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Instituto de Parasitología y Biomedicina
"López - Neyra"
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[ Staff | Summary of Research | Funding Agencies | Publications | Doctoral Theses | Patents | Teaching]




IDENTIFICATION OF ANTIGENS AND IMMUNOSTIMULATORY MOLECULES CANDIDATES FOR IMMUNOTHERAPY AGAINST TRYPANOSOMATID PATHOGENS. STUDY AT MOLECULAR LEVEL OF THE TRANSPOSITION AND INTEGRATION MECHANISM OF L1Tc MOBILE ELEMENT FROM T. cruzi. ANALYSIS OF ITS FUNCTIONALITY



Group Leader
    • Manuel Carlos López López     
        email: mclopez (@ipb.csic.es)
        Tlf: 958181661



    Staff Research Posdoctoral
    • Adriana Egui Machado     
    • Francisco Macías Huete     


    Staff Research Predoctoral
    • Ana García Castro     


    Technical Assistants
    • Almudena López-Barajas de la Puerta     

     

    SUMMARY OF RESEARCH


     

    Identification of antigens and immunostimultatory molecules candidates for inmunotherapy against trypanosomatid pathogens

     

    Parasites of the Trypanosomatidae family are the etiological agent of leishmaniosis and American tripanosomiasis (Chagas? Disease) characterized by presenting unspecific clinical symptoms together with an alteration of the host immune system. The parasites are transmitted by insect vectors, producing high morbidity and mortality rates. It has been estimated that 300 million persons live in endemic areas and that there are 500.000 new cases each year. Nowadays iin development countries there has been a high increase in the rate of infection due probably to the existence of additional transmission ways, such as blood transfusions (T. cruzi). As it occurs for Leishmania infantum, there is a higher rate of canine infections and an association with immunosupression states.



    Given that existing chemotherapy is toxic and not very specific, vaccines, despite the difficulties involved in their developing, are probably the most effective way of responding to the world-wide important problem presented by these infectious pathologies. Although the protective antiparasitic response mechanisms of the host are not fully understood, it is clear, for both diseases, that effective protection requires induction of a multiple immune response incorporating serialized cellular activation and antibody production with a balance towards Th1 and induction of parasite´s antigen-specific CTLs. Undoubtedly, it requires immunization with suitable antigenic protein/s associated to carrier molecules, stimulators/modulators of the immune response. The genetic vaccines or DNA vaccines, as well as recombinant proteins, may be an excellent way of inducing this type of multiple response and of generating effective protection.



    The scientific objective of our laboratory is focused on identifying and studying at molecular and immunological level specific proteins from Leishmania and Trypanosoma cruzi which are antigenic molecules and candidates for vaccines, as well as their encoding genes. Likewise, we have special interest in the characterization of biological molecules with immunostimulatory capability. The final aim of the laboratory is directed to analyze the capacity of the chimeric recombinant proteins or DNA vectors to limit the pathological consequences of leishmaniosis and trypanosomiasis and to induce protection against parasite´s infection





     

    Study at molecular level of the transposition and integration mechanism of L1Tc mobile element from T. cruzi. Analysis of its functionality

     

    The genome of a large number of prokaryotic and eukaryotic organisms contains a surprisingly high proportion of repeated long and short interspersed nucleotide elements (LINE and SINE) DNA sequences with the potential capacity to transpose in the host genome. These mobile elements have been considered for decades as selfish elements. However, at present these sequences have been taken as important elements to generate variations in genome structure and expression associated to species evolution. Although the biological properties of these sequences (regulation, replication and interaction with their host organisms) are not well understood, the available data indicate that they represent challenging and fascinating biological elements playing crucial functional roles. In this context the resolution of these functions and mechanisms will be essential to know how the repeated elements dialogue to achieve the concrete modeling of the genetic information and consequently to fully understand the biology of the host organisms.



    The genome of the parasite pathogen Trypanosoma cruzi has a large proportion of repeated and dispersed DNA sequences which share common characteristics with SINE sequences from higher eukaryotes, and a LINE type element known as L1Tc encoding for the enzymes required for its retrotransposition. These retrotransposon sequences have been linked to the high plasticity observed in the T. cruzi genome and furthermore, seem to be involved in the chromosomal organization and control of the expression of specific genes, crucial for the pathogenicity and survival of the parasite.



    The objectives of our laboratory are focused on the characterization of the molecular and functional characteristics of the different polypeptides encoded by the LINE-L1Tc element from T. cruzi as well as its putative regulatory sequences. Likewise, we are interested in determining at molecular level, the retrotransposition and integration mechanisms of this mobile element and in the identification of the effect that de novo retrotransposition events have on the genome of the aforementioned parasite pathogen.





     


    FUNDING AGENCIES LAST 5 YEARS

    - VALORIZACIÓN DE NUEVAS VACUNAS CONTRA PATÓGENOS RESPIRATORIOS PARA LA REDUCCIÓN DEL USO DE ANTIBIÓTICOS EN PORCINO. PROYECTO, PN2017 -RETOS COLABORACION - PRG. RETOS DE LA SOC., Ref: RTC-2017-6601-2, (2018 - 2020).

    - Red de investigación colaborativa en enfermedades tropicales RICET. PROYECTO, PN2016 - REDES TEMATICAS INV. COOPERATIVA, Ref: RD16/0027/0005, (2017 - 2021).

    - BIOMARCADORES INMUNOLOGICOS ANTIGENO-ESPECIFICOS (CELULAS T) ASOCIADOS AL CONTROL DE LA INFECCION POR T. CRUZI.. PROYECTO, PN2016 - PROY I+D+I - PRG. RETOS DE LA SOCIEDAD, Ref: SAF2016-81003-R, (2016 - 2020).

    - BNT005: Inmunidad celular para la prevención y tratamiento de la leishmaniasis en humanos. Investigación para el desarrollo de una vacuna. PROYECTO, PN2016 -RETOS COLABORACION - PRG. RETOS DE LA SOC., Ref: RTC-2016-5005-1, (2016 - 2018).

    - Diseño de enfoques de tipo molecular e inmunológico para el control de la enfermedad de Chagas. PROYECTO, PN2013 - PROY I+D+I - PRG. RETOS DE LA SOCIEDAD, Ref: SAF2013-48527-R, (2014 - 2016).

    - Red de investigación cooperativa en enfermedades tropicales RICET. RED FIS, , Ref: RD12/0018/0021, (2013 - 2017).

    - DESARROLLO DE UNA VACUNA PARA EL TRATAMIENTO Y PREVENCION DE LA LEISHMANIOSIS VISCERAL CANINA. PROYECTO, INNPACTO 2012 - PN2012 - SUBPROGRAMA INNPACTO 2012, Ref: IPT-2012-0697-010000, (2013 - 2016).

     

     

    PUBLICATIONS LAST 5 YEARS

    -Egui, A.; López, M.C.; Gómez, I.; Simón, M.; Segovia, M.; Thomas, M.C., Differential phenotypic and functional profile of epitope-specific cytotoxic CD8+ T cells in benznidazole-treated chronic asymptomatic Chagas disease patients, Biochimica et Biophysica Acta - Molecular Basis of Disease, 2020, Vol. 1866: 3-165629, ARTÍCULO, Id:790664

    -Franco-Martínez, L.; Villar, M.; Tvarijonaviciute, A.; Escribano, D.; Bernal, L.J.; Cerón, J.J.; Thomas, M.d.C.; Mateos-Hernández, L.; Tecles, F.; de la Fuente, J.; López, M.C.; Martínez-Subiela, S., Serum proteome of dogs at subclinical and clinical onset of canine leishmaniosis, Transboundary and Emerging Diseases, 2020, Vol. 97: 318-327, ARTÍCULO, Id:774803

    -Risueño, J.; Spitzová, T.; Bernal, L.J.; Muñoz, C.; López, M.C.; Thomas, M.C.; Infante, J.J.; Volf, P.; Berriatua, E., Longitudinal monitoring of anti-saliva antibodies as markers of repellent efficacy against Phlebotomus perniciosus and Phlebotomus papatasi in dogs, Medical and Veterinary Entomology, 2019, Vol. 33: 99-109, ARTICULO, Id:743780

    -Egui A; Ledesma D; Pérez-Antón E; Montoya A; Gómez I; Robledo SM; Infante JJ; Vélez ID; López MC; Thomas MC, Phenotypic and Functional Profiles of Antigen-Specific CD4+ and CD8+ T Cells Associated With Infection Control in Patients With Cutaneous Leishmaniasis., Frontiers in cellular and infection microbiology, 2018, Vol. 8: 393-393, ARTICULO, Id:756009

    -Ontoria, E.; Hernández-Santana, Y.E.; González-García, A.C.; López, M.C.; Valladares, B.; Carmelo, E., Transcriptional profiling of immune-related genes in Leishmania infantum-infected mice: Identification of potential biomarkers of infection and progression of disease, Frontiers in cellular and infection microbiology, 2018, Vol. 8: 197, ARTICULO, Id:727592

    -Pérez-Antón, E.; Egui, A.; Thomas, M.C.; Puerta, C.J.; González, J.M.; Cuéllar, A.; Segovia, M.; López, M.C., Impact of benznidazole treatment on the functional response of Trypanosoma cruzi antigen-specific CD4+CD8+T cells in chronic Chagas disease patients, PLoS Neglected Tropical Diseases, 2018, Vol. 12: 5-e0006480, ARTICULO, Id:723199

    -Macías, F.; Afonso-Lehmann, R.; López, M.C.; Gómez, I.; Carmen Thomas, M., Biology of trypanosoma cruzi retrotransposons: From an enzymatic to a structural point of view, Current Genomics, 2018, Vol. 19: 110-118, ARTICULO DE REVISION, Id:715936

    -Ledesma, D.; Berriatua, E.; Thomas, M.C.; Bernal, L.J.; Ortuño, M.; Benitez, C.; Egui, A.; Papasouliotis, K.; Tennant, B.; Chambers, J.; Infante, J.J.; López, M.C., Performance of Leishmania PFR1 recombinant antigen in serological diagnosis of asymptomatic canine leishmaniosis by ELISA, BMC Veterinary Research, 2017, Vol. 13: 1-304, ARTICULO, Id:683957

    -Montenegro, M.; Cuervo, C.; Cardenas, C.; Duarte, S.; Díaz, J.R.; Thomas, M.C.; Lopez, M.C.; Puerta, C.J., Identification of a type I nitroreductase gene in non-virulent Trypanosoma rangeli, Memorias do Instituto Oswaldo Cruz, 2017, Vol. 112: 504-509, ARTICULO, Id:688992

    -Requena, J.M.; Rastrojo, A.; Garde, E.; López, M.C.; Thomas, M.C.; Aguado, B., Genomic cartography and proposal of nomenclature for the repeated, interspersed elements of the Leishmania major SIDER2 family and identification of SIDER2-containing transcripts, Molecular and Biochemical Parasitology, 2017, Vol. 212: 9-15, ARTICULO, Id:625257

    -Egui, A.; Lasso, P.; Thomas, M.C.; Carrilero, B.; González, J.M.; Cuéllar, A.; Segovia, M.; Puerta, C.J.; López, M.C., Expression of inhibitory receptors and polyfunctional responses of T cells are linked to the risk of congenital transmission of T. cruzi, PLoS Neglected Tropical Diseases, 2017, Vol. 11: 6-e0005627, ARTICULO, Id:688987

    -Requena, J.M.; Rastrojo, A.; Garde, E.; López, M.C.; Thomas, M.C.; Aguado, B., Dataset for distribution of SIDER2 elements in the Leishmania major genome and transcriptome, Data in Brief, 2017, Vol. 11: 39-43, ARTICULO, Id:625518

    -Mateus, J.; Pérez-Antón, E.; Lasso, P.; Egui, A.; Roa, N.; Carrilero, B.; González, J.M.; Thomas, M.C.; Puerta, C.J.; López, M.C.; Cuéllar, A., Antiparasitic treatment induces an improved CD8+ T cell response in chronic chagasic patients, Journal of Immunology, 2017, Vol. 198: 3170-3180, ARTICULO, Id:657078

    -Macías, F.; López, MC.; Thomas, MC., The Trypanosomatid Pr77-hallmark contains a downstream core promoter element essential for transcription activity of the Trypanosoma cruzi L1Tc retrotransposon, BMC Genomics, 2016, Vol. 17: 1-105, ARTICULO, Id:598499

    -Lasso, P.; Beltrán, L.; Guzmán, F.; Rosas, F.; Thomas, M.C.; López, M.C.; González, J.M.; Cuéllar, A.; Puerta, C.J., Promiscuous recognition of a Trypanosoma cruzi CD8+ T cell epitope among HLA-A2, HLA-A24 and HLA-A1 supertypes in chagasic patients, PLoS ONE, 2016, Vol. 11: 3-e0150996, ARTICULO, Id:605874

    -Requena, JM; Rastrojo, A; Garde,E; López, MC; Thomas MC; Aguado B, Genomic cartography and proposal of nomenclature for the repeated, interspersed elements of the Leishmania major SIDER2 family and identification of SIDER2-containing transcripts., Molecular and Biochemical Parasitology, 2016, Vol. 212: 9-15, ARTICULO, Id:623764

    -Lasso, P.; Cárdenas, C.; Guzmán, F.; Rosas, F.; Thomas, M.C.; López, M.C.; González, J.M.; Cuéllar, A.; Campanera, J.M.; Luque, F.J.; Puerta, C.J., Effect of secondary anchor amino acid substitutions on the immunogenic properties of an HLA-A∗0201-restricted T cell epitope derived from the Trypanosoma cruzi KMP-11 protein, Peptides, 2016, Vol. 78: 68-76, ARTICULO, Id:605130

    -Paola Lasso; Constanza Cárdenas; Fanny Guzmán; Fernando Rosas; María Carmen Thomas; Manuel Carlos López; John Mario González; Adriana Cuéllar; Josep Maria Campanera; F. Javier Luque; Concepción Judith Puerta, Effect of secondary anchor amino acid substitutions on the immunogenic properties of an HLA-A*0201-restricted T cell epitope derived from the Trypanosoma cruzi KMP-11 protein., Peptides, 2016, Vol. 78: 68-76, ARTICULO, Id:598487


     

     

    DOCTORAL THESES LAST 5 YEARS

     

    2019

    Elena Pérez Antón

    Investigación de las bases inmunológicas implicadas en la enfermedad de Chagas provocadas por el protozoo parásito Trypanosoma cruzi

    IPBLN CSIC

     

     
    2017

    Darién Ledesma Arroyo

    Desarrollo de herramientas útiles para el control de la leishmaniosis canina.

    "NOTA: Se requerirá la firma de un documento de confidencialidad a los/as asistentes"

    IPBLN CSIC

     

     

     

     


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