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Trypanosoma Infectious Processes

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TEAM :
Paola MINOPRIO

Sophie GOYARD

Simon D'ARCHIVIO

Alain COSSON
 
Patricia Maria LOURENçO DUTRA

Marie Jesus ROJAS

Laurence BOUTOUT
ADDRESS : 
Institut Pasteur
Laboratoire des Processus Infectieux à Trypanosoma

Département d'Infection et Epidémiologie

25 rue du Dr. Roux

75724 Paris cedex 15 - France
 
Tel: (33) 1 45 68 86 15
Lab: (33) 1 40 61 34 46 / 44 38 92 65
Fax: (33) 1 40 61 31 85

Assistante :
Laurence Boutout, (33) 1 45 68  80 11 / (33) 1 45 68 85 65

                                                                                                                                  
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[Summary]
[
Sommaire] [Collaborations] [Publications]


[T. cruzi Genome]
[T. vivax DB] [TriTryps database] [Virtual library Chagas'disease and Carlos Chagas]

For Chagas' disease press info:  http://www.pasteur.fr/actu/presse/documentation/chagas.html


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Summary


Neglected tropical diseases kill, impair or permanently disable millions of people every year, often resulting in life-long physical pain, social stigmatization and abuse. They affect 1 billion people, primarily poor populations living in tropical and subtropical climates. WHO is currently focusing on 13 most neglected tropical diseases, notably : Chagas disease, Human African trypanosomiasis, Leishmaniasis, Lymphatic filariasis, Cholera, Onchocerciasis, Buruli ulcer, Leprosy, Dengue, Schistosomiasis, Dracunculiasis, Soil-transmitted helminthiasis and Trachoma. Less than 1% of the 1393 new drugs registered during 1975–1999 was for tropical diseases. Less than 0.001% of the US$ 60–70 billion went towards developing new and urgently needed treatments for tropical diseases.


Drug for Neglected Diseases (DNDi) home page (click)


Summary

The studies of the team are centered on understanding the disturbances of the host immune system triggered by Trypanosoma infectious processes. The group is particularly interested in molecules that play a role in parasite escape and persistence in the host and, more precisely, those at the origin of the ‘non specific’ polyclonal B lymphocyte activation observed upon infection. Proline racemases were identified in Trypanosoma cruzi - responsible for Chagas’ disease, in the African trypanosome Trypanosoma vivax - responsible for Nagana – and in other pathogenic bacteria, such as Clostridium sticklandii and the nosocomial Clostridium difficile. Hydroxyproline epimerases were also characterized in bacteria of medical and veterinary importance (i.e. Pseudomonas aeruginosa, Brucella mellitensis, Brucella suis, etc). These enzymes are mitogenic for host B cells and play significant roles in microorganism biology and infectivity. The team uses genetic, molecular and proteomic approaches to validate those mitogens and other virulence factors as potential targets for immuno- and therapeutic interventions against trypanosoma infections. [TOP]

Trypanosoma cruzi Infections induce a pronounced dysregulation of the immune system in humans and in experimental mouse models. This manifests itself as an initial hypergammaglobulinemia and immunosuppression followed by tissue damage associated with the chronic phases of the disease. Although natural killer cells and parasite-derived suppressive substances have been evoked to explain the immunosuppression, we favoured the hypothesis that this is due to a parasite-provoked intense non specific polyclonal activation of host lymphocytes during the early phases of acute infection. Our studies in infected mice have shown that amongst the activated lymphocyte populations, there is a marked expansion of CD5-positive B-cells (B1) and double negative gamma/delta-T cells. Our studies allowed us to propose that the amplification in the B-cell and T- cell populations observed early after infection is mainly triggered by mechanisms independent of BCR- and TCR- specificities and thus by the presence of parasite-derived mitogenic and superantigenic moieties. [TOP]

We had identified parasite molecules involved in B cell proliferation and activation. One of these parasite molecules is a proline-racemase, whose gene is the first eukaryotic proline racemase gene described so far. Interestingly, the ability of proline racemase to activate B cells is dependent on exposed epitopes in the active ligand-free enzyme. However, the mechanism of lymphocyte activation remains obscure. We pursued the molecular, biochemical and functional analyses of the parasite proline racemase (TcPRAC) and defined a protein signature capable of identify putative proline racemases and also hydroxyproline epimerases of several microorganisms of medical and agricultural importance. Furthermore, we had shown that parasite proline racemase is essential since TcPRAC mutant parasites where TcPRAC gene was 'knocked down' are not viable. Conversely, parasites over expressing TcPRAC genes present an increased differentiation into infective forms and are more virulent to host cells. We are now using new molecular strategies to study the role of different parasite genes during development based in reverse genetics. More current data revealed that TcPRAC may participate in the mechanisms  of D-proline addition into recently formed polypeptide chains contributing to parasite evasion. Present proteomic approches of the group include the identification of D-proline bearing parasite proteins. We have recently obtained the crystallographic structure of TcPRAC, defined the catalytic mechanism of the enzyme and associated its B- cell mitogenic property to TcPRAC epitopes that undergo significant conformational changes upon inhibitor binding. TvPRAC is a homologue of the enzyme identified and characterized in T. vivax. Ongoing studies with recently identified new inhibitors of the enzyme aim at designing new compounds to be used in therapeutic approaches. [TOP]


A new model to study Nagana an experimental murine model for T. vivax has been developed by the team.
T. vivax can grow, expand and be transmitted in vivo following predictable kinetics in the peripheral blood of different strains of mice that can be considered according to their susceptibility or resistance to different parasite inocula. Sustained and reproducible infections were obtained, successfully supporting the analysis and the dynamics of parasitological, histological and pathological parameters of the infection, closely resembling those observed in the field with cattle trypanosomiasis. Moreover, the team has also characterized the main immunological parameters of the mouse infection with the parasite. T. vivax infection results in severe B lymphocytes depletion, associated to a defect in B-cell development. [TOP]


Interestingly, although American and African trypanosomes present distinct life cycle features and induce different pathologies, their core proteome present a remarkably high degree of synteny and harbor more than 6000 commun genes most of them involved in metabolic pathways. Basic research on the intricacies of trypanosomatids biology during development in their different hosts are necessary to reveal essential metabolic parasite molecules and consequently promising targets to the design of rational therapies. Our studies aim at reveal potential strategies for immuno- and therapeutic interventions against trypanosoma infections. [TOP]



The Diseases:

Trypanosoma cruzi (Chagas' disease) 
Trypanosoma vivax (Nagana : Animal African Trypanosomosis)


T. cruzi is the etiological agent of Chagas’ disease, one of the most neglected diseases. The recent release of the genome has brought about new expectations into the better understanding of parasite biological processes by the identification of genes involved in development and acquisition of virulence. The parasite is genetically pleiomorphic and develops in a complex biological cycle characterized by several life stages that alternate between the insect vector and the mammal host. More than hundred species may be infected by the parasite. T. cruzi may be also trasmitted congenitally, by blood transfusion or tissue transplantation and thus a globalization of the disease is observed in non endemic areas such as USA, canada, Europe and Asia due to population migration. No vaccins are available and only two registered compounds that possess several side effects are available for acute phases of the disease. Human sleeping sickness, leishmaniasis and Chagas’ disease are vector-born diseases that threaten the lives of millions of individuals in African and South American countries. African trypanosomiasis, usually transmitted by tsetse flies, is caused by several species of trypanosomes (i. e. T. brucei brucei, T. b. rhodesiense, T. b. gambiense, T. congolense, T. vivax and T. simian) that can infect only humans and/or other mammals (trypanosomosis, Nagana). T. vivax, a major livestock trypanosome, is transmitted between wild and domestic ruminants by tsetse flies, tabanids and other varieties of biting flies in Africa and Latin america. To date, inconsistent with the prevalence and the incidence of T. vivax trypanosomosis in the new world and hence with its economical impact, there have been very little reports about the parasite biology and the immunopathogenesis it induces in mammalian hosts



The Present collaborations  :



Philippe Uriac, Nicolas Gouault,
Université de Rennes, France

Marcelo Alves, Wim Degrave, Tania Araujo Jorge,
FIOCRUZ, Rio de Janeiro, Brasil
Arnaud Blondel, Ahmed Haouz, Frédéric Saul

Thierry Lang, Thierry Rose, Marie-Anne Nicola, Brice Rotureau

Institut Pasteur, France
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P
ublications
:
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Genetic Engineering of Trypanosoma (Dutonella) vivax and in vitro differentiation under axenic conditions. D'Archivio, S., Medina, M., Cosson, A., Chamond, N.,  Rotureau, B. Minoprio, P., Goyard, S. PlosNTD, 5 (12) : e1461 (p. 1 -12), 2011

Drug Discovery Targeting Amino Acid Racemases. Conti, P., Tamborini, L., Pinto, A., Blondel, A., Minoprio, P., Mozzarelli, A. De Micheli, C. Chem. Rev.  111(11) : 6919-46,
2011

Trypanosoma vivax
infections: pushing ahead with mouse models for the study of Nagana. II. Immunobiological Dysfunctions. Blom-Potar MC, Chamond N, Cosson A, Jouvion G, Droin-Bergère S, Huerre, M., Minoprio, P. PlosNTD, 4 (8) e793 (p.1-13), 2010.


Trypanosoma vivax infections : Pushing ahead with mouse models for the study of Nagana. I. Parasitological, Hematological and Pathological Parameters. Chamond N, Cosson A, Blom-Potar MC, Jouvion G, D'Archivio S,
Medina, M, Droin-Bergère, S., Huerre, M. Goyard, S.,
Minoprio, P. PlosNTD, 4 (8) : e792 (p.1-10), 2010.

Medium/High throughput D-amino acid oxidase colorimetric method for determination of D-amino acids. Application for amino acid racemases.
Berneman A, Alves-Ferreira M, Coatnoan N, Chamond N, Minoprio P
 J. Microbiol. Biochem. Technol.139-146 (2010)

 

Intravenous immunoglobulin increases survival time in the acute phase of experimental Chagas disease. Perdigão Olivieri B, Vasconcellos R, Nóbrega A, Minoprio P, Kaveri SV, Araújo-Jorge, T.C. Paras Immunol. 32(6): 464-9, 2010

Inhibition of Trypanosoma cruzi proline racemase affects host-parasite interactions and the outcome of in vitro infection. Coutinho L, Ferreira MA, Cosson A, Batista MM, Batista Dda G, da Gama-Jaén-Batista, D., Minoprio, P., Degrave, W.M., Berneman, A. and Correia Soeiro, M.N.  Mem Inst Oswaldo Cruz 104: 1055-1062, 2009

Proline racemases: insights into Trypanosoma cruzi peptides containing D-proline. N. Coatnoan, A. Berneman, N. Chamond, P. Minoprio. Mem Inst Oswaldo Cruz, 104 : 295-300, 2009

Chamond, N., A. Cosson, N. Coatnoan, and P. Minoprio. Proline racemases are conserved mitogens: characterization of a Trypanosoma vivax proline racemase. Mol Biochem Parasitol 165:170-179, 2009

Goytia, M., N. Chamond, A. Cosson, N. Coatnoan, D. Hermant, A. Berneman, P. Minoprio.  Molecular and structural discrimination of proline racemase and hydroxyproline-2-epimerase from nosocomial and bacterial Pathogens. PLOSone. 2(9):e88, 2007

Crystal Structure, Catalytic Mechanism and Mitogenic Properties of Trypanosoma cruzi Proline Racemase.Buschiazzo, A., Goytia, M., Schaeffer, F., Degrave, W.M., Shepard, W., Grégoire, C., Chamond, N., Cosson, A., Berneman, B., Coatnoan, N.,  Alzari, P., PP. Minoprio.  Proc. Nat. Acad. Sci. 103, 1705-1710 (2006) Supp. Info.

Trypanosoma cruzi proline racemases are involved in parasite differentiation and infectivity. Chamond, N., Goytia, M, Coatnoan, N., Barale, J.C., Cosson, A., Degrave, W.M., Minoprio, P. Mol. Microbiol 58, 46-60, (2005)


Biochemical characterization of proline racemases from the human protozoan parasiteTrypanosoma cruzi and definition of putative protein signatures. N. Chamond, C. Grégoire, N. Coatnoan, C. Rougeot, L.H. Freitas-Junior, J. F. da Silveira, W.M. Degrave and P. Minoprio. 2003. J. Biol. Chem. 278 : 15484-15494

Increased Trypanosoma cruzi invasion and heart fibrosis associated with high TGFß-levels in mice deficient in alpha-2 macroglobulin.  M.C., Waghabi, C.M.L.M. Coutinho, M.N.C. Soeiro, M.C.S. Pereira, J.J. Feige, M. Keramidas, A. Cosson, P. Minoprio, F. Van Leuven, and T.C. Araújo-Jorge. 2002.  Infect. Immun. , 70: 5115-5123.

Immunotherapy of Trypanosoma cruzi infections. N. Chamond, N. Coatnoan and P. Minoprio. 2002. Curr. Drugs Targets.  2: 247-254

Impact of polyclonal lymphocyte responses on parasite evasion and persistence. P. Minoprio. 2002. (book chapter) In :  'Molecular mechanisms of Chagas disease pathogenesis'. Bioscience publisher Eurekah.. Editor. J. Kelly.

Increased Trypanosoma cruzi invasion and heart fibrosis associated with high transforming growth factor beta levels in mice deficient in alpha(2)-macroglobulin. Waghabi, M.C., Coutinho, C.M., Soeiro, M.N., Pereira, M.C., Feije, J.J., Keramidas, M. Cosson, A., Minoprio, P., Van Leuven, F., Araujo-Jorge, T.C. Infect. Immun. 70, 5115-5123 (2002)

Significant association between the skewed natural antibody repertoire of xid mice and resistance to Trypanosoma cruzi infection. E. C. Santos.Lima, R. Vasconcelos, B. Reina.San.Martin, C. Fesel, A. Cordeiro.da.Silva, A. Berneman, A. Cosson, A. Coutinho and P. Minoprio. 2001. Eur. J. Immunol. 31 : 634-645.

Parasite polyclonal activators: new targets for vaccination approaches? P. Minoprio. 2001. Internat. J. Parasitol.31 : 588-591

A B-cell mitogen from a pathogenic trypanosome is a eukaryotic proline racemase. B. Reina-San-Martin, W. Degrave, C. Rougeot, A. Cosson, N. Chamond, A. Cordeiro-da-Silva, M. Arala-Chaves and P. Minoprio. 2000. Nature Medicine. 6 : 890-897.
- See also commentary in News and Views, "A B-cell activator in Chagas disease", Nature Med. Vol. 6 No. 8, p 865-866 (2000), by Dr. John Kelly. Press release ; Communiqué de presse ; Comunicado de imprensa.

Lymphocyte polyclonal activation: a pitfall for vaccine design against infectious agents. B. Reina-San-Martin, A. Cosson and P. Minoprio. 2000. Parasitol. Today. 16 : 62-67.
Additional references to our paper entitled "Lymphocyte Polyclonal Activation : a Pitfall for Vaccine Design against Infectious Agents" in Parasitology Today Vol. 16, No 2, p 62-67, 2000, by B. Reina-San Martin, A. Cosson and P. Minoprio.

Changes in the cytokine profile of lupus-prone (NZB/NZW)F1 induced by Plasmodium chabaudi and their implications in the reversal of clinical symptoms. M. N. Sato, P. Minoprio, S. Avrameas and T. Ternynck. 2000. Clin. Exp. Immunol. 119 : 333-339.

A Trypanosoma cruzi alkaline antigen induce polyclonal B cell activation of normal murine spleen cells by T-cell-independent, BCR-directed stimulation. C. Montes, E. Zuniga, P. Minoprio, E. Vottero-de-Cima and A. Gruppi. 1999. Scan. J. Immunol. 50 : 159-166.

Theileria annulata in CD5-positive macrophages and B1 B cells. M. F. Moreau, J. L. Thibaud, L. B. Milled, M. Chaussepied, M. Baugartner, W. C. Davies, P. Minoprio and G. Langsley. 1999. Infect. Immunity. 67 : 6678-6682.

X-linked immunodeficiency affects the outcome of Schistosoma mansoni infection in the murine model. S. Gaubert, A. Viana-da-Costa, C. A. Maurage, E. C. S. Lima, J. Fontaine, S. Lafitte, P. Minoprio, A. Capron and J. M. Grzych. 1999. Parasite Immunol. 21 : 89-101.

A 24 kDa Trypanosoma cruzi antigen is a B cell activator. A. Cordeiro.da.Silva, A. Guevara.Espinoza, A. Taibi, A. Ouaissi and P. Minoprio. 1998. Immunology. 94 : 189-196.

Evidence for a protective role of tumor necrosis factor in the acute phase of Trypanosoma cruzi infection in mice. E. C. Santos-Lima, I. Garcia, M.-H. Vicentelli, P. Vassalli and P. Minoprio. 1997. Infect. Immun. 65 : 457-465.

Chagas' disease is attenuated in mice lacking gd T cells. E. C. Santos-Lima and P. Minoprio. 1996. Infec. Immun. 64 : 215-221.

Vb6-bearing cells are involved in resistance to Trypanosoma cruzi infection in XID mice. A. Cordeiro-da-Silva, E. C. S. Lima, M.-H. Vicentelli and P. Minoprio. 1996. Internat. Immunol. 8 : 1213-1219.

The influence of T cell subsets on Trypanososma cruzi multiplication in different organs. M. Russo, N. Starobinas, M. C. Garibaldi.Marcondes, P. Minoprio and M. Hontebeyrie-Joskowicz. 1996. Immunol. Letters. 49 : 163-168.

Ig-Isotypes patterns of primary and secondary B cell responses to Plasmodium Chabaudi Chabaudi correlate with IFN-g and IL-4 cytokine production and with CD45RB expression by CD4+ spleen cells. M. R. d'Imperio-Lima, J. M. Alvarez, G. C. Furtado, T. L. Kipnis, A. Coutinho and P. Minoprio. 1996. Scand. J. Immunol. 43 : 263-270.

Murine ascariasis. II.  Immunological dysfunction and evidence for chronic activation of Th2 lymphocytes. P. Jungman, A. Freitas, A. Bandeira, A. Coutinho and P. Minoprio. 1996. Scand. J. Immunol. 43 : 604-612.

Intranasal inoculation of Bordetella bronchiseptica in mice induces long lasting antibody immune responses. P. Gueirard, P. Minoprio and N. Guiso. 1996. Scand. J. Immunol. 43 : 263-270.

Defects in the regulation of anti-DNA antibody production in aged lupus-prone (NZB x NZW)F1 mice : analysis of T cell cytokine synthesis. M. Sato, P. Minoprio, S. Avrameas and T. Terninck. 1995. Immunology. 85 : 26-32.

The relative impact of bacterial virulence and host genetic background on cytokine expression during Mycobacterium avium infection of mice. A. G. Castro, P. Minoprio and R. Appelberg. 1995. Immunology. 85 : 556-561.

In vivo evidence of a non-T cell origin of interleukin 5. A. G. Castro, P. Minoprio and R. Appelberg. 1995. Scand. J. Immunol. 41 : 288-292.

Endogenous IL-10 and IFN-g production controls thymic cell proliferation in mice acutely infected by Trypanosoma cruzi. M. d. C. Leite-de-Moraes, P. Minoprio, M. Dy, M. Dardenne, W. Savino and M. Hontebeyrie-Joskowicz. 1994. Scand. J. Immunol. 39 : 51-58.

Skewed Vb TCR repertoire of CD8+ T cells in murine Trypanosoma cruzi infection. M. d. C. Leite-de-Moraes, A. Coutinho, M. Hontebeyrie-Joskowicz, P. Minoprio, H. Eisen and A. Bandeira. 1994. Int. Immunol. 6 : 387-392.

Role of gamma interferon and tumour necrosis factor alpha during T-cell-independent and -dependent phases of Mycobacterium avium infection. R. Appelberg, A. G. Castro, J. Pedrosa, R. Silva, I. Orme and P. Minoprio. 1994. Infec. Immunity. 62 : 3962-3971.

Role of IL-6 in the induction of protective T cells during mycobacterial infections in mice. R. Appelberg, A. G. Castro, J. Pedrosa and P. Minoprio. 1994. Immunology. 82 : 361-364.

Murine AIDS protects mice against experimental cerebral malaria: down regulation by IL-10 of a Th1 CD4+ mediated pathology. M. Eckwalanga, M. Marussig, M. Dias.Tavares, J. C. Buanga, E. Hullier, J. Pavlovitch, P. Minoprio, D. Portnoi, L. Renia and D. Mazier. 1994. Proc. Nat. Acad. Sci. 91 : 8097-8101.

Increase of B lymphocyte numbers and activity during experimental murine schistosomiasis mansoni. M. C. E. Cheikh, H. Dutra, P. Minoprio and R. Borojevic. 1994. Bra. J. Biol. Res. 27 : 1605-1617.

Xid-associated resistance to experimental Chagas'disease is IFN-g-dependent. P. Minoprio, M. Cury-El-Cheikh, E. Murphy, M. Hontebeyrie-Joskowicz, R. Coffman, A. Coutinho and A. O'Garra. 1993. J. Immunol. 151 : 4200-4208.

Chagas' disease : Trypanosoma cruzi versus the host immune system. M. Hontebeyrie-Joskowicz and P. Minoprio. 1991. Res. Immunol. 142 : 125-126.

V-region-related and -unrelated immunosuppression accompanying infections. M. Arala-Chaves, M. R. d'Imperio-Lima, A. Coutinho, C. Pena-Rossi and P. Minoprio. 1992. Mem. Inst. Osw. Cruz. 87 : 35-41.

CD5 B cells: Potential role in the (auto)immune responses to Trypanosoma cruzi infection. M. Cury-El-Cheikh, M. Hontebeyrie-Joskowicz, A. Coutinho and P. Minoprio. 1992. Ann. New York Acad. Sci. 651 : 557-569.

Xid immunodeficiency imparts increased parasite clearance and resistance to pathology in experimental Chagas'disease. P. Minoprio, A. Coutinho, S. Spinella and M. Hontebeyrie-Joskowicz. 1991.Internat. Immunol. 3 : 427-433.

Chagas'disease: CD5 B-cell dependent Th2 pathology? P. Minoprio. 1991. Res. Immunol. 142 : 137-140.

Is TNFa involved in early susceptibility of Trypanosoma cruzi-infected C3H/He mice? N. Starobinas, M. Russo, P. Minoprio and M. Hontebeyrie-Joskowicz. 1991. Res. Immunol. 142 : 117-122.

Immunobiology of murine T. cruzi infection: the predominance of parasite-nonspecific responses and the activation of TcRI T cells. P. Minoprio, S. Itohara, C. Heusser, S. Tonegawa and A. Coutinho. 1989. Immunol. Rev. 112 : 183-207.

Indiscriminate representation of VH-gene families in the murine B lymphocyte responses to Trypanosoma cruzi. P. Minoprio, L. Andrade, M.-P. Lembezat, L. S. Ozaki and A. Coutinho. 1989. J. Immunol. 142 : 4017-4021.

Preferential expansion of Ly1-B and CD4- CD8- T cells in the polyclonal lymphocyte responses to murine Trypanosoma cruzi infection. P. Minoprio, A. Bandeira, P. Pereira, T. A. Mota-Santos and A. Coutinho. 1989. Intern. Immunol. 1 : 176-184.

Susceptible mice present higher macrophage activation than resistant mice during infections with myotropic strains of Trypanosoma cruzi. M. Russo, N. Starobinas, R. Ribeiro-dos-Santos, P. Minoprio, H. Eisen and M. Hontebeyrie-Joskowicz. 1989. Paras. Immunol. 11 : 385-395.

Most B cells in acute Trypanosoma cruzi infection lacks parasite specificity. P. Minoprio, O. Burlen, P. Pereira, B. Guilbert, L. Andrade, M. Hontebeyrie-Joskowicz and A. Coutinho. 1988. Scand. J. Immunol. 28 : 553-561.

Parasitic load increases and myocardial inflammation decreases in Trypanosoma cruzi- infected mice after inactivation of helper T cells. M. Russo, N. Starobinas, P. Minoprio, A. Coutinho and M. Hontebeyrie-Joskowicz. 1988. Ann. Inst. Pasteur/ Immunol. 139 : 225-236.

Depletion of L3T4 T lymphocytes during Trypanosoma cruzi infection inhibits macrophage and B lymphocyte activation but not tissue inflammatory reaction. M. Russo, P. Minoprio, A. Coutinho, H. Eisen and M. Hontebeyrie-Joskowicz. 1988. Mem. Inst. Osw. Cruz. 83 : 527-538.

Suppression of polyclonal antibody production in Trypanosoma cruzi infected mice by treatment with anti-L3T4 antibodies. P. Minoprio, H. Eisen, M. Joskowicz, P. Pereira and A. Coutinho. 1987. J. Immunol. 139 : 545-550.

Lymphocyte activity in mice infected with Trypanosoma cruzi. P. Minoprio, M. R. d. I. Lima, P. Araujo, M. Joskowicz, H. Eisen and A. Coutinho. 1986. In Parasitic infections, immunology and micotic infections, General Topics. Eds. W. Marget W. Lang, E. Gabler Sandberger, Vol. III : 237-239.

Persistance of polyclonal B cell activation with undetectable parasitemia in late stages of experimental Chagas'disease. M. R. d'Imperio-Lima, H. Eisen, P. Minoprio, M. Joskowicz and A. Coutinho. 1986. J. Immunol. 137 : 353-356.

Polyclonal lymphocyte responses to murine Trypanosoma cruzi infection. II. Cytotoxic T lymphocytes. P. Minoprio, A. Coutinho, M. Joskowicz, M. R. d. I. Lima and H. Eisen. 1986. Scand. J. Immunol. 24 : 669-679.

Polyclonal lymphocyte responses to murine Trypanosoma cruzi infection. I. Quantitation of both T and B cell responses. P. Minoprio, H. Eisen, L. Forni, M. R. d'Imperio-Lima, M. Joskowicz and A. Coutinho. 1986. Scand. J. Immunol. 24 : 661-668.

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Sommaire:

Cette équipe a comme thème de recherches, l’étude des mécanismes immunitaires déclenchés lors des processus infectieux pouvant être responsables de l’immunosuppression et de l'échappement des parasites. Les modèles expérimentaux étudiés, sont ceux de l’infection murine par le parasite Trypanosoma cruzi, responsable de la Maladie de Chagas (Carlos Chagas, 1909), et de l'infection murine par le parasite T. vivax, responsable de la trypanosomose animale (Nagana).
 

La maladie de Chagas

 

Après une phase aiguë suivant l'infection, la maladie évolue vers la chronicité chez plus d'un tiers des personnes infectées. La phase chronique apparaît après 10 à 20 ans d'infection "silencieuse". Des lésions irréversibles peuvent toucher le coeur, l'oesophage, le colon, et le système nerveux périphérique : 27% des personnes infectées souffrent de symptômes cardiaques (cardiopathies chroniques), qui peuvent conduire à la mort subite; 6% des individus sont atteints de lésions chroniques de l'appareil digestif; 3% des personnes infectées ont des atteintes du système nerveux périphérique (troubles neurologiques). Les cardiopathies affectent à présent près de 2 millions d’individus.

 

Prévention, traitement et vaccins

En dehors de la lutte vectorielle par des insecticides, il n'existe aucun moyen de contrôle de la maladie de Chagas, aucun traitement efficace pour les formes chroniques, ni vaccin. Le DNDi (Drugs for Neglected Diseases initiative), une initiative pour lutter contre les maladies négligées comme la maladie de chagas, a été créé récemment. Il regroupe l'Institut Pasteur, le Conseil Indien pour la recherche Médicale (Inde), la Fondation Oswaldo Cruz (Brésil), l'Institut de Recherche Médicale du Kenya, Médecins Sans Frontières et le ministère de la Santé de Malaisie. Ces partenaires travaillent en étroite collaboration avec le Programme des Nations Unies pour le Développement (PNUD), la Banque mondiale et le Programme Spécial de Recherche et de Formation sur les Maladies Tropicales de l'Organisation Mondiale de la Santé (OMS/TDR) sur la recherche de nouveaux médicaments. Des fonds privés et public (Sanofi/Aventis/Ministère) ont été dédiés à l’Institut Pasteur pour la recherche sur les maladies parasitaires négligées, dont la maladie de Chagas.


 A l’Institut Pasteur 

 

Le Laboratoire d’Immunobiologie des infections à Trypanosoma, dirigé par Paola Minoprio, étudie les perturbations du système immunitaire lors de l'infection expérimentale par le parasite responsable de la maladie de Chagas. Des stratégies plus rationnelles de manipulation du système immunitaire visant un meilleur pronostic du processus infectieux et des méthodes thérapeutiques contre le développement d'une pathologie chronique sont étudiées. Actuellement l'équipe analyse les effets d'inhibiteurs spécifiques d'un enzyme parasitaire qui permet à T. cruzi et à d'autres trypanosomatidés (i.e. Trypanosoma vivax) d'échapper aux réponses immunitaires et est essentielle pour le développement du (des) parasite(s) chez hôte mammifère. La définition du mécanisme réactionnel de l'enzyme et de sa structure 3D ont ouvert la voie à la recherche d’une chimiothérapie contre la maladie de Chagas, voire contre d’autres agents infectieux utilisant cet enzyme, notamment le Nagana, la forme animale de la Maladie du Sommeil. Ainsi, deux nouveaux inhibiteurs ont été identifiés récemment. Ces molécules de base sont très prometteuses pour dériver des nouveaux candidats thérapeutiques contre ces maladies négligées.



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