Towards novel treatment options for human and animal trypanosomiasis

Ondertitel:from mechanistic insights in antiparasitic compounds to immunological aspects of early infection

Human African trypanosomiasis is a neglected tropical disease caused by the tsetse fly-transmitted unicellular protozoa Trypanosoma brucei gambiense and T. b. rhodesiense. Inoculation of the parasite into the skin results in infection of the host. The first stage of the disease is characterized by non-specific flu-like symptoms due to parasite multiplication in the lymphatics and the bloodstream. Parasite invasion of the central nervous system causes severe neurological symptoms. A wide range of other trypanosome species are responsible for disease in wild and domestic animals causing a widespread socioeconomic problem. The therapies that are currently available are limited in number and face disadvantages of toxicity and drug resistance. Despite decades of research, effective vaccines to protect humans and animals from infection are still lacking. In addition, asymptomatic individuals who remain undiagnosed and hence untreated can still contribute to disease transmission. The development of novel treatment strategies will therefore be crucial to achieve disease elimination. The first aim of this thesis was to evaluate and characterize novel anti-trypanosomal compounds. The medicinal chemistry group of the UGent developed a series of nucleoside analogues based on structural elements of the natural nucleoside antibiotics tubercidin and cordycepin, which were previously shown to have high antiparasitic potency but accompanied by extreme host toxicity. We identified 2 promising nucleoside analogues with high activity against Stage-II disease. Mechanistic evaluation using a whole-genome RNAi library identified TbAT1, ADKIN and 4EIP as involved in their mode-of-action. Evaluation of the adenosine analogues for the treatment of animal trypanosomiasis was able to identify compounds showing a broad activity profile across multiple parasite species/strains. The second aim was to characterize the early immunological events that occur upon the bite of an infected tsetse fly to gather the scientific knowledge necessary to develop novel intervention strategies based on the host-parasite interplay. Neutrophils were previously identified as being rapidly recruited to the site of infection, exhibiting a surprising pro-parasitic response. Detailed in vitro and in vivo analysis of the role of the neutrophil showed that neutrophils become activated upon parasitic stimulation but without a negative impact om parasite replication. In naturally infected mouse models, neutrophils play a role in parasite retention at the site of infection and impact on systemic organ colonization. Analysis of parasite burdens in various tissues identified the lungs as a site of strong parasite proliferation pointing to a potential role as parasitic tissue reservoir. Parasite presence resulted in a large influx of immune cells and change in the transcriptional profile, however, without detrimental effect on lung function. Depletion of specific immune cell subsets including eosinophils, NK cells and IgM+ B cells may underly the increased susceptibility of patients to opportunistic infections.

ISBN:978-90-5728-743-5

Jaar van publicatie:2022

Trefwoorden:Doctoral thesis

Toegankelijkheid:Closed