Translational parasitology Group

Development of a controlled human infection model for schistosomiasis and transfer of this model to Uganda

At CHIC we dedicate a large part of our efforts to advancing our understanding and the development of vaccines to combat schistosomiasis. The production of eggs by the paired Schistosoma mansoni worm in the mesenteric venules causes damage to the surrounding tissue, affecting the lives of hundreds of millions of people around the world. We have developed protocols and molecular tools to produce the Schistosoma mansoni larvae (cercariae) of only one sex (male or female). These single-sex cercariae can develop into adult worms within their hosts but cannot produce eggs. Having investigated these infections in animal models first, we subsequently developed a controlled human infection model for single-sex schistosomes (both a male and a female model) through the exposure of healthy individuals to low numbers of infectious cercariae. Novel diagnostic tools developed by Dr. Govert van Dam and Dr. Paul Corstjens allowed us to detect the infection over time with a highly sensitive lateral flow assay (upconverting phosphor lateral flow assay for detection of circulating anodic antigen).

We now proceeded to also test the immune response after repeated infection with male schistosoma mansoni cercariae in healthy volunteers. This study is ongoing, for up-to-date information on the recruitment of volunteers, please refer to https://controlledhumaninfectionscentre.com/ Dr. Emma Houlder leads a research program to identify antigen specific responses from these controlled infection studies which may serve as future vaccine candidates.

Recently, CHIC has embarked on a long-term collaboration with Prof. Elliott at the Ugandan Virus Research Institute (UVRI), to transfer the technology of controlled human infections for schistosomiasis to Entebbe, at the lakeshore of lake Victoria where schistosomiasis is endemic. In addition, CHIC has dedicated efforts to test the Smp80 vaccine, one of the most promising vaccines against Schistosoma mansoni, developed by Prof. Siddiqui at Texas Tech University Health Sciences Center in a clinical trial using its controlled human infection model. This study is funded by the Wellcome Trust.

Publications:

Immunological Considerations for Schistosoma Vaccine Development: Transitioning to Endemic Settings.

Driciru E, Koopman JPR, Cose S, Siddiqui AA, Yazdanbakhsh M, Elliott AM, Roestenberg M.Front Immunol. 2021 Mar 4;12:635985. doi: 10.3389/fimmu.2021.635985. eCollection 2021.

Controlled human infection models to evaluate schistosomiasis and hookworm vaccines: where are we now?

Koopman JPR, Driciru E, Roestenberg M.Expert Rev Vaccines. 2021 Nov;20(11):1369-1371. doi: 10.1080/14760584.2021.1951244. Epub 2021 Jul 15.

Katayama Syndrome Without Schistosoma mansoni Eggs.

Langenberg MCC, Hoogerwerf MA, Janse JJ, van Lieshout L, Corstjens PLAM, Roestenberg M; CoHSI clinical trial team.Ann Intern Med. 2019 May 21;170(10):732-733. doi: 10.7326/L18-0438. Epub 2019 Jan 8.

A controlled human Schistosoma mansoni infection model to advance novel drugs, vaccines and diagnostics.

Langenberg MCC, Hoogerwerf MA, Koopman JPR, Janse JJ, Kos-van Oosterhoud J, Feijt C, Jochems SP, de Dood CJ, van Schuijlenburg R, Ozir-Fazalalikhan A, Manurung MD, Sartono E, van der Beek MT, Winkel BMF, Verbeek-Menken PH, Stam KA, van Leeuwen FWB, Meij P, van Diepen A, van Lieshout L, van Dam GJ, Corstjens PLAM, Hokke CH, Yazdanbakhsh M, Visser LG, Roestenberg M.Nat Med. 2020 Mar;26(3):326-332. doi: 10.1038/s41591-020-0759-x. Epub 2020 Feb 17.

Immunological investigation into the early stages of parasitic disease

Our clinical trials and our novel in vitro tools allow us to study the human host response to (early) invasion of parasites. We are interested to understand how and if early responses to parasites may be beneficial for the induction of protective immunity of the human host. For this purpose, we established ex vivo skin models for parasites, using left-over skin from plastic surgical operations. Previously, we found that Plasmodium falciparum sporozoites interact with human macrophages as they are deposited in human skin. These macrophages subsequently upregulate expression of PDL1, an immune regulatory marker, and secrete the regulatory cytokine IL-10. Similar responses can be found when macrophages interact with cercariae of Schistosoma mansoni.  

We are keen to investigate how these early responses dictate later adaptive immunity and whether these can be enhanced by repeated exposure to the early stage of infection with parasites. Recently, we have completed a study of repeated infection with Necator americanus hookworms and are currently studying the responses of healthy volunteers to genetically attenuated Plasmodium falciparum parasites.

In collaboration with the immunoparasitology group we exploit advanced immunological profiling tools, e.g. CyTOF and RNAseq, to dissect immune responses of volunteers infected in one of our trials to link these responses to the in vitro and ex vivo immunological models.

Publications

Plasmodium sporozoites induce regulatory macrophages.

Winkel BMF, Pelgrom LR, van Schuijlenburg R, Baalbergen E, Ganesh MS, Gerritsma H, de Korne CM, Duszenko N, Langenberg MCC, Chevalley-Maurel SC, Smits HH, de Jong EC, Everts B, Franke-Fayard B, Roestenberg M.PLoS Pathog. 2020 Sep 8;16(9):e1008799. doi: 10.1371/journal.ppat.1008799. eCollection 2020 Sep.PMID: 32898164 

Protective immunity differs between routes of administration of attenuated malaria parasites independent of parasite liver load.

Haeberlein S, Chevalley-Maurel S, Ozir-Fazalalikhan A, Koppejan H, Winkel BMF, Ramesar J, Khan SM, Sauerwein RW, Roestenberg M, Janse CJ, Smits HH, Franke-Fayard B.Sci Rep. 2017 Sep 4;7(1):10372. doi: 10.1038/s41598-017-10480-1.PMID: 28871201 

Early Induction of Human Regulatory Dermal Antigen Presenting Cells by Skin-Penetrating Schistosoma Mansoni Cercariae.

Winkel BMF, Dalenberg MR, de Korne CM, Feijt C, Langenberg MCC, Pelgrom L, Ganesh MS, Yazdanbakhsh M, Smits HH, de Jong EC, Everts B, van Leeuwen FWB, Hokke CH, Roestenberg M.Front Immunol. 2018 Oct 31;9:2510. doi: 10.3389/fimmu.2018.02510. eCollection 2018.PMID: 30429854 

Development of imaging tools to visualize parasites

In collaboration with the Interventional Molecular Imaging laboratory led by Prof. F.W.B. van Leeuwen we develop novel tools to visualize the migration, development and transition of parasites from one host to the other. We were able to, for the first time, create movies of Plasmodium falciparum sporozoites migrating in ex vivo human skin. We subsequently developed automated tools to quantitate the movement of these parasites. Using this software, we were able to identify different movement patterns of radiation-attenuated and non-attenuated sporozoites. In addition, we assessed the role of medium composition on motility patterns of Plasmodium falciparum sporozoites.

We were the first to also visualize the invasion of Schistosoma mansoni cercariae in human skin and evaluate different invasion patterns.

In the future, we will continue to develop novel tools to visualize this unchartered area of research.

Publications:

Winkel BMF*, de Korne CM*, van Oosterom MN, Staphorst D, Meijhuis M, Baalbergen E, Ganesh MS, Dechering KJ, Vos MW, Chevalley-Maurel SC, Franke-Fayard B, van Leeuwen FWB, Roestenberg M

Radiation impairs movement of Plasmodium falciparum malaria sporozoites in human skin, Sci Rep. 2019 Sep 17;9(1):13436.

Winkel BMF, de Korne CM, van Oosterom MN, Staphorst D, Bunschoten A, Langenberg MCC, Chevalley-Maurel SC, Janse CJ, Franke-Fayard B, van Leeuwen FWB, Roestenberg M.

A tracer-based method enables tracking of Plasmodium falciparum malaria parasites during human skin infection. Theranostics 2019; 9(10):2768-2778.