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Tolerance and Resistance to parasite Infection: Trypanosomatidae as paradigm (TRIT)

Research project P7/41 (Research action P7)

Persons :

Description :

Unravelling (i) the mechanisms used by parasites to actively perturb the immune response and hereby intrude their host, and (ii) the mechanisms by which the host balances the inflammatory immune response required to eliminate these parasites while avoiding inflammation-associated tissue damage, represent a major challenge for public health programs. We propose to use Trypanosomatidae (prototypes: African trypanosomes Trypanosoma brucei, T. congolense, T. vivax and Leishmania donovani) as model organisms to investigate the dialogue between the parasite and its hosts.

Our main objectives are to (1) study how parasites counteract the capacity of the (insect and mammalian) host to eliminate the pathogen (called resistance to infection); (2) investigate how parasite- and vector- derived molecules modulate host (patho)physiology; (3) address how the host in turn attempts to control the tissue pathogenicity during parasite infection (called tolerance of the host to infection) (see Fig. 1, Form D).

This proposal is a direct continuation of the previous collaborative IAP network P6/15 (Molecular dialogue between parasite and hosts: the trypanosome model) which was strongly supported during the IAP phase VI ex-post evaluation. The new network include 4 partners that were collaborating to the P6/15 project, the ULB (Dr. E. Pays/B. Vanhollebeke), the VUB (Dr. P. De Baetselier), the ITG (Dr. J. Van Den Abbeele) and the LMUM (Dr. M. Boshart). The complementary and scientifically recognized unique expertises of these partners in the field of African trypanosomiasis (see below) have been re-enforced by the ITG group of Dr. J-C. Dujardin recognized for its expertise in Leishmania biology, genomics and metabolomics. In addition, the IEM group of Dr. B. Ryffel will contribute to the network through its expertise in immunopathogenicity of infection. The two latter partners will extend our research to other parasites (following the recommendation of the IAP phase VI ex-post evaluation), and provide original tools that will contribute to the success and international visibility of the network.
The IAP phase VII will give the opportunity to the new young group leaders who emerged during the IAP phase VI (Dr. B. Vanhollebeke, ULB; Dr. S. Magez, VUB; Dr. J. Van Den Abbeele, ITG) to further establish their international and national scientific position. In particular, Dr. B. Vanhollebeke will endorse the role of scientific coordinator, with the help of Prof. E. Pays during the period remaining before retirement (July 2014). In addition, since Prof. P. De Baetselier will retire in September 2015, Prof. S. Magez will endorse the role of scientific promoter for the VUB.

Work package 1: How do parasites adapt to immune and drug pressure in their host?
(1) The ULB will detail how trypanosome species that infect humans (T. brucei gambiense) resist to killing by the trypanolytic factor ApoL1. Also, ULB and VUB will dissect the mechanism by which ApoL1 enters trypanosomes independently from the haptoglobin-hemoglobin receptor (termed TLF2 uptake).
(2) The ULB, ITG-1 and LMUM groups will unravel the signalling/differentiation activity occurring during the development of trypanosomes in the mammalian hosts. A particular attention will be devoted to the characterization of the endocytic machinery.
(3) The ITG-1 and LMUM will focus on metabolic adaptations of trypanosomes to cope with oxidative stress and nutrient availability at different developmental stages in the tsetse fly.
(4) The ITG-2 in concert with ULB and LMUM will aim to characterize the adaptation to oxidative stress behind the higher in vivo survival skills of antimonial-resistant versus antimonial-sensitive Leishmania donovani in natural (drug-free) conditions.
Work package 2: How do parasite- and vector- derived molecules modulate the (patho)physiology of the host?
(1) The VUB will assess how enzymes released by trypanosomes (ex sialidases) can damage host immune cells and, in collaboration with IEM, how trypanosome elicited inflammation contributes to anemia of chronic disease.
(2) The VUB, ITG-1 and IEM will investigate how B-cell destruction is triggered by parasites (transmitted by needle or by tsetse infected flies), which intracellular signal cascades leads to this immunopathogenic damage and their consequences for vaccination.
(3) The ITG-1 and ITG-2 will investigate how trypanosome infection modifies the tsetse fly salivary gland environment. In addition, in collaboration with the VUB, ITG-1 will detail how immune-active components of the saliva from the insect vector (identified by ITG-1) influence the development of the parasite and the innate immune response of the mammalian host at the biting site.

Work package 3: Which mechanisms control host tissue pathogenicity during parasite infection?
(1) The ULB will study how immunomodulatory molecules from trypanosomes already identified by the network influence resistance and tolerance to infection, and in collaboration with the VUB and LMUM will aim to unravel how these molecules influence the arginine metabolism as well as the signalling pathway (cAMP, autophagy) involved in inflammatory/anti-inflammatory immune response (early induction/inhibition of IL-10, TNF, …).
(2) The capacity of ApoLs to modulate myeloid cell activation and hereby inflammation will be addressed by the ULB. In this respect original transgenic mice (ApoL KO or ApoL1 expressor) will be analyzed.
(3) The VUB will identify mechanisms by which the anti-trypanosome immune response, in particular the response mediated by distinct myeloid cell subpopulations identified in the previous P6/15 project (including “tissue-resident” and “tissue-recruited subpopulation), contribute to hepatic and brain inflammation, as well as to anemia of chronic disease. This research will benefit from the expertise of IEM in relevant murine models of human pathologies in lung inflammation, host response to infection and neuropathology. Of note, the VUB has identified a potential marker for Kuppfer cells that is currently used to generate transgenic (knock-in) mice allowing tracking and ablating this selected myeloid cell population to evaluate their role in liver injury caused by trypanosome infection. Moreover, we will take advantage of the unique capacity of ITG-1 to infect mice with trypanosome infected tsetse flies to evaluate the contribution of distinct myeloid cell subpopulations to tolerance in a more natural setting. Furthermore, Nanobodies®, camelid-derived single-domain antibodies originally identified in VUB and proved as valuable tools to target inflammatory cells in vivo will be produced as tools to test in collaboration with ULB and IEM the activity of selected molecules in vivo/in vitro, to trace expressing cells through microscopy or in vivo imaging, etc.
(4) The ITG-2, in collaboration with the VUB, will study the host response upon natural L. donovani strains with differential in vivo survival skills, aiming to identify host factors essential for control of these respective clinical lines.

Specific expertise of the partners

ULB: molecular biology of trypanosomes, mechanism of resistance of trypanosomes to innate immune components
VUB: immunopathogenicity of trypanosomes, unravelling the molecular/and functional B cells and myeloid cell diversity (monocytes, macrophages, DCs), using it as an in vivo sensor to track inflammatory responses and as a target for therapeutic intervention
ITG-1: trypanosome-tsetse fly transmission model; trypanosome development in the tsetse fly; molecular biology of tsetse fly
ITG-2: comparative genomics and metabolomics (integrated systems biology) to study the mechanisms of resistance of Leishmania to drug treatment and immune response
LMUM: Cyclic AMP and PKA biochemistry, signalling mechanisms in trypanosome life cycle development and in the host-parasite interaction, energy metabolism and its regulation in the life cycle
IEM: lung, brain and intestinal immunopathogenicity caused by different pathogens (Plasmodium, Listeria, Mycobacteria, Toxoplasma, …); generation and provision of specific murine models (KO mice), running the Genomic and Transcriptomic Affimetrix Plateform GENOTRANS.

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