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Investigación

Leishmaniasis and Chagas Disease

Líneas de investigación

Content with Investigacion Virología Molecular .

Research

The Molecular Virology group focuses its research on the study of HIV-1 genetic variation and viral evolution using both in vitro and ex vivo approaches, structured around the following research lines:

- Non-progressor patients. These patients maintain control of the disease in the absence of antiretroviral therapy and have therefore been proposed as a model of functional cure. Our objective is to study the contribution of viral factors to disease control through biological characterization and analysis of viral evolution in individuals with undetectable viral loads (elite controllers, EC), compared with individuals showing other patterns of viral control.

- Viral envelope. This viral protein is key in determining viral fitness. Therefore, its functionality significantly affects infection progression. In collaboration with Dr. Blanco and Dr. Valenzuela, we study which specific events (CD4 binding, fusogenicity, etc.) are associated with envelope functionality. To this end, we have analyzed envelopes from individuals with different patterns of disease progression. Some of these have been contributed to the AIDS Research Network envelope biobank for broader use.

- Dual infection. Infection with more than one viral variant (either through co-infection or superinfection) may have consequences for infection pathogenesis. Within our group, different aspects of DI have been analyzed, including its detection in non-progressor patients, its prevalence and incidence in Spain, and its influence on the neutralizing antibody response.

- Molecular Epidemiology. The group has analyzed viral evolution throughout the epidemic in Spain and in other countries (the Netherlands, Italy, Germany, Uruguay, Panama, Brazil, etc.).

- Role of amino acid residues in reverse transcriptase. We study the role of specific amino acid residues in HIV-1 reverse transcriptase in enzymatic function and replication capacity using an infectious molecular clone previously obtained by the group.

- “In vitro” variability. Serial passage studies have been used to detect the mechanisms responsible for the gain or loss of viral fitness.

- Antiviral studies. We have analyzed the selection of resistance mutations in vitro against different antivirals, as well as the effect of these mutations on viral fitness, and the activity of new antivirals such as ATR inhibitors.

 

Virological Diagnosis and Reference in HIV and HTLV Infections

The research group provides diagnostic and reference activities through the service portfolio of the National Center for Microbiology to the entire Spanish National Health System.

These services include:

  • Diagnosis and reference of HIV infection (types 1 and 2) through detection of specific antibodies and detection of proviral DNA by PCR.

  • Diagnosis and reference of HTLV-I/II infection through detection of specific antibodies and detection of proviral DNA by PCR. Quantification of HTLV-1 proviral load by real-time PCR.

European Union Reference Laboratory (EURL) in the field of in vitro diagnostic medical devices for microbiological diagnosis (IVD) of HIV and HTLV (Regulation 2023/2713 of December 5th, 2023). Our role is to confirm the reliability and effectiveness of devices for detecting these pathogens and to ensure their specific performance requirements through laboratory testing before they can be marketed within the European Union.

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Alastruey-Izquierdo A, Alcazar-Fuoli L, Rivero-Menéndez O, Ayats J, Castro C, García-Rodríguez J, Goterris-Bonet L, Ibáñez-Martínez E, Linares-Sicilia MJ, Martin-Gomez MT, Martín-Mazuelos E, Pelaez T, Peman J, Rezusta A, Rojo S, Tejero R, Anza DV, Viñuelas J, Zapico MS, Cuenca-Estrella M; the FILPOP2 Project from GEMICOMED (SEIMC) and REIPI. Molecular Identification and Susceptibility Testing of Molds Isolated in a Prospective Surveillance of Triazole Resistance in Spain (FILPOP2 Study). Antimicrob Agents Chemother. 2018 Aug 27;62(9):e00358-18. doi: 10.1128/AAC.00358-18. PMID: 29941643; PMCID: PMC6125503.

Alastruey-Izquierdo A, Alcazar-Fuoli L, Rivero-Menéndez O, Ayats J, Castro C, García-Rodríguez J, Goterris-Bonet L, Ibáñez-Martínez E, Linares-Sicilia MJ, Martin-Gomez MT, Martín-Mazuelos E, Pelaez T, Peman J, Rezusta A, Rojo S, Tejero R, Anza DV, Viñuelas J, Zapico MS, Cuenca-Estrella M; the FILPOP2 Project from GEMICOMED (SEIMC) and REIPI. Molecular Identification and Susceptibility Testing of Molds Isolated in a Prospective Surveillance of Triazole Resistance in Spain (FILPOP2 Study). Antimicrob Agents Chemother. 2018 Aug 27;62(9):e00358-18. doi: 10.1128/AAC.00358-18. PMID: 29941643; PMCID: PMC6125503.

PUBMED DOI

Gonçalves SM, Lagrou K, Rodrigues CS, Campos CF, Bernal-Martínez L, Rodrigues F, Silvestre R, Alcazar-Fuoli L, Maertens JA, Cunha C, Carvalho A. Evaluation of Bronchoalveolar Lavage Fluid Cytokines as Biomarkers for Invasive Pulmonary Aspergillosis in At-Risk Patients. Front Microbiol. 2017 Nov 29;8:2362. doi:10.3389/fmicb.2017.02362. PMID: 29238334; PMCID: PMC5712575.

Gonçalves SM, Lagrou K, Rodrigues CS, Campos CF, Bernal-Martínez L, Rodrigues F, Silvestre R, Alcazar-Fuoli L, Maertens JA, Cunha C, Carvalho A. Evaluation of Bronchoalveolar Lavage Fluid Cytokines as Biomarkers for Invasive Pulmonary Aspergillosis in At-Risk Patients. Front Microbiol. 2017 Nov 29;8:2362. doi:10.3389/fmicb.2017.02362. PMID: 29238334; PMCID: PMC5712575.

PUBMED DOI

Alcazar-Fuoli L, Buitrago M, Gomez-Lopez A, Mellado E. An alternative host model of a mixed fungal infection by azole susceptible and resistant Aspergillus spp strains. Virulence. 2015;6(4):376-84. doi: 10.1080/21505594.2015.1025192. PMID: 26065322; PMCID: PMC4601236.

Alcazar-Fuoli L, Buitrago M, Gomez-Lopez A, Mellado E. An alternative host model of a mixed fungal infection by azole susceptible and resistant Aspergillus spp strains. Virulence. 2015;6(4):376-84. doi: 10.1080/21505594.2015.1025192. PMID: 26065322; PMCID: PMC4601236.

PUBMED DOI

Alcazar-Fuoli L, Cairns T, Lopez JF, Zonja B, Pérez S, Barceló D, Igarashi Y, Bowyer P, Bignell E. A modified recombineering protocol for the genetic manipulation of gene clusters in Aspergillus fumigatus. PLoS One. 2014 Nov 5;9(11):e111875. doi: 10.1371/journal.pone.0111875. PMID: 25372385; PMCID:PMC4221250.

Alcazar-Fuoli L, Cairns T, Lopez JF, Zonja B, Pérez S, Barceló D, Igarashi Y, Bowyer P, Bignell E. A modified recombineering protocol for the genetic manipulation of gene clusters in Aspergillus fumigatus. PLoS One. 2014 Nov 5;9(11):e111875. doi: 10.1371/journal.pone.0111875. PMID: 25372385; PMCID:PMC4221250.

PUBMED DOI

Bertuzzi M, Schrettl M, Alcazar-Fuoli L, Cairns TC, Muñoz A, Walker LA, Herbst S, Safari M, Cheverton AM, Chen D, Liu H, Saijo S, Fedorova ND, Armstrong-James D, Munro CA, Read ND, Filler SG, Espeso EA, Nierman WC, Haas H, Bignell EM. The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis. PLoS Pathog. 2014 Oct 16;10(10):e1004413. doi: 10.1371/journal.ppat.1004413.

Bertuzzi M, Schrettl M, Alcazar-Fuoli L, Cairns TC, Muñoz A, Walker LA, Herbst S, Safari M, Cheverton AM, Chen D, Liu H, Saijo S, Fedorova ND, Armstrong-James D, Munro CA, Read ND, Filler SG, Espeso EA, Nierman WC, Haas H, Bignell EM. The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis. PLoS Pathog. 2014 Oct 16;10(10):e1004413. doi: 10.1371/journal.ppat.1004413.

DOI

Yasmin S, Alcazar-Fuoli L, Gründlinger M, Puempel T, Cairns T, Blatzer M, Lopez JF, Grimalt JO, Bignell E, Haas H. Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):E497-504. doi: 10.1073/pnas.1106399108. Epub 2011 Nov 21. PMID: 22106303; PMCID: PMC3286978.

Yasmin S, Alcazar-Fuoli L, Gründlinger M, Puempel T, Cairns T, Blatzer M, Lopez JF, Grimalt JO, Bignell E, Haas H. Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):E497-504. doi: 10.1073/pnas.1106399108. Epub 2011 Nov 21. PMID: 22106303; PMCID: PMC3286978.

PUBMED DOI

Impaired Cytotoxic Response in PBMCs From Patients With COVID-19 Admitted to the ICU: Biomarkers to Predict Disease Severity.

Impaired Cytotoxic Response in PBMCs From Patients With COVID-19 Admitted to the ICU: Biomarkers to Predict Disease Severity. Vigón L, Fuertes D, García-Pérez J, Torres M, Rodríguez-Mora S, Mateos E, Corona M, Saez-Marín AJ, Malo R, Navarro C, Murciano-Antón MA, Cervero M, Alcamí J, García-Gutiérrez V, Planelles V, López-Huertas MR, Coiras M (AC). Front Immunol. 2021 May 26;12:665329. doi: 10.3389/fimmu.2021.665329. eCollection 2021. PMID: 34122423.

PUBMED DOI

Identification of Immunological Parameters as Predictive Biomarkers of Relapse in Patients with Chronic Myeloid Leukemia on Treatment-Free Remission

Identification of Immunological Parameters as Predictive Biomarkers of Relapse in Patients with Chronic Myeloid Leukemia on Treatment-Free Remission. Vigón L, Luna A, Galán M, Rodríguez-Mora S, Fuertes D, Mateos E, Piris-Villaespesa M, Bautista G, San José E, Rivera-Torres J, Steegmann JL, de Ory F, Pérez-Olmeda M, Alcamí J, Planelles V, López-Huertas MR, García-Gutiérrez V, Coiras M (AC). J Clin Med. 2020 Dec 25;10(1):42. doi: 10.3390/jcm10010042. PMID: 33375572.

PUBMED DOI

Content with Investigacion Resistencia a Antibióticos e IRAS .

List of staff

Información adicional

The Leishmaniasis and Chagas Disease Unit supports the National Health System through a multidisciplinary approach that includes the development and validation of diagnostic tests, the molecular characterization of parasites, molecular epidemiology, field studies, as well as experimental research into new therapeutic and prophylactic approaches for their control.
The laboratory has extensive experience in the characterization of the cellular and humoral immune response of leishmaniasis and post-treatment monitoring, as well as in asymptomatic individuals and in experimental animal models. The laboratory also contributes to immunological studies of the pathogenesis of leishmaniasis under immunosuppressive conditions (HIV/Leishmania co-infection, malnutrition, immunosuppressive treatment...). The laboratory has been a WHO Collaborating Center for Leishmaniasis since 1997, providing technical support to the various research and training activities of the WHO and participating in the evaluation of outbreaks of human leishmaniasis in endemic countries.
The laboratory also participates in the evaluation of prognostic markers for the evolution of T. cruzi infection and vertical (transplacental) transmission, an important public health problem in our country. It also carries out studies on the pharmacokinetics of drugs against Chagas disease.

The current director of CNM is Dr. José Miguel Rubio Muñoz.

Dr. José Miguel Rubio has a degree in Biological Sciences from the Universidad Autónoma de Madrid (1986) and a PhD in Biological Sciences from the same university (1992). He carried out his doctoral thesis at the Department of Genetics of the Universidad Autónoma de Madrid, as Associate Professor (1988-1989), and at the School of Biology of the University of East Anglia in Norwich, UK, as Senior Research Assistant (1989-1992).

During his postdoctoral period he obtained a grant from the European Commission within the Human Capital and Mobility Program to be carried out at the University of “La Sapienza” in Rome, Italy and the Institute of Molecular Biology and Biotechnology in Crete, Greece (1993-1994). Subsequently, he made a further stay funded by the WHO and the university itself at the Department of Entomology, Wageningen University, The Netherlands (1994-1996).

Since 1997 he has been a member of the Instituto de Salud Carlos III (ISCIII), where he joined the Department of Parasitology of the National Center of Microbiology, as an EU-INCO postdoctoral fellow and later with a grant from the Autonomous Community of Madrid (CAM). She was part of the founding group of the National Center for Tropical Medicine (2003-2006) and of the 24/7 Alerts and Emergencies Unit (2006-2018) and is currently Head of the Malaria and Emerging Parasitosis Unit of the National Microbiology Center and is part, as research staff, of the Center for Biomedical Research Network on Infectious Diseases (CIBERINFEC/ISCIII).

During his scientific career he has been Visiting Scientist at the Leonidas e Marie Dean Center (FIOCRUZ-AMAZONAS, Manaus, Brazil) and is an External Consultant of the Parasitology Departments of Cairo University (Egypt) and the Medical Research Center (MRC) of Kuala Lumpur (Malaysia).  He also belongs or has belonged to different national and international committees:  Member of the expert group for malaria control of the European Centre for Disease Control (ECDC) since 2011; Expert-Evaluator for health programs of the European Commission since 2004; Spanish Representative (commissioned by ISCIII and MSC) in the Technical Scientific Committee of the TDR (WHO) 2007-2008; Spanish Deputy Focal Point for microbiology at the European Centre for Disease Control (ECDC) from 2012 to 2020; and, member of the Research Ethics Committee of ISCIII until 2019.

In this period he has published more than 100 articles in international indexed journals, 10 book chapters and has been co-editor of two books in the area of malaria, tropical medicine and neglected diseases. He has participated in 58 competitively funded research projects, 20 of them international, having been the principal investigator in 8 national and 11 international projects as PI of the project or WP leader. In addition, he has led five agreements with companies. Currently he has been awarded four sexenios of research, being presented this year 2025 to the fifth. In the teaching field, he participates in different postgraduate programs in the areas of microbiology and parasitology, having directed seven doctoral theses and more than 20 Master's or Degree final projects, both nationally and internationally. ​​​​​

El laboratorio de Referencia e Investigación en Resistencia a Antibióticos ofrece una amplia cartera de servicios al Sistema Nacional de Salud, las cuales pueden solicitarse en cnm-laboratorios.isciii.es. Jefe del Laboratorio: Jesús Oteo Iglesias (Punto focal Nacional de Resistencia antibiótica).

Dispone de dos programas de Vigilancia oficiales y gratuitos que engloban los ensayos ofertados ya sea como aislamientos individuales o mediante estudio de brotes. El Laboratorio utiliza asimismo técnicas de PCR en tiempo real para la detección de genes de resistencia, estas técnicas se han adaptado a un formato multiplex que permite detectar varios genes en la misma reacción. En los últimos años se han incluido metodologías basadas en la secuenciación de genomas completos para el análisis de bacterias multiresistentes (WGS).

Programa de vigilancia de Haemophilus influenzae. Responsables: María Pérez Vázquez (Punto focal Nacional de Haemophilus influenzae) y Belén Aracil. Laboratorio encargado de la identificación, estudio de sensibilidad y análisis genotípico de aislados de Haemophilus influenzae, centrándose esencialmente en la patología invasiva debida este patógeno. 

Programa de vigilancia de Resistencia a Antibióticos. Responsables: María Pérez Vázquez  y Belén Aracil (Punto focal Nacional de Resistencia antibiótica). Laboratorio encargado de la identificación, el estudio de sensibilidad antibiótica, y el diagnóstico fenotípico y genotípico de los diferentes mecanismos de resistencia a antibióticos fundamentalmente en enterobacterias y gram-negativos no fermentadores y Enterococcus spp.

Estudio de brotes. Responsables: Belén Aracil y María Pérez Vázquez. El programa incluye la caracterización de brotes nosocomiales y clones emergentes de alto riesgo mediante diferentes técnicas moleculares (tabla resumen). Éstas, nos permiten realizar estudios filogenéticos con el fin de obtener una información detallada acerca la relación entre los diferentes aislados y su trazabilidad. El objetivo final es generar datos que se transfieren a los hospitales como ayuda para la prevención o control de la propagación del brote.

Acreditación y Calidad. Responsable: Belén Aracil. El laboratorio Referencia e Investigación en Resistencia a Antibióticos ha sido de los primeros en el ISCIII en la utilización de técnicas acreditadas por la Entidad Nacional de Acreditaciones (ENAC). Este laboratorio consiguió la primera acreditación homologada de técnicas diagnósticas en 2012, programa que ha sido ampliado, de manera que en la actualidad más de la mitad de las técnicas ofrecidas al Sistema Nacional de Salud están debidamente acreditadas por ENAC.

Técnicos responsables de las técnicas realizadas en el Laboratorio: Noelia Lara Fuella y Verónica Bautista Sánchez.

En la siguiente imagen se resumen las técnicas ofrecidas al Sistema Nacional de Salud.

PROGRAMAS NOMBRE CARTERA SERVICIO PATÓGENO DETERMINACIÓN, DETECCIÓN, ANÁLISIS MÉTODOS

Programa de vigilancia de Haemophilus

Programa de vigilancia de resistencia a antibióticos.

 Identificación bacteriana

Haemophilus sp.

Enterobacterias, gram-negativos no fermentadores, Enterococcus spp

 Identificación bacteriana

Bioquímicos

MALDI TOF

Secuenciación de RNAr
​ Identificación capsular

Haemophilus influenzae

 

 Identificación capsular fenotípica y genotípica

Aglutinación serológica en latex

PCR ind/multiplex
​ Determinación de Sensibilidad

Haemophilus sp.

Enterobacterias, gram-negativos no fermentadores, Enterococcus

 

 Determinación de Sensibilidad

Microdilución                

Tiras epsilon               

Kirby Bauer
​ Métodos fenotípicos de detección de mecanismos de resistencia

Enterobacterias, gram-negativos no fermentadores,

 

 Métodos fenotípicos de detección de mecanismos de resistencia

Discos y tabletas combinados con inhibidores                

Tiras combinadas     

Test de Hodge modificado

CabaNP                               

Inmunocromatografía CBP
​ Métodos genotípicos de detección de mecanismos de resistencia

Haemophilus sp.

Enterobacterias, gram-negativos no fermentadores, Enterococcus

 

 ADN, PCR y secuenciación

PCR ind/multiplex

Análisis comparativo de las secuencias
​ Tipificación molecular/análisis filogenéticos

Haemophilus sp.

Enterobacterias, gram-negativos no fermentadores, Enterococcus

 

Corte enzimas de restricción, electroforesis

ADN, PCR y secuenciación

Preparación de librerías y secuenciación y análisis de genomas completos

 

PFGE

 

MLST

 

WGS