|Immunobiology of Trypanosoma Infections|
|HEAD||Dr. MINOPRIO Paola / firstname.lastname@example.org|
|MEMBERS||BLOM-POTAR Marie Christine / BOUTOUT Laurence / COATNOAN Nicolas / COSSON Alain / D’ARCHIVIO Simon / Dr. GOYARD Sophie / MEDINA Mathieu
The laboratory’s primary goal is to identify molecules which are both implicated in parasite evasion of the host’s immune system and could ultimately be used as targets in the development of new anti-trypanosomiasis therapies. The teamhas been studying experimental models of Chagas’ disease and animal sleeping sickness, two of the “most neglected diseases” that afflict the poor and powerless in developing regions of sub-Saharan Africa, Asia and the Americas. Together they cause an estimated 500,000 to 1 million deaths annually. Chagas’ disease, the third largest disease burden in Latin America, is caused by Trypanosoma cruzi. It affects at least 10 million people and 100 million people are at risk. Animal trypanosomosis (Nagana) is major livestock challenge, which is mainly caused by Trypanosoma vivax, causes about 3 million cattle deaths annually, has a severe impact on African’s agriculture, and was recently introduced into South America and Mauritius. No vaccines have yet been developed against these seriously disabling or life-threatening illnesses.
Two new TcPRAC inhibitors were identified by multidisciplinary strategies of drug design
Trypanosoma cruzi Proline Racemase (TcPRAC) is an enzyme released upon infection by the infective forms of the parasite. TcPRAC is a T-cell independent B-cell mitogen that secreted by the parasite induces indiscriminate activation and terminal maturation of B cells. Most of these cells secrete antibodies that do not recognize parasite antigens, contributing to parasite evasion of the host immune system, persistence and disease progression. TcPRAC was also shown to be involved in parasite infectivity and fate inside host cells. As a result, the enzyme is a putative target for the development of both chemotherapy and/or immunotherapeutics. Our previous studies revealed that the catalytic site of the enzyme is small, what could be seen as a challenge for the identification of putative enzyme inhibitors. To widen the chemical space accessible to virtual screening, intermediate conformations between liganded (closed) and free (opened) enzyme structures were calculated to take account of the flexibility of TcPRAC observed upon ligand binding. Derived transitional conformation models were then used to perform docking simulations for several thousand molecules in accessible chemical libraries. Two compounds, Oxo-PA and Br-OxoPA, were identified and shown to exert 3-6 times more inhibition than the known, water-insoluble, PRAC inhibitor – pyrrole carboxilic acid (PYC). The apparent Ki of these molecules is significantly lower than that of PYC. These novel inhibitors were shown to hamper parasite/host cell interaction in vitro. Christallographic data of the enzyme combined with these ligands are now been used to improve our knowledge of the chemical structure of the TcPRAC / inhibitor complex and the physico-chemical characteristics of the inhibitors. New derivatives were designed and synthesized according to the most relevant molecular modeling data and are presently under study in the laboratory (colls. A. Blondel, A. Haouz & F. Saul, Department of Structural Biology and Chemistry & N. Gouault and P. Uriac, University of Rennes).
Nagana : the animal sleeping sickness
Infections caused by T. vivax and T. congolense which predominate in livestock and small ruminants have been subject to little study. In order to circumvent the major constraints inherent to studying T. vivax/host interactions in the field, we developed in vivo murine models of T. vivax trypanosomosis. We showed that the mouse experimental model reproduce most features of the infection in cattle. Thus, anemia and non-specific (parasite-directed) polyclonal hypergammaglobulinemia are the most common disorders coincident with the rise in parasitemia, but also thrombocytopenia and a reduced number of B lymphocytes in the periphery. We showed that the decrease observed in peripheral B cell populations does not seem to be compensated by newly arriving B cells from the bone marrow. The infection nevertheless prompts intense production of stem cells that mature into myeloid and lymphoid precursors. In spite of this, B cell numbers are specifically reduced in the periphery as the infection progresses. Thus, negative feedback seems to be set in motion by the infection in the bone marrow, more precisely affecting the maturation of B precursors and consequently the output of mature B cells. The origin of these phenomena is unclear but this doubtless creates a homeostatic imbalance that contributes to the inefficient immune response against T. vivax infection. More than reflecting only the main parasitological parameters of the animal infection, the mouse model can be used to elucidate the immunopathological mechanisms involved in parasite evasion and persistence, and the tissue damage seen during infection and disease. Given that TcPRAC appears to be involved in the key developmental processes of T. cruzi, we hypothesized that PRAC may also be present - and share similar biological functions – in T. vivax. We showed that the PRAC gene was indeed present in T. vivax (TvPRAC). The gene is functional and the protein it codes, TvPRAC, is equally mitogenic for B cells. It is interesting to note that the compounds identified as TcPRAC inhibitors do show comparable abilities to inhibit TvPRAC. Work in progress aims at genetically inactivate TvPRAC by the construction of null mutant T. vivax to verify if the gene is essential for parasite development. This would qualify TvPRAC as a new target for the development of a chemotherapy against animal trypanosomosis.
Keywords: Chagas'disease, Trypanosoma cruzi, Nagana, African trypanosomiasis, B-cell mitogens, proline racemase
- Chamond N, Cosson A, Coatnoan N, Minoprio P (2009) Proline racemases are conserved mitogens: characterization of a Trypanosoma vivax proline racemase. Mol Biochem Parasitol. 165:170-9.
- Coatnoan N, Berneman A, Chamond N, Minoprio P (2009) Proline racemases: insights into Trypanosoma cruzi peptides containing D-proline. Mem Inst Oswaldo Cruz. 104 Suppl 1:295-300.
- Chamond N, Cosson A, Blom-Potar MC, Jouvion G, D'Archivio S, Medina M, Droin-Bergere S, Huerre M, Goyard S, Minoprio P (2010) Trypanosoma vivax infections: pushing ahead with mouse models for the study of Nagana. I. Parasitological, hematological and pathological parameters. PLoS Negl Trop Dis. 4:e792.
- Blom-Potar MC, Chamond N, Cosson A, Jouvion G, Droin-Bergere S, Huerre M, Minoprio P (2010) Trypanosoma vivax infections: pushing ahead with mouse models for the study of Nagana. II. Immunobiological dysfunctions. PLoS Negl Trop Dis. 4:e793.
- Berneman A, Alves-Ferreira M, Coatnoan N, Chamond N, Minoprio P (2010) Medium/High Throughput D-Amino Acid Oxidase Colorimetric Method for Determination of D-Amino Acids. Application for Amino Acid Racemases. J Microbial Biochem Technol. 2:139-146.
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