Host-parasite interaction

Description

Parasitic infections are extremely common worldwide, affecting billions of people. In our society they form medical problems in travellers and in migrants but in many low to middle income countries they are major causes of morbidity and mortality. The understanding of how parasites interact with their human host has far reaching consequences and is of importance to disciplines beyond parasitology. The program “Host-parasite interaction” focuses on understanding host-parasite interactions at the molecular, cellular and population level and the knowledge gained is being applied to achieve the two missions of the Department of Parasitology (PARA): 1) developing effective vaccines against parasitic diseases and 2) identifying parasite-derived immune modulatory molecules to control hyper-inflammatory diseases.

Specifically, genetic modification of malaria parasites, pioneered within this program has provided fundamental insight into malaria parasite behaviour and its interaction with the host, key for being at the forefront of malaria vaccine development. Following observations made in models systems a vaccine is entering Phase I/II clinical trials. Moreover, the study of parasitic helminths has led to in depth characterization of highly specialized glycoconjugates that interact with the human host leading to immune modulation and metabolic change. This knowledge is used not only for helminth vaccine development but also for developing new therapies for the hyper inflammatory diseases asthma and diabetes. With respect to this, recent efforts are directed towards the development of controlled human infection models to link and translate the research outcomes to the clinic. The novel diagnostic technologies developed/being developed within the program thread into, and support, a multitude of clinical and research activities within and outside of LUMC, extending to Africa and Asia.

In terms of research capital, the innovative diagnostic methods, the glycomic techniques, the parasite genome manipulation, (molecular) imaging of pathogens, specialized cellular immunological and metabolic assays, disease models, controlled human infections as well as well-established field study sites all ensure a versatile and flexible environment that is highly responsive to the evolving societal needs here and elsewhere.

Aim and focus

Ambition: To develop effective vaccines against parasitic diseases and to develop parasite-derived immune modulatory molecules for control of hyper-inflammatory diseases by focusing on:

• Genetic modification of malaria parasites to develop a vaccine and to gain insight into immunity
• Glycobiology of parasitic infections and development of glycoconjugates as vaccine candidates
• Immunometabolism to switch immune responses
• Identification of parasite-derived modulatory molecules to cure asthma and diabetes
• Controlled human infection models to test vaccines and drugs, and to dissect immune and metabolic responses
• Development and application of novel diagnostic approaches for the clinic, for travellers and for worldwide control programs

Together, research aims on the one hand at developing vaccines against malaria and helminth infections, in order to participate in the global fight against poverty-related and neglected diseases, while on the other, we seek to develop immune modulatory molecules based on fundamental knowledge of parasite-host interactions to combat hyper inflammatory diseases. In this way we serve the needs in our society and those around us.

Position in international context

Internationally, this program is among the frontrunners when considering malaria vaccine development, parasite glycobiology and immunomodulation. In addition, the diagnostic test for schistosomiasis, developed at PARA, has been recommended as the test of choice for use in the elimination program by the WHO.

The expertise in genetic modification and bio-imaging as well as the extensive bank of modified parasites has put us as a central link for international malaria research. Moreover, the expertise in dedicated mass spectrometry for glycan analysis, the unique glycan arrays and a bank of well-characterized parasite-derived molecules with disease modifying activity gives us a key role in international networks for vaccine, drug and diagnostic target discovery. The expertise in cellular immunology at PARA, disease models and access to population cohorts, translates into international collaborations on clinical trials testing parasite vaccines and drugs. The PIs are often asked to shape research in academic institutions abroad and attract PhD students and post-doctoral fellows with their own funding, from all over the world.

The program attracts funding from national (ZonMw, STW, NWO-CW, KNAW, LongFonds) and international (Gates foundation and EU) funding bodies as well as charity or industry, and the department holds several patents.

Content / highlights / achievements

• Using genomic and post-genomic technologies in combination with genetic modification of malaria parasites the following was achieved: (i) generation and preclinical testing of genetically attenuated parasites that induce protective immunity, resulting in the creation of genetically attenuated parasite vaccine candidate ready for testing in humans; (ii) identification of novel vaccine candidate antigens for development of sub-unit vaccines; (iii) analysis of multiple loss-of-function mutants uncovering novel aspects of malaria parasite drug resistance and pathology.
• Using novel approaches for the integrated structural analysis of glycoconjugates and the development of a new glycan array it has been possible to i) identify glycans and glycoconjugates that play an essential role in the biology of schistosomes and their interaction with the host; ii) understand how anti carbohydrate responses contribute to immunity.
• Through population studies in Africa and Asia, the question of how parasitic infections drive Th2 and regulatory responses has been addressed. The identification of the single molecules capable of affecting innate and adaptive immune responses has driven i) the structural and functional characterization of immune modulatory molecules that affect metabolism to induce a Th2 and Treg responses via dendritic cells (DCs), ii) the identification of molecules and pathways that affect inflammatory allergic reactions as well as insulin sensitivity.
• The first ever controlled human schistosome infection in the world, whereby single sex cercaria are used to infect volunteers.
• The development of novel diagnostic tests, multiplex real-time PCR approach and point-of-care technology in support of intervention studies and epidemiology. In addition, this work has resulted in important changes in the diagnostic approach of intestinal parasites in the Netherlands.

Future themes

• Translation of research findings to the clinic: With the ability to conduct controlled malaria and schistosome infections in volunteers, it will now be possible to speed up vaccine testing. Our cellular and molecular expertise will help to analyse correlates of protection in the upcoming trials. Malaria vaccine work will focus on different genetically attenuated parasites and subunit vaccines, optimising routes of administration and increasing vaccine potency.
• The activities surrounding the link between parasites and non-communicable diseases will move beyond allergic diseases and will expand into metabolic disorders and type-2 diabetes. The future work will zoom in on the use of helminth derived molecules to improve allergies and insulin sensitivity.
• Focus on immune modulation at the level of cell metabolism: this area with a strong fundamental research aspect, can have important impact on the understanding of immunologic memory in vaccine development, regulatory cell development during chronic parasitic infections as well as manipulation to switch immune activity from a pro-inflammatory to an anti-inflammatory and vice versa.
• Application of the new diagnostic platforms to better understand the fundamental mechanisms determining the distribution and control of helminth infections. With respect to the new unique schistosomiasis diagnostic test, stronger collaboration with industrial partners and NGOs will be fostered to work towards commercialisation. New collaborations have started with Delft University of Technology and their Delft Global program to develop smart mobile diagnostic devices for detection of malaria and helminth infections that can be an integral part of eHealth initiatives.

Cohesion within LUMC

The research is embedded in the LUMC Research Profile “Immunity, Infection and Tolerance” (IIT). The immune metabolism work is part of the emerging area of Immunometabolism within IIT. In addition, the use of metabolomics profiling and cellular phenotyping will contribute to the consolidation of the LUMC immune monitoring platform. The activities in our program are also embedded in the two generic research profile areas of Biomedical Imaging and Innovation in Health Strategy and Quality of Care. There are well established joint research projects with Pulmonology, Center of Proteomics and Metabolomics, Endocrinology, Infectious Diseases, Medical Microbiology and Molecular Cell Biology.