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erlenmyer-research
Research group/lab

Chronic viral hepatitis and liver cancer

Studies on biomarkers and immune mechanisms involved in infections with hepatitis viruses and hepatocellular carcinoma

About our research group/lab

Our research

Translational immunological studies on chronic viral hepatitis

Our research is focused on immunology of chronic viral infections (HBV, HCV or HEV as well as HIV), and the long-term consequences of these infections, such as fibrosis and hepatocellular carcinomas (HCC).  Our interest is in unravelling 1) why immune responses are insufficient to clear the viruses in chronic patients; 2) the parameters that determine disease progression (e.g. fibrosis or liver cancer) in patients with chronic viral hepatitis, and 3) the mechanisms underlying the differences in efficacy of antiviral therapy

To achieve this, we use immuno-monitoring of patients at various disease stages and during standard-of-care and novel experimental antiviral therapy (in phase I/II clinical trials). Since hepatitis viruses replicate exclusively in the liver, we use the technique of fine-needle aspiration of the cells to samples the liver, a technique that we used in numerous research projects in the last decade.

Risk factors and biomarkers for early detection of HCC

Hepatocellular carcinoma (HCC) is the most frequent liver malignancy and is the second most common cause of cancer-related death worldwide. Diagnosis of HCC by imaging is often at a late stage of disease when treatment options are limited. To improve early diagnosis of HCC and define mechanisms of carcinogenesis, our research aims to identify risk factors and  biomarkers associated with HCC development.

The project is funded by the EU Horizon2020 program, and  coordinated by the Erasmus MC “ESCALON”( European-Latin American network for the assessment of biomarkers to predict and diagnose hepatobiliary malignancies and characterization of risk factors for cancer development). More information can be found at: www.escalon.eu

Coordinators: André Boonstra and José Debes

Beneficiaries from: 6 Latin American countries (Argentina, Brasil, Colombia, Chile, Ecuador, Peru), 4 EU countries (Germany, UK, Spain, Netherlands) and Canada.

Systems biology of blood and liver to study viral hepatitis

Our research group examines transcriptomics, gene polymorphisms, metabolomics, and proteomics to identify biomarkers that predict disease progression and the response to antiviral therapy of individual patients chronically infected with HBV, HCV, HEV and HIV.

The transcriptomes of peripheral blood, liver/isolated hepatocytes, and purified immune cells (B cell, T cell, NK cell, monocytes) obtained from patients infected with HBV, HCV, or HIV are profiled by microarray, bulk RNA-seq and single cell RNA-Seq. The transcriptomes are evaluated in detail using analyses for individual genes and gene sets/modules to understand molecular factors underlying the disease progression, differential responses to therapeutic intervention, and predictive values of gene expression.

Key Publications

Recent key publications (out of >125)

1. Debes JD, Boonstra A, Balderramo D, Mattos AZ, Arrese M. Hepatobiliary cancers in South America, where disparity strikes. Lancet Gastro Hepatol. 2019. 4(8): 581. 

2. Brouwer WP, Chan HLY, Lampertico P, Hou J, Tangkijvanich P, W Reesink HW, Zhang W, Mangia A, Tanwandee T, Montalto G, Simon K, Ormeci N, Chen L, Tabak F, Gunsar F, Flisiak R, Ferenci P, Akdogan M, Akyuz F, Hirankarn N, Jansen L, Wong V, Liang X, Shalom Chen S, Groothuismink ZMA, Jaroszewicz J, Ozaras R, Kozbial K, Brahmania M, Xie Q, Chotiyaputta W, Xun Q, Pazgan-Simon M, Oztas E, Verhey E, Montanari NR, Sun J, Hansen BE, Boonstra A, Janssen HLA. For the GIANT-B Global Consortium. Genome wide association study identifies variants associated with early and sustained response to interferon in chronic hepatitis B patients: the GIANT-B study. Clin Inf Dis. 2019. Available online.

3. Hoogeveen RC, Robidoux MP, Schwarz T, Cheney JA, Kvistad D, Aneja J, Chung RT, Boonstra A, Kim AY, Timm J, Lewis-Ximenez LL, Tonnerre P, and Lauer GM. Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection. Gut. 2019. 68(5):893-904.

4. Boeijen LL, Hou J, de Groen RA, Verbon A, Boonstra A. Persistent replication of HIV, HCV and HBV results in distinct gene expression profiles by human NK cells. J Virol 2019. Accepted.

5. Peltenburg NC, Schoeman JC, Hou J, Mora F, Harms AC, Lowe SH, Bierau J, Bakker JA, Verbon A, Hankemeier T, Boonstra A. Persistent metabolic changes in HIV infected patients during the first year of combination antiretroviral therapy. Scientific Reports. 2018 Nov 16;8(1):16947.

6. Debes JD, van Tilborg M, Groothuismink ZMA, Hansen BE, Schulze zur Wiesch J, von Felden J, de Knegt RJ, Boonstra A. Serum immune signatures associated with HCC development in DAA-treated HCV patients. Gastroenterology. 2018. Feb; 154(3):515-517. 

7. Beudeker BJ, van Oord GW, Arends JA, Schulze zur Wiesch, van der Heide M, de Knegt RJ, Verbon A, Boonstra A, Claassen MAA. MAIT cell frequency and function in blood and liver of HCV mono- and HCV/HIV co-infected patients with mild versus advanced fibrosis. Liver Int. 2018. Mar;38(3):458-468. 

8. Boeijen LL, Montanari NR, de Groen RA, van Oord GW, van der Heide M, de Knegt RJ, Boonstra A. Mucosal-associated invariant T (MAIT) cells are more activated in chronic hepatitis B, but not depleted in blood: reversal by antiviral therapy. J Inf Dis. 2017. 216(8):969-976

9. Hou J, Brouwer WP, Kreefft K, Janssen HLA, French PJ, Vanwolleghem T, Boonstra.A. Unique liver transcriptomics profiles in chronic hepatitis B: intrinsic intrahepatic functional clusters discriminate distinct clinical phases. PlosOne. 2017. 12(6):e0179920. 

10. Vanwolleghem T, Boonstra A. Focus on the liver: host–virus interactions in HBV. J Hepatol. 2017. 66(5): 884-885.

11. Debes JD, de Knegt RJ, Boonstra A. The path to cancer, and back: Immune modulation during hepatitis C virus infection, progression to fibrosis and cancer, and unexpected roles of new antivirals. Transplantation. 2017. 101(5):910-915. 

12. Schoeman JC, Hou J, Harms AC, Vreeken RJ, Berger R, Hankemeier T, Boonstra A. Integrating metabolomics and transcriptomics to characterise the natural progression of chronic hepatitis B. Genome Medicine. 2016. 8(1): 64.

13. Spaan M, van Oord G, Kreefft K, Hou J, Hansen BE, Janssen HLA, de Knegt RJ, Boonstra A. Immunological analysis during interferon-free therapy for chronic hepatitis C virus infection reveals modulation of the natural killer cell compartment. J Inf Dis. 2016. 213(2): 216-23.

14. Vanwolleghem T, Hou J, van Oord G, Andeweg AC, Osterhaus ADME, Pas SD, Janssen HLA, Boonstra A. Re-evaluation of HBV clinical phases by system biology identifies unappreciated roles for the innate immune response and B cells. Hepatology. 2015. 62(1): 87-100. 

15. Spaan M, Claassen MA, Hou J, Janssen HLA, de Knegt RJ, Boonstra A. The intrahepatic T-cell compartment does not normalize years after therapy-induced hepatitis C virus eradication. J Inf Dis. 2015. 212(3): 386-390.
 

Our team

André Boonstra, PhD, principal investigator
José Debes, MD, principal investigator
Anthonie Groothuismink, research technician
Gertine van Oord, research technician
Noé Rico Montanari, MSc, PhD student
Ruben Hoogeveen, MD, PhD student
Judith Verhagen, PhD, project manager
Zgjim Osmani, PhD student
Boris Beudeker, MD PhD student
Gulce Sari, PhD student
Jeffrey Oliveira, research technician
Arlin Keo, bioinformatician