Niels Bovenschen studied Medical Biology at the Free University in Amsterdam. After obtaining his PhD degree in 2003 at Sanquin Research at CLB Amsterdam, he worked as a postdoc in Leiden (TNO, Gaubius Laboratory) for one year. In 2004, he moved to the department of Pathology at the University Medical Center Utrecht (UMCU). In 2006, he has received a prestigious personal VENI grant Netherlands from the Netherlands Organization for Scientific Research (NWO) for his work on the serine protease components (i.e. granzymes) in the cytolytic granules of cytotoxic lymphocytes. In 2009 he received project funding from the Dutch Society for Cancer Research (KWF) and he became an independent group leader at the department of Pathology (UMCU). In 2012, he was appointed as Associate Professor at the same department. His research group now focuses on the role of granzymes in eliminating tumor cells and virus-infected cells, and the role of extracellular granzymes during inflammation. These aims fit within the UMCU focus area Immunity & Infection. He is in charge of Pathology Research Laboratory and the Laboratory of Translational Immunology core facility Proteins. He coordinates (bio)medical educational programs at the Utrecht University.
Effector Phase Immunity
Granule-exocytosis by cytotoxic lymphocytes (CTLs/NK cells) constitutes the main pathway for eliminating tumor cells and virus-infected. In humans, cytotoxic granules contain five serine proteases called granzymes (GrA, B, H, K, and M) that induce cell death or block viral replication by cleaving specific intracellular substrates.
My lab is interested in the physiological relevance and molecular mechanisms by which granzymes attack tumor cells and virus-infected cells. Granzymes also exist in the blood circulation following virus infections and inflammatory disorders. We are currently addressing the role of these extracellular granzymes in modulating effector cytokine responses.
1. Antiviral effects of granzymes
Human cytomegalovirus (HCMV) reactivation in immune-compromised patients can trigger devastating disease. Treatment of HCMV infection is an urgent clinical problem, limited by inefficacy, toxicity of antiviral drugs, and the ongoing appearance of drug-resistant viruses. Cytotoxic lymphocytes are crucial in anti-HCMV immunity via delivering a set of pro-apoptotic serine proteases called granzymes inside virus-infected cells. However, the physiological importance and molecular mechanisms of human granzymes in controlling HCMV remain enigmatic. My group recently demonstrated for the first time that human GrM efficiently inhibits HCMV replication in the absence of host cell death. This points to a previously unrecognized noncytotoxic mechanism by which our immune system can mediate direct anti-HCMV activity. In this project, we aim to uncover the antiviral effector activity of our immune system and use this to develop novel anti-HCMV therapeutic strategies.
2. Antitumor effects of granzymes
Granule-exocytosis by cytotoxic lymphocytes constitutes the main pathway for eliminating tumor cells. Granzymes can activate at least two general distinct pathways of cell death with unique morphological hallmarks that cooperate during cytotoxic lymphocyte cytotoxicity. This redundancy likely evolved to provide protection against tumor cells with diverse strategies to evade immune surveillance. Unlike GrA and GrB, little is known about the cell death mechanism of GrH, GrK, and GrM. In this project, we aim to determine the relevance and mechanisms of these granzymes and how tumors can evade from this cytotoxic immune response.
3. Extracellular role of granzymes
Evidence is emerging that granzymes also play a role in controlling inflammation. Granzyme serum levels are elevated in patients with autoimmune diseases and infections, including sepsis. However, the function of extracellular granzymes in inflammation largely remains unknown. The current project aims to uncover the extracellular roles of granzymes in inflammatory disorders.
Current External Activities
- Chairman: Scientific board of Pediatric Brain Cancer Foundation Koppie-AU
- Academic Editor: PLoS ONE
- Editorial Board Member: Front. Cell. Dev. Biol.
Personal Fellowships & Awards
- 2017: UU Teaching Fellow, Utrecht University, the Netherlands
- 2010: Travel Award, International Herpesvirus Workshop, Salt Lake City, USA
- 2007: Best oral presentation, Dutch Society for Pathology, Ede, The Netherlands
- 2006: NWO VENI Grant (ZonMw) (Grant application 016.066.044).
- 2003: Young Investigator Award, International Society Thrombosis and Haemostasis, Birmingham, UK
5 recent key publications:
de Poot SA, van Erp EA, Meeldijk J, Broekhuizen R, Goldschmeding R, Olthof MC, Steeghs EM, Bovenschen N. Bioluminescent reporters to monitor killer cell-mediated delivery of granzymes inside target cells. Blood. 2015:126:2893-2895 [IF 11,8]
Wensink AC, Kemp V, Fermie J, García Laorden MI, van der Poll T, Hack CE, and Bovenschen N. Granzyme K synergistically potentiates LPS-induced cytokine responses in human monocytes. Proc Natl Acad Sci USA. 2014;111:5974-9. [IF 9.8]
- de Poot SA, Bovenschen N. Granzyme M: behind enemy lines. Cell Death Differ. 2014;21:359-68. [IF 8.4]
- de Poot SA, Lai KW, van der Wal L, Plasman K, Van Damme P, Porter AC, Gevaert K, and Bovenschen N. Granzyme M targets topoisomerase II alpha to trigger cell cycle arrest and caspase-dependent apoptosis. Cell Death Differ. 2014;21:416-26. [IF 8.4]
- van Domselaar R, de Poot SA, Remmerswaal EB, Lai KW, Ten Berge IJ, and Bovenschen N. Granzyme M targets host cell hnRNP K that is essential for human cytomegalovirus replication. Cell Death Differ. 2013; 20:419-429. [IF 8.4]
- 2017: Project grant CSC
- 2015: Project grant CSC
- 2015: Project grant Pediatric Brain Cancer Foundation Koppie-AU.
- 2013: Project grant Pediatric Brain Cancer Foundation Koppie-AU.
- 2012: Infection & Immunity Center Utrecht seeding project grant.
- 2009: Dutch Cancer Society (KWF) project grant.
- 2008: UMCU/DLA Research project grant.
- 2006: NWO/ZonMw VENI grant (Netherlands Organization for Scientific Research)
Associated Team Members
- Ellen Kok (PhD student)
- Liling Shan (PhD student)
- Shuang Li (PhD student)
- Jan Meeldijk (Senior technician, core facility Proteins)
- Roel Broekhuizen (Senior technician)
- Annick Verbakel (Master Student)
- Oliver Thompson (Master Student)
- Rianne Bouma (Master Student)
- Natascha Wolf (Bachelor Student)