I. Identification of biomarkers to monitor disease and vaccination induced immunity.
To investigate the human immune response to newly developed or existing vaccines, or during infection/disease on a population scale, we have recently developed a dual-color Reverse Transcription Multiplex Ligation-dependent Probe Amplification (dcRT-MLPA) assay, which can rapidly profile mRNA expression of host genes. dcRT-MLPA allows analysis of host immune gene expression in relation to vaccination, infection, co-infection, disease or therapeutic interventions and can also be used to probe differences in immune reactivity in populations in (and between) different areas, e.g. due to environmental or genetic factors which may impact on vaccine efficacy, such as co-infections with helminths.
Recent work probing differences in immune gene expression activity in populations yielded new candidate biomarkers associated with tuberculosis disease and the response to chemotherapy. Current research lines aim:
- To identify and validate novel host-derived biomarkers in tuberculosis (with regard to protection; progression towards disease; response to intervention).
- To understand the human transcriptomic response during co-infections and co-morbidity (Tuberculosis-Helminths, Malaria-Helminths, HIV-Helminths, Tuberculosis-HIV, Tuberculosis-Diabetes Mellitis).
- To understand the human transcriptomic response during Plasmodium falciparum vaccination, challenge, infection and cure.
II. Dissecting key hubs in the intracellular host networks involved in controlling intracellular pathogens using chemical genetics and genetic knock down.
Since multi]drug (MDR) and extensively drug (XDR) resistant bacteria are rapidly emerging and the number of remaining drugable targets in pathogens is relatively small, we aim to use host]targeted treatment as an innovative therapeutic approach for intracellular infectious diseases. We have identified new host molecules that are manipulated by Mycobacterium tuberculosis and/or Salmonella to promote pathogen survival and are currently investigating the underlying mechanisms by which the identified intracellular host networks control intracellular pathogen survival. In addition, we have already identified novel lead chemical compounds for tuberculosis (TB) therapy that act on host proteins and are identifying new ones, which also act on MDR/XDR bacteria. The compounds will be tested in combinatorial regimens together with classical antibiotics in vitro in cell lines and primary macrophages and in vivo in zebrafish and mouse TB models. If proven efficacious, these new strategies may be translatable to other chronic infectious diseases caused by intracellular pathogens, such as M.leprae,Chlamydia, Listeria and Leishmania.
1. Haks M. C., Krimpenfort P., Van den Brakel J. H. N., and Kruisbeek A. M. (1999) Pre-TCR signaling and inactivation of p53 induces crucial cell survival pathways in pre-T cells. Immunity. 11, 91-101.
2. Haks M. C., Pépin E., Van den Brakel J. H. N., Smeele S. A. A., Belkowski S. M., Kessels H. W. H. G., Krimpenfort P., and Kruisbeek A. M. (2002). Contributions of the T cell receptor-associated CD3g-ITAM to thymocyte selection. J. Exp. Med. 196, 1-13.
3. Haks M. C., Lefebvre J. M., Lauritsen J. P. H., Carleton M., Rhodes M., Miyazaki T., Kappes D. J., and Wiest D. L. (2005). Attenuation of gdTCR signaling efficiently diverts thymocytes to the ab lineage. Immunity. 22, 595-606.
4. Lauritsen J. P. H., Haks M. C., Lefebvre J. M., Kappes D. J., and Wiest D. L. (2006). Recent insights into the signals that control ab/gd-lineage fate. Immunol. Rev. 209, 176-190.
5. Joosten S. A., Goeman J. J., Sutherland J. S., Opmeer L., de Boer K. G., Jacobsen M., Kaufmann S. H. E., Finos L., Magis-Escurra C., Ota M. O. C., Ottenhoff T. H. M., and Haks M. C. (2012). Identification of biomarkers for tuberculosis disease using a novel dual-color RT-MLPA assay. Genes Immun. 13, 71-82.
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Following my masters in Medical Biology at the Free University and the University of Arizona, Tucson, USA, I did my PhD in Immunology at the Netherlands Cancer Institute (Regulation of T-cell development by cytokine and antigen receptors). I received postdoctoral training at the Fox Chase Cancer Center, Philadelphia, USA (Molecular requirements for productive pre-TCR signaling) and Leiden University Medical Center during which period I focused on the genetic programs associated with (i) distinct levels of T-cell activation and (ii) the enhanced effector function and survival of anti-tumor CTLs.
My current research focuses on (i) the identification of host biomarkers to monitor disease development, response to treatment, and vaccination induced immunity and (ii) the discovery of host regulatory networks as targets for novel immunomodulatory drugs to control intracellular (multi-drug resistant) bacterial infections.
Grants were received from FCCC (postdoctoral fellowship), Dutch Cancer Society, Jan Veltkamp Foundation, Netherlands Organisation for Scientific Research (NWO), and the Commission of European Communities.
Leids Universitair Medisch Centrum
2333 ZA Leiden
Tel: 071 5264024
2300 RC Leiden