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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
    • Raquel Nicole Afonso Lehmann     
    • Adriana Egui Machado     
    • Francisco Macías Huete     


    Staff Research Predoctoral
    • Celia Benítez Gil     
    • Inmaculada María Gómez García     


    Technical Assistants
    • Almudena López-Barajas de la Puerta     


    Authorized Staff
    • Juan Miguel Carrillo Sánchez     
    • Elena Pérez Antón     

     

    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

    - 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 - 2019).

    - 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).

    - Sistema de biomarcadores de eficacia terapéutica y patología de la enfermadad de Chagas.. PROYECTO, PROYECTOS INTRAMURALES, Ref: 201220E135, (2012 - 2014).

    - SISTEMA DE RETROTRANSPOSICION DE LOS ELEMENTOS L1TC LINE Y NARTC SINE-LIKE DE TRYPANOSOMA CRUZI. ANALISIS COMPARATIVO DEL CONTENIDO Y DISTRIBUCION GENOMICA DE ESTOS ELEMEN. PROYECTO, PN2010 - I.F.N.O.- BIOLOGÍA FUNDAMENTAL Y DE SISTEMAS, Ref: BFU2010-16470, (2011 - 2014).

    - Inmunogenicidad y potencial uso en inmunoterapia frente a leishmaniosis de moléculas quiméricas (plasmidos DNA) formadas por los antígenos PFR, K11 y L25 de Leishmania infantum y la proteína H70 co. PROYECTO, PLAN ANDALUZ DE INVESTIGACION, Ref: P08-CVI-04037, (2009 - 2014).

     

     

    PUBLICATIONS LAST 5 YEARS

    -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:1528

    -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:1516

    -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:1511

    -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:1508

    -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:1500

    -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:1495

    -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:1381

    -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:1362

    -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:1337

    -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:1326

    -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:1325

    -Lasso, P.; Mateus, J.; Pavía, P.; Rosas, F.; Roa, N.; Thomas, M.C.; López, M.C.; González, J.M.; Puerta, C.J.; Cuéllar, A., Inhibitory receptor expression on CD8+ T cells is linked to functional responses against trypanosoma cruzi antigens in chronic chagasic patients, Journal of Immunology, 2015, Vol. 195: 3748-3758, ARTICULO, Id:1433

    -Egui A.; Thomas M.C.; Carrilero B.; Segovia M.; Alonso C.; Marañón C.; López M.C, Differential phenotypic and functional profiles of TcCA-2-specific cytotoxic CD8+ T cells in the asymptomatic versus cardiac phase in chagasic patients., PLoS ONE, 2015, Vol. 10: 3-e0122115, ARTICULO, Id:1410

    -Pinazo M.J.; Thomas M.C.; Bustamante J.; Correira de Almeida I.; López M.C.; Gascon J., Biomarkers of therapeutic responses in chronic Chagas disease: state of the art and future perspectives, Memorias do Instituto Oswaldo Cruz, 2015, Vol. 110: 422-432, ARTICULO, Id:1403

    -Finkelsztein, E.J.; Diaz-Soto, J.C.; Vargas-Zambrano, J.C.; Suesca, E.; Guzmán, F.; López, M.C.; Thomas, M.C.; Forero-Shelton, M.; Cuellar, A.; Puerta, C.J.; González, J.M., Altering the motility of Trypanosoma cruzi with rabbit polyclonal anti-peptide antibodies reduces infection to susceptible mammalian cells, Experimental Parasitology, 2015, Vol. 150: 36-43, ARTICULO, Id:1392

    -Afonso-Lehmann, R.N.; Thomas, M.C.; Santana-Morales, M.A.; Déniz, D.; López, M.C.; Valladares, B.; Martínez-Carretero, E., A DEVH-box RNA Helicase from Leishmania braziliensis is Associated to mRNA Cytoplasmic Granules, Protist, 2015, Vol. 166: 457-467, ARTICULO, Id:1388

    -Viotti, R.; Alarcón De Noya, B.; Araujo-Jorge, T.; Grijalva, M.J.; Guhl, F.; López, M.C.; Ramsey, J.M.; Ribeiro, I.; Schijman, A.G.; Sosa-Estani, S.; Torrico, F.; Gascon, J., Towards a paradigm shift in the treatment of chronic chagas disease, Antimicrobial Agents and Chemotherapy, 2014, Vol. 58: 635-639, ARTICULO DE REVISION, Id:1240

    -Sánchez-Luque, F.J.; López, M.C.; Carreira, P.E.; Alonso, C.; Thomas, M.C., The wide expansion of hepatitis delta virus-like ribozymes throughout trypanosomatid genomes is linked to the spreading of L1Tc/ingi clade mobile elements, BMC Genomics, 2014, Vol. 15: null-, ARTÍCULO, Id:1239

    -Díaz-Bello, Z.; Thomas, M.C.; López, M.C.; Zavala-Jaspe, R.; Noya, O.; De Noya, B.A.; Abate, T., Trypanosoma cruzi genotyping supports a common source of infection in a school-related oral outbreak of acute Chagas disease in Venezuela, Epidemiology and Infection, 2014, Vol. 142: 156-162, ARTÍCULO, Id:1171

    -Fernández-Villegas, A.; Thomas, M.C.; Carrilero, B.; Téllez, C.; Marañón, C.; Murcia, L.; Moralo, S.; Alonso, C.; Segovia, M.; López, M.C., The innate immune response status correlates with a divergent clinical course in congenital Chagas disease of twins born in a non-endemic country, Acta Tropica, 2014, Vol. 140: 84-90, ARTÍCULO, Id:1170

    -Cuervo, C.; Thomas, M.C.; López, M.C.; Puerta, C.J., Sequence polymorphism in the Trypanosoma rangeli HSP70 coding genes allows typing of the parasite KP1(+) and KP1(-) groups, Experimental Parasitology, 2013, Vol. 133: 447-453, ARTÍCULO, Id:1046

    -Murcia, L.; Carrilero, B.; Munoz-Davila, M.J.; Thomas, M.C.; López, M.C.; Segovia, M., Risk factors and primary prevention of congenital chagas disease in a nonendemic country, Clinical Infectious Diseases, 2013, Vol. 56: 496-502, ARTÍCULO, Id:1044

    -Muñoz-Calderón, A.; Díaz-Bello, Z.; Valladares, B.; Noya, O.; López, M.C.; Alarcón de Noya, B.; Thomas, M.C., Oral transmission of Chagas disease: Typing of Trypanosoma cruzi from five outbreaks occurred in Venezuela shows multiclonal and common infections in patients, vectors and reservoirs, Infection, Genetics and Evolution, 2013, Vol. 17: 113-122, ARTÍCULO, Id:1034

    -Montenegro, M.; Cardenas, C.; Cuervo, C.; Bernal, C.; Grisard, E.C.; Thomas, M.C.; Lopez, M.C.; Puerta, C.J., Molecular characterization of calcineurin B from the non-virulent Trypanosoma rangeli kinetoplastid indicates high gene conservation, Molecular Biology Reports, 2013, Vol. 40: 4901-4912, ARTÍCULO, Id:1027

    -Marañón, C.; Egui, A.; Fernández-Villegas, A.; Carrilero, B.; Thomas, M.C.; Segovia, M.; López, M.C., Benznidazole treatment reduces the induction of indoleamine 2,3-dioxygenase (IDO) enzymatic activity in Chagas disease symptomatic patients, Parasite Immunology, 2013, Vol. 35: 180-187, ARTÍCULO, Id:993


     

     

    DOCTORAL THESES LAST 5 YEARS

     

    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

     

     
    2014

    Adriana Egui Machado

    Dinámica de la respuesta de linfocitos TCD8+ específicos de antígenos parasitarios en pacientes chagásicos bajo tratamiento

    Instituto de Parasitología y Biomedicina "López-Neyra" CSIC-Universidad de Granada

     

     

     

     


    Sede: Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento, 17. 18016 Armilla (Granada)(ESPAÑA). TEL:+34 958181621. FAX:+34 958181632

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