Research Dorien Mabille

Abstract

African trypanosomiasis is a tsetse fly transmitted disease indigenous for the African continent. Millions of people in 36 sub-Saharan African countries are currently at risk of this fatal infection. The current drugs are faced with limitations of toxicity and drug resistance and to date not a single effective vaccine is available. For both vaccine development and elimination endeavours, an adequate understanding of the immunology of infection onset, disease progression and distribution of parasites to tissue sanctuary niches is crucial. Our recent work has identified the skin and lungs as overlooked tissue reservoirs. Although they are sites of strong parasite proliferation, the limited organ-specific pathology has led us to overlook their importance in disease establishment and parasite transmission. Asymptomatic individuals who remain undiagnosed may pose a significant constraint for disease control. Understanding both colonization of skin and lungs as major reservoir tissues and specific parasite adaptations, will support the identification of parasite- or host-specific markers for diagnosis and increase our insight into the immunological basis of increased susceptibility to secondary pulmonary infections. Hence, we will use unbiased approaches linking parasite and tissue transcriptomes and evaluate the use of breathomics as novel diagnostic method.

Researcher(s)

• Promoter: Caljon Guy
• Co-promoter: Lamote Kevin
• Fellow: Mabille Dorien

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

Abstract

Human African trypanosomiasis is a tsetse fly-transmitted disease indigenous for the African continent. Millions of people in 36 countries in sub-Saharan Africa are currently at risk of this often fatal infection. The drugs that are currently available are faced with limitations of toxicity and drug resistance and not a single effective vaccine is yet available. For both vaccine development and elimination endeavours, an adequate understanding of the immunology of infection onset is crucial. Mast cells (MCs) are immune sentinels in the skin that are amongst the first to contact the Trypanosoma parasite following a tsetse fly bite. These cells play major roles in orchestrating early inflammatory responses, regulating vascular permeability and influencing immunity development in lymph nodes. Despite seminal work in mosquito-transmitted viral diseases, MCs remain underexplored as target cell during parasitic infections. Combining our expertise in MCs and our work with Trypanosoma as well as the possibility to use the natural vector in our inhouse insectary, the role of MCs will be assessed in natural Trypanosoma infections. Using human MCs derived from progenitors in donor blood, a battery of cellular activation markers will provide insights in the interaction with the Trypanosoma parasite and tsetse fly-derived components. The mast cell role will be further explored in appropriate animal models of mast cell deficiency following a natural infection by a tsetse fly bite. To summarize, the preliminary results of our in vitro and in vivo experiments will provide insight towards novel intervention strategies and foundations for future research.

Researcher(s)

• Promoter: Mabille Dorien

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

Abstract

Neutrophils and macrophages are cells of the innate immune system of the mammalian host with a range of potential effector functions against pathogens. These cells are rapidly recruited to sites of parasite infection. Counterintuitively, neutrophils favor the onset of parasite infections as we have described for sleeping sickness parasites (Trypanosoma brucei sp.) inoculated by the bites of tsetse flies. Indeed, selective neutrophil removal or genetic conditions resulting in lower neutrophil levels in the blood yield a higher level of resistance to trypanosome infection. Monocytes on the other hand are activated to differentiate into M1 macrophages that contribute to parasite control in the early stage of infection. The differential impact of neutrophils and macrophages suggests that specific inhibition of neutrophil functions could result in higher levels of resistance to infection. This project will compare the responses of neutrophils and monocytes to parasite presence by capturing their kinase activity fingerprints. Kinase targets in cell type specific and common responsive pathways will be identified. Kinase inhibitors from commercially available or proprietary collections will be used to selectively inhibit the parasite-induced responses and to evaluate the impact on parasite infection. Collectively, this project will forward our understanding of early trypanosome transmission and is directed at revealing novel transmission-blocking concepts and strategies.

Researcher(s)

• Promoter: Caljon Guy
• Co-promoter: Maes Louis
• Fellow: Mabille Dorien

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

Abstract

Neutrophils and macrophages are cells of the innate immune system of the mammalian host with a range of potential effector functions against pathogens. These cells are rapidly recruited to sites of parasite infection. Counterintuitively, neutrophils favor the onset of parasite infections as we have described for sleeping sickness parasites (Trypanosoma brucei sp.) inoculated by the bites of tsetse flies. Indeed, selective neutrophil removal or genetic conditions resulting in lower neutrophil levels in the blood yield a higher level of resistance to trypanosome infection. Monocytes on the other hand are activated to differentiate into M1 macrophages that contribute to parasite control in the early stage of infection. The differential impact of neutrophils and macrophages suggests that specific inhibition of neutrophil functions could result in higher levels of resistance to infection. This project will compare the responses of neutrophils and monocytes to parasite presence by capturing their kinase activity fingerprints. Kinase targets in cell type specific and common responsive pathways will be identified. Kinase inhibitors from commercially available or proprietary collections will be used to selectively inhibit the parasite-induced responses and to evaluate the impact on parasite infection. Collectively, this project will forward our understanding of early trypanosome transmission and is directed at revealing novel transmission-blocking concepts and strategies.

Researcher(s)

• Promoter: Caljon Guy
• Co-promoter: Maes Louis
• Fellow: Mabille Dorien

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project