly be a major step forward. To identify/monitor multi-component host biomarker signatures at the transcriptomic level in large human cohort studies, we have developed and validated a dual-color reverse-transcriptase multiplex ligation-dependent probe lification (dcRT-MLPA) method, permitting rapid and accurate expression profiling of as many as 60-80 transcripts in a single reaction. dcRT-MLPA is sensitive, highly reproducible, high-throughput, has an extensive dynamic range and is as quantitative as QPCR. We have used dcRT-MLPA to characterize the human immune response to Mtb in several cohort studies in two genetically and geographically erse populations. A biomarker signature was identified that is strongly associated with active TB disease, and was profoundly distinct from that associated with treated TB disease, latent infection or uninfected controls, demonstrating the discriminating power of our biomarker signature. Identified biomarkers included apoptosis-related genes and T-cell/B-cell markers, suggesting important contributions of adaptive immunity to TB pathogenesis.
Publisher: Elsevier BV
Date: 08-2022
Publisher: Springer Science and Business Media LLC
Date: 06-12-2018
DOI: 10.1038/S41467-018-07635-7
Abstract: New biomarkers of tuberculosis (TB) risk and disease are critical for the urgently needed control of the ongoing TB pandemic. In a prospective multisite study across Subsaharan Africa, we analyzed metabolic profiles in serum and plasma from HIV-negative, TB-exposed in iduals who either progressed to TB 3–24 months post-exposure (progressors) or remained healthy (controls). We generated a trans-African metabolic biosignature for TB, which identifies future progressors both on blinded test s les and in external data sets and shows a performance of 69% sensitivity at 75% specificity in s les within 5 months of diagnosis. These prognostic metabolic signatures are consistent with development of subclinical disease prior to manifestation of active TB. Metabolic changes associated with pre-symptomatic disease are observed as early as 12 months prior to TB diagnosis, thus enabling timely interventions to prevent disease progression and transmission.
Publisher: Public Library of Science (PLoS)
Date: 10-09-2013
Publisher: Elsevier BV
Date: 04-2014
Publisher: Public Library of Science (PLoS)
Date: 23-09-2011
No related grants have been discovered for Simone A Joosten.