- Infectious Diseases
- Host directed therapy
My mission is to dissect immunological and host-genetic mechanisms of protective and pathologic immunity to mycobacterial infections, in order to design more effective intervention strategies, including novel vaccination strategies, innovative diagnostics and anti-microbial treatments.
Tuberculosis research is a major theme in my research programs. Its TB research is fundamental, preclinical, translational as well as clinical in nature and includes partly humanized animal models of TB. Research efforts aim to develop better vaccines, as well as diagnostic, immunologic, transcriptomic and metabolic “biomarker signatures”. This work has led to a number of first-in-man clinical studies with new, molecularly defined synthetic TB vaccines. Systems biology, chemical genetics, transcriptomics, metabolomics and immunomics approaches are used to identify key cellular signalling pathways in host defense to intracellular pathogens in general, and M. tuberculosis and Salmonellae in particular. Correlates of protection and prospective correlates of risk of developing TB are being identified. Moreover, there is strong interest in co-infections (Helminth-infections; HIV) and co-morbidities including type-2 diabetes, a major TB-risk factor. Using technologies developed in the TB research program, recent work also enabled identification of biomarkers of Ebola-vaccine induced human responses. Extensive international collaborative networks have been established, which include leading partners from EU, US and TB endemic areas/countries (SA, Gambia, Gabon, Ethiopia, Indonesia, Brazil, China, etc.). The group has a strong international reputation, and an extensive portfolio of external competitive projects.
A second major interest has been leprosy. This work led to the first description of Thelper 1 and Treg subsets in humans. From 1986-2011 I headed this group, but this is now being lead by prof. dr. Annemieke Geluk, please visit her website.
Some specific contributions of the Ottenhoff group
Amongst some of our scientific contributions are the discovery of the first specific antigens for mycobacterium reactive T-cells in humans; the identification of the first Thelper-1 cells in humans; the discovery of a new human immunodeficiency due to genetic mutations in the receptor for interleukin-12; the cloning of the first monoclonal T-regulatory cells in humans; involved in many human genetic studies that identified, with excellent collaborators, multiple new genetic variants impacting on risk of tuberculosis and leprosy; (together with prof. JJ Neefjes) the identification of a new human PKB/Akt1 controlled signaling pathway, that is manipulated by Salmonella and Mtb to inhibit phagosomal-lysosomal fusion. One current focus is on the role of T cell subsets (T-helper, T-regulatory), macrophage subsets, intracellular signaling networks, cellular function and systems biology. A related, translation-oriented focus is on Mtb antigen discovery, vaccine design and biomarker discovery. We also have executed several clinical phase I/IIa first in human trials with new TB vaccines, together with prof. Jaap van Dissel, including their immune monitoring. We participate and play prominent roles in many high profile international research consortia, which include partners from EU, US and developing countries in Asia, Africa and South America. Funding mostly comes from EC, BMGF, NL Government (NWO, STW/TTW) and other bodies.
For an updated list of publications, see:
Some selected publications (ref 41 contains an open access link to Science 2019 366: 302-303)
Some Selected Publications last 15 years
1. THM Ottenhoff, FAW Verreck, EGR Lichtenauer-Kaligis, MA Hoeve, O Sanal, JT van Dissel. Genetics, cytokines and human infectious disease: lessons from weakly pathogenic mycobacteria and salmonellae. Nature Genetics 32:97-105 (2002).
2. FAW Verreck, T de Boer, DML Langenberg, MA Hoeve, M Kramer, E Vaisberg, R Kastelein, A Kolk, R de Waal-Malefyt and THM Ottenhoff. Human IL-23-producing type-1 macrophages promote but IL-10-producing type-2 macrophages subvert immunity to (myco)bacteria. Proc. Natl. Acad. Sci. USA 101:4560-65 (2004).
3. E vd Vosse, MA Hoeve and THM Ottenhoff. Human genetics of intracellular infectious diseases: molecular and cellular immunity against mycobacteria and salmonellae. Lancet Infect Dis. 4:739–49 (2004).
4. FAW Verreck, T de Boer, DML Langenberg, L van der Zanden, THM Ottenhoff. Phenotypic and functional profiling of human pro-inflammatory type-1 and anti-inflammatory type-2 macrophages in response to microbial antigens, IFNg- and CD40L-mediated costimulation. J Leukoc Biol. 79:285-293 (2005).
5. MA Hoeve, T de Boer, DML Langenberg, NDL Savage, R de Waal Malefijt, FAW Verreck* and THM Ottenhoff* (*: shared last authorship). Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T-cells. Eur J Immunol. 36:661-670 (2006).
6. C Kuijl, NDL Savage, M Marsman, A Tuin, L Janssen, DA Egan, M Ketema, R vd Nieuwendijk, SJF vd Eeden, A Geluk, A Poot, G van der Marel, RL Beijersbergen, H Overkleeft, THM Ottenhoff and J.J. Neefjes. Intracellular bacterial growth is controlled by a network around PKB/Akt1. Nature 450:725-730 (2007).
7. E Sahiratmadja, B Alisjahbana, T de Boer, I Adnan, A Maya, H Danusantoso, RHH Nelwan, S Marzuki, JWM van der Meer, R van Crevel, E van de Vosse, and THM Ottenhoff. Dynamic Changes in Pro- and Anti-inflammatory Cytokine Profiles (IFN-γ, TNF-α, IL-12/23, and IL-10) and IFN-γReceptor Signalling Integrity Correlate with Tuberculosis Disease Activity and Response to Curative Treatment. Infect Immun. 75:820-829 (2007).
8. SA Joosten, KE van Meijgaarden, NDL Savage, T de Boer, F Triebel, A van der Wal, E de Heer, MR Klein, A Geluk, THM Ottenhoff. Identification of a new human CD8+ regulatory T-cell subset which mediates suppression through the chemokine CCL4. Proc Natl Acad Sci USA 104:8029-8034 (2007).
9. S Davila, ML Hibberd, RH Dass, HEE Wong, E Sahiratmadja, C Bonnard, B Alisjahbana, R van Crevel, E van de Vosse, THM Ottenhoff, M Seielstad. Genetic Association and Expression Studies Indicate a Role of Toll-Like Receptor 8 in Pulmonary Tuberculosis. PLoS Genet. Oct 4(10):e1000218 (2008).
10. S Nejentsev, T Thye, JS Szeszko, H Stevens, Y Balabanova, F Drobniewski, E. van de Vosse, B Alisjahbana, R van Crevel, JA Todd, THM Ottenhoff, E Png, M Seielstad, R Horstmann. Analysis of association of the TIRAP (MAL) S180L variant and tuberculosis in three populations. Nature Genetics 40:261-262 (2008).
11. NDL Savage, T de Boer, KV Walburg, SA Joosten, KE van Meijgaarden, A Geluk and THM Ottenhoff. Human anti-inflammatory macrophages induce Foxp3+GITR+CD25+ regulatory T cells, which suppress via membrane-bound TGFβ-1. J. Immunol. 181:2220-2226 (2008).
12. GF Black, BA Thiel, M Ota, SK Parida, R Adegbola, WH Boom, HM Dockrell, KLMC Franken, AH Friggen, PC Hill, MR Klein, M Lalor, H Mayanja, G Schoolnik, K Stanley, K Weldingh, SHE Kaufmann, G Walzl, THM Ottenhoff and the GCGH Biomarkers for TB Consortium. Immunogenicity of novel dosR regulon encoded candidate antigens of Mycobacterium tuberculosis in three high-burden populations in Africa. Clin Vaccine Immunol. 16:1203-1212 (2009).
13. SA Joosten, KE van Meijgaarden, PC van Weeren, F Kazi, A Geluk, NDL Savage, JW Drijfhout, DR Flower, WA Hanekom, MR Klein, THM Ottenhoff. Mycobacterium tuberculosis-derived peptides presented by HLA-E are targets for human CD8 T-cells with immunoregulatory activity. PLoS Pathogens 6(2):e1000782 (2010).
14. N Caccamo, SA Joosten, G Guggino, G Gelsomino, P Di Carlo, L Titone, D Galati, M-L Bocchino, A Matarese, A Salerno, A Sanduzzi, CLMC Franken, F Dieli* and THM Ottenhoff* (*: shared last authorship). Multifunctional CD4 T cells are associated with Mycobacterium tuberculosis infection and define a correlate of active disease. Eur J Immunol. 40:2211-2220 (2010).
15. van Dissel JT, Arend SM, Prins C, Bang P, Tingskov PN, Lingnau K, Nouta J, Klein MR, Rosenkrands I, Ottenhoff TH, Kromann I, Doherty TM, Andersen P. Ag85B-ESAT-6 adjuvanted with IC31 promotes strong and long-lived Mycobacterium tuberculosis specific T cell responses in naïve human volunteers. Vaccine 28:3571-3581 (2010).
16. SA Joosten, JJ Goeman, JS Sutherland, L Opmeer, KG de Boer, M Jacobsen, SHE Kaufmann, L Finos, C Magis-Escurra, MOC Ota, THM Ottenhoff and MC Haks. Identification of biomarkers for tuberculosis using a novel dual-colour RT-MLPA assay. Genes Immun. 13(1):71-82 (2011).
17. van Dissel JT, Soonawala D, Joosten SA, Prins C, Arend SM, Bang P, Tingskov PN, Lingnau K, Nouta J, Hoff ST, Rosenkrands I, Kromann I, Ottenhoff TH, Doherty TM, Andersen P. Ag85B-ESAT-6 adjuvanted with IC31(®) promotes strong and long-lived Mycobacterium tuberculosis specific T cell responses in volunteers with previous BCG vaccination or tuberculosis infection. Vaccine 29:2100-2109 (2011).
18. THM Ottenhoff and SHE Kaufmann. Vaccines against tuberculosis: where are we and where do we need to go? PLoS Pathogens, May;8(5):e1002607 (2012). Epub 2012 May 10.
19. THM Ottenhoff. The knowns and unknowns of the immunopathogenesis of tuberculosis (State of the Art article). Int J Tuberc Lung Dis. 2012 Nov;16(11):1424-32. doi: 10.5588/ijtld.12.0479.
20. THM Ottenhoff. New pathways of protective and pathological host defense to mycobacteria. Invited review. Trends Microbiol. 2012 Sep;20(9):419-28. doi: 10.1016/j.tim.2012.06.002.
21. T Thye, E Owusu-Dabo, F Vannberg, R van Crevel, J Curtis, E Sahiratmadja, Y Balabanova, C Ehmen, B Muntau, G Ruge, J Sievertsen, J Gyapong, V Nikolayevsky, R Adegbola, P Hill, F Drobniewski, E van de Vosse, M Newport, B Alisjahbana, S Nejentsev, THM Ottenhoff, AVS Hill, RD Horstmann, Christian G. Meyer. A novel susceptibility locus for tuberculosis on chromosome 11p13 downstream the WT1 gene. Nature Genetics 44(3):257-259 (2012).
22. THM Ottenhoff; R Hari Dass; Y Ninghan; M Zhang; Hazel Wong; Edhyana Sahiratmadja; Chiea Chuen Khor; Bachti Alisjahbana; R van Crevel; Mark Seielstad; Esther van de Vosse; Sangkot Marzuki; Martin Lloyd Hibberd. Genome-wide Expression Profiling Identifies Novel Interferon Response Pathways In Active Mycobacterium tuberculosis Infection. PLoS One. 2012;7(9):e45839. doi: 10.1371/journal.pone.0045839. Epub 2012 Sep 21
23. SA Joosten, HA Fletcher, Tom HM Ottenhoff. A helicopter perspective on TB biomarkers: pathway and process based analysis of gene expression data provides new insight into TB pathogenesis. PLoS ONE, volume 8, Issue 9, e73230 (2013)
24. M Kaforou, VJ Wright, T Oni, N French, ST Anderson, N Bangani, CM Banwell, AC Crampin, HM Dockrell, B Eley, RS Heyderman, ML Hibberd, F Kern, PR Langford, L Ling, M Mendelson, TH Ottenhoff, F Zgambo, RJ Wilkinson, LJ Coin, M Levin on behalf of the ILULU consortium. Detection of tuberculosis in HIV-infected and -uninfected African adults using whole blood RNA expression signatures: a case-control study. PLoS Med 10(10): e1001538. doi:10.1371/journal.pmed.1001538
25. S Commandeur, KE van Meijgaarden, C Prins, AV Pichugin, K Dijkman, AH Friggen,* KLMC Franken, G Dolganov, I Kramnik, GK Schoolnik, F Oftung, GE Korsvold, A Geluk, THM Ottenhoff. An unbiased genome-wide Mycobacterium tuberculosis gene expression approach to discover antigens targeted by human T cells expressed during pulmonary infection. J Immunol. 190:1659-1671 (2013).
26. ST Anderson, M Kaforou, AJ Brent, VJ Wright, CM Banwell, G Chagaluka, AC Crampin, HM Dockrell, N French, MS Hamilton, ML Hibberd, F Kern, PR Langford, L Ling, R Mlotha, THM Ottenhoff, S Pienaar, V Pillay, J. SG Scott, H Twahir, RJ Wilkinson, LJ Coin, RS Heyderman, M Levin, B Eley on behalf of the ILULU consortium and KIDS TB Study Group. Diagnosis of childhood tuberculosis and host RNA expression in Africa. New Eng. J Med, 370(18):1712-1723 (2014).
27. M van der Vaart, CJ Korbee, GEM Lamers, AY Tengeler, R Hosseini, MC Haks, THM Ottenhoff, HP Spaink, AH Meijer. DRAM1 links pathogen recognition via TLR-MYD88 to autophagic defense against tuberculosis. Cell Host Microbe, Jun 11;15(6):753-67, (2014).
28. Nadia Caccamo, Gabriella Pietra, Lucy C. Sullivan, Andrew G. Brooks, Teresa Prezzemolo, Marco P. La Manna, Diana Di Liberto, Simone A. Joosten, Krista E. van Meijgaarden, Paola Di Carlo, Lucina Titone, Lorenzo Moretta, Maria C. Mingari*, Tom H.M. Ottenhoff*, and Francesco Dieli* (*: equal contributions). Human CD8 T lymphocytes recognize Mycobacterium tuberculosis antigens presented by HLA-E during active tuberculosis and express type 2 cytokines. Eur J Immunol, Jan 29. doi: 10.1002/eji.201445193 (2015).
29. Krista E van Meijgaarden, Mariëlle C Haks, Nadia Caccamo, Francesco Dieli, Tom HM Ottenhoff*, Simone A Joosten* (*: equal contributions). Human CD8+ T-cells recognizing peptides from Mycobacterium tuberculosis (Mtb) presented by HLA-E have an unorthodox Th2-like, multifunctional, Mtb inhibitory phenotype and represent a novel human T-cell subset. PLoS Pathogens, Mar 24;11(3):e1004671. doi: 10.1371/journal.ppat.1004671 (2015).
30. Ronacher K, Joosten SA, van Crevel R, Dockrell, HM, Walzl, G, Ottenhoff THM. Acquired immunodeficiencies and tuberculosis: focus on HIV/AIDS and diabetes mellitus. Immunol Rev. Mar;264(1):121-37. doi: 10.1111/imr.12257 (2015).
31. M Coppola, KE van Meijgaarden, KLMC Franken, S Commandeur, G Dolganov, I Kramnik, GK Schoolnik, I Comas, O Lund, C Prins, SJF van den Eeden, GE Korsvold, F Oftung, A Geluk and THM Ottenhoff. New Genome-Wide Algorithm Identifies Novel In-Vivo Expressed Mycobacterium tuberculosis Antigens Inducing Human T-Cell Responses with Classical and Unconventional Cytokine Profiles. Scientific Reports, 2016 Nov 28;6:37793. doi:10.1038/srep37793
32. SA Joosten, KE van Meijgaarden, F del Nonno, A Baiocchini, L Petrone, V Vanini, HH Smits, F Palmieri, D Goletti, THM Ottenhoff. Patients with tuberculosis have a dysfunctional circulating B-cell compartment, which normalizes following successful treatment. PLoS Pathogens 2016 Jun 15;12(6):e1005687. doi: 10.1371/journal.ppat.1005687
33. DE Zak, A Penn-Nicholson, TJ Scriba, E Thompson, S Suliman, L Amon, H Mahomed, M Erasmus, W Whatney, GD Hussey, D Abrahams, F Kafaar, T Hawkridge, S Verver, EJ Hughes, M Ota, J Sutherland, R Howe, H Dockrell, WH Boom, B Thiel, THM Ottenhoff, H Mayanja-Kizza, K Downing, M Hatherill, J Valvo, S Shankar, SHE Kaufmann, G Walzl, A Aderem, WA Hanekom and other members of the ACS and GC6-74 cohort study teams. Prospective blood RNA signatures of tuberculosis disease risk. Lancet. 2016 Jun 4;387(10035):2312-22. doi: 10.1016/S0140-6736(15)01316-1. Epub 2016 Mar 24.
34. A Huttner, C Combescure, S Grillet, MC Haks, E Quinten, C Modoux, ST Agnandji, J Brosnahan, JA Dayer, AM Harandi, L Kaiser, D Medaglini, T Monath, the VEBCON and VSV-EBOVAC Consortia, P Roux-Lombard, PG Kremsner, THM Ottenhoff, CA Siegrist. A dose-dependent plasma signature of the safety and immunogenicity of the rVSV-Ebola vaccine in Europe and Africa. Science Translational Medicine, 2017
35. CJ Korbee, MT Heemskerk, D Kocev, E van Strijen, O Rabiee, KLMC Franken, L Wilson, NDL Savage, S DÅ¾eroski, MC Haks*, THM Ottenhoff* (*: equal contributions). Combined Chemical Genetics and Data-driven Bioinformatics Approach Identifies Receptor Tyrosine Kinase Inhibitors as Host-directed Antimicrobials. Nature Communications, 2018.
36. SA Joosten, KE van Meijgaarden, SM Arend, C Prins, F Oftung, GE Korsvold, SV Kik, RJW Arts, R van Crevel, MG Netea, THM Ottenhoff. Mycobacterial Growth Inhibition is associated with trained innate immunity. J Clin. Invest., 2018.
37 K Dijkman, C Sombroek, R Vervenne, S Hofman, C Boot, E Remarque, C Kocken, THM Ottenhoff, I Kondova, M Khayum, K Haanstra, M Vierboom, FAW Verreck. Prevention of tuberculosis infection and disease by local BCG in repeatedly exposed rhesus macaques. Nature Medicine 25:255, Jan 2019
38 J Weiner 3rd, J Maertzdorf, J Sutherland, F Duffy, E Thompson, S Suliman, G McEwen, B Thiel, S Parida, J Zyla, W Hanekom, R Mohney, WH Boom, H Mayanja-Kizza, R Howe, H Dockrell, THM Ottenhoff, T Scriba, D Zak, G Walzl and SHE Kaufmann. Metabolite changes in blood predict the onset of tuberculosis. Nature Communications, 2018 Dec 6;9(1):5208
39 Vrieling F, Wilson L, Rensen PCN, Walzl G, Ottenhoff THM*, Joosten SA* (*: equal contributions). Oxidized low-density lipoprotein (oxLDL) supports Mycobacterium tuberculosis survival in macrophages by inducing lysosomal dysfunction. PLoS Pathog. 2019 Apr 18;15(4):e1007724.
40 Joosten SA, Ottenhoff THM, Lewinsohn DM, Hoft DF, Moody DB, Seshadri C; Collaboration for Tuberculosis Vaccine Discovery - Donor-Unrestricted T-cells Working Group, Bill and Melinda Gates Foundation. Harnessing donor unrestricted T-cells for new vaccines against tuberculosis. Vaccine 2019 May 21;37(23):3022-3030. doi: 10.1016
41 THM Ottenhoff and SA Joosten. Mobilizing unconventional T cells: modulating unconventional antigen presentation could treat infections and cancer (Perspective on invitation). Science, 2019, 366(6463):302-303. doi: 10.1126/science.aay7079
Training and Degrees
1982 MD degree, Leiden University Medical Center (LUMC)
1986 PhD (cum laude), Leiden University “HLA class II immune response genes in leprosy”
2001 Professor at LUMC and Leiden University (Dept. Infectious Diseases)
Some academic Honors and Indicators of Esteem
1989-1993 CC Huygens Fellowship Award (Netherlands Organization for Scientific Research)
2003-2013 Member of the "Gezondheidsraad" (Netherlands Government Council of Health), Section Infection and Immunity.
2008 Co-founding Member Tuberculosis Vaccine Initiative (see www.tbvi.eu)
2010 Eurolife Distinguished Faculty Speaker Medal, Trinity College, Dublin, Ireland
Several personal awards (CJ Kok award, Eijkman Medal, Swierenga Medal, American Acad. Microbiology distinction).
Regular presentations as invited speaker on international, national congresses and public meetings.
Member of many large projects’ Steering Committees
Participation in advisory boards (monitoring- and evaluation committees)
Formal member of Senior Management Team TBVI since 2015
image courtesy: Kees J. Korbee
Leids Universitair Medisch Centrum
2333 ZA Leiden
Tel: +31 71 526 2620
2300 RC Leiden