Human immune response against mycobacteria:
a Biomarkers of human TB disease or protection against TB disease: Biomarkers of (early) TB disease development or more importantly biomarkers of protection against disease would greatly contribute to the development of novel vaccines against tuberculosis. The recently developed dcRT-MLPA (dual-colour reverse transcriptase multiplex ligation dependent probe amplification) facilitates analyses of gene expression levels in large samples sets for groups of genes and is thus extremely suitable for biomarker monitoring in various clinical cohorts. Studies involve TB disease prediction, treatment responses, vaccine induced biomarkers and biomarkers of TB disease in patients with concomitant co-morbidities.
b. Vaccine induced responses: Vaccination against TB remains challenging and no vaccines have yet achieved long-term protective efficacy. We are involved in testing and evaluation of novel vaccine candidates in humans, including detailed immunological monitoring. Moreover, we investigate BCG, the currently available vaccine against TB and decipher different components of the human immune response following vaccination in great detail.
c. Regulatory T cells: Mycobacteria including the BCG vaccine do not only induce effector immune responses, but our research has shown that also CD8+ regulatory T cells are induced in humans following mycobacterial exposure. We characterize these novel human Treg populations in great detail including phenotypes, mechanism of suppression, non-classical restriction, multifunctionality, capacity to lyse mycobacteria and their interaction with other components of the immune system.
II. Tuberculosis and diabetes:
Epidemiological data indicate an association between TB and type 2 diabetes (T2D), specifically, the incidence of T2D is 2-3 fold higher in patients with TB and treatment of TB is less efficient. The mechanism for the increased sensitivity is unknown and may be due to molecular interactions altered following exposure to metabolic components.
a. Intracellular effects on Mtb in macrophages: Macrophages are affected by altered metabolic conditions during metabolic syndrome and T2D. We have characterized in detail various human macrophage subsets and utilize these subsets as tools to investigate various aspects of macrophage biology. We investigate the effect of altered metabolites, including hyperglycemia, lipids, insulin on macrophage phenotype and function, in particular the capacity to kill mycobacteria following infection with live Mtb. In addition, we will employ metabolomics to investigate the key host metabolic pathways altered following infection with live Mtb.
b. Biomarkers of TB-DM: Since patients affected by both TB and T2D have a decreased treatment efficiency, biomarkers of treatment response may be valuable predictors. Biomarkers of treatment response in TB only patients will be evaluated for their value in patients with concomitant TB and T2D. Furthermore, the aim will be to identify biomarkers specific for patients with TB and T2D.
Joosten SA, Fletcher HA, Ottenhoff TH. A helicopter perspective on TB biomarkers: pathway and process based analysis of gene expression data provides new insight into TB pathogenesis. PLoS One. 2013 Sep 16;8(9):e73230
Joosten SA, Goeman JJ, Sutherland JS, Opmeer L, de Boer KG, Jacobsen M, Kaufmann SH, Finos L, Magis-Escurra C, Ota MO, Ottenhoff TH, Haks MC. Identification of biomarkers for tuberculosis disease using a novel dual-color RT-MLPA assay. Genes Immun. 2012 Jan;13(1):71-82.
Joosten SA, van Meijgaarden KE, van Weeren PC, Kazi F, Geluk A, Savage ND, Drijfhout JW, Flower DR, Hanekom WA, Klein MR, Ottenhoff TH. Mycobacterium tuberculosis peptides presented by HLA-E molecules are targets for human CD8 T-cells with cytotoxic as well as regulatory activity. PLoS Pathog. 2010 Feb 26;6(2):e1000782.
Joosten SA, van Meijgaarden KE, Savage ND, de Boer T, Triebel F, van der Wal A, de Heer E, Klein MR, Geluk A, Ottenhoff TH. Identification of a human CD8+ regulatory T cell subset that mediates suppression through the chemokine CC chemokine ligand 4. Proc Natl Acad Sci U S A. 2007 May 8;104(19):8029-34.
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After graduating in Biomedical Sciences from Utrecht University in 1999, I studied the immunological involvement in chronic renal transplant rejection in the department of Nephrology and obtained my PhD at Leiden University in 2004 on the thesis entitled ‘Pathobiology of chronic renal allograft rejection’. I obtained certification in Immunology and in Experimental Pathobiology from the SMBWO. Following my PhD I started working in the department of Infectious Diseases and focussed on mycobacterial infections. I spent a few months at the University of Capetown, Capetown, South Africa to work on immune responses following BCG vaccination in infants.
My current work focusses on TB biomarkers, detailed characterization of novel human T-cell subsets and more recently macrophage biology and metabolism.
I have received a NWO-VENI grant (fellowship), LUMC Gisela Thier fellowship and was co-applicant on several EC framework projects, including NEWTBVAC and TANDEM.
Leiden University Medical Center
2333 ZA Leiden
Tel: +31 71 5264024
P.O. Box 9600
2300 RC Leiden