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Investigation

Arbovirus and imported viral diseases

Research Lines

Content with Investigacion Inmunopatología del SIDA .

Research Lines:

1.    Molecular mechanisms associated to the protection of HIV-1 infection in limb-girdle muscular dystrophy dominant D2 (LGMDD2) patients.
2.    Generation of neutralizing antibodies for therapeutic use based on the broad-spectrum neutralizing response against founder viruses.
3.    Characterization of the immune memory against SARS-CoV-2 in a population over 65 years of age.
4.    Screening and characterization of new anti-latency drugs against HIV-1.
5.    Study of viral entry and HIV tropism in viruses of special epidemiological relevance in Spain. 
6.    Genetic mechanisms of protection and control of HIV-1 infection in populations with extreme phenotypes.

Clinical studies:

1.    Phase 1 clinical trial to evaluate the safety and immunogenicity of HIV-1 envelope-based 763SIP8/MPLA-5 vaccine as a preventive vaccine in healthy uninfected adults. 
2.    ENE-COVID-Senior: Prospective observational study in a cohort of elderly nursing home residents to establish their immune status after receiving a complete vaccination regimen.

Implementation of new technologies:

1.    Identification of HIV-1 integration sites by deep sequencing.
2.    Single cell transcriptomics with simultaneous TCR/BCR sequencing.
3.    Epidemiological intelligence for prediction of SARS-CoV-2 variants likely to emerge in different vaccination settings.
 

Research projects

Content with Investigacion Inmunopatología del SIDA .

1.    Immune response to SARS-CoV-2 infection: effect in naïve vaccinees and seropositives against the most transmissible variants and relevance of host genetics.
Principal Investigator: Javier García Pérez. 
Funding Agency: Acción Estratégica en Salud Intramural 2021(ISCIII)
Funding: 135.000 €
Duration: 2022-2025. 
Project Reference: PI21CIII/00025.
2.    Design and generation of viral stocks of new SARS-CoV-2 variants (omicron subvariants) and analysis of their susceptibility to antibodies neutralization.
Principal Investigator: Javier García Pérez.
Funding Agency: Hipra Scientific S.L.U.
Funding: 103.771 €
Duration: 2023-2025.
Project Reference: MVP 198/23.
3.    Characterization of a mutation in transportin 3 that protects against HIV infection: molecular mechanisms and discovery of new drugs.
Principal Investigator: José Alcamí y Javier García Pérez.
Funding Agency:     Proyectos de I+D+I, Generación de Conocimiento y Retos Investigación de la Agencia Estatal de Investigación.
Funding: 240.000 €
Duration: 2022-2026. 
Project Reference: PID2021-125978OB-C21 funded by MICIU/AEI/10.13039/501100011033 and by FEDER, UE

4.    Generation of immunogens based on HIV-1 envelopes from acutely infected individuals with a broad neutralizing response against founder viruses.
Principal investigator: Nuria González Fernández.
Funding Agency: Acción Estratégica en Salud Intramural 2023 (ISCIII)
Funding: 82.000 €
Duration: 2024-2026. 
Project Reference: PI23CIII/00039.
5.    Phase 1 clinical trial to evaluate the safety and immunogenicity of HIV-1 envelope-based 763SIP8/MPLA-5 vaccine. 
Principal Investigator: Josep Mallolas Masferrer.
Funding Agency: Proyectos de Investigación Clínica Independiente, Acción Estratégica en Salud 2021-2023 (ISCIII).
Funding: 173.200 €
Duration: 2024-2026. 
Project Reference: ICI23/00025.
6.    Service of immunological determinations of the ENE-COVID SENIOR II protocol.
Principal Investigator: Mayte Pérez Olmeda y Javier García Pérez. 
Funding Agency: Fundación para la investigación biomédica del Hospital Universitario La Paz
Funding: 185.037 €
Duration: 2024-2025. 
Project Reference: MOTR 219/24.
7.    Characterization of the immune memory against SARS-CoV-2 in a population over 65 years of age using single cell transcriptomics.
Principal Investigator: Javier García Pérez y Francisco Díez Fuertes.
Funding Agency: Acción Estratégica en Salud Intramural 2021(ISCIII)
Funding: 152.000 €
Duration: 2025-2027. 
Project Reference: PI24CIII/00058
8. Evaluation of rimonabant and cannbinooid analogues in HIV infection and viral latency.
Principal Investigator: Luis Miguel Bedoya del Olmo. 
Funding Agency: Universidad Complutense de Madrid
Funding: 12.000 €
Duration: 2024-2025. 
Project Reference: PR12/24-31553.
9. Discovery of new inhibitors of HIV-1 RNA biogenesis based on blocking the ribonucleoprotein RRE-Rev.
Principal Investigator: José Gallego Sala. Associate Researcher: Luis Miguel Bedoya del Olmo
Funding Agency: Department of Innovation, Universities, Science and Digital Society. Generalitat Valenciana.
Funding: 543,683.84 €
Duration: 2025-2027. 
Project Reference: PROMETEO/2021/036.

Publications

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Provirus reactivation is impaired in HIV-1 infected individuals on treatment with dasatinib and antiretroviral therapy.

Provirus reactivation is impaired in HIV-1 infected individuals on treatment with dasatinib and antiretroviral therapy. Vigón L, Martínez-Román P, Rodríguez-Mora S, Torres M, Puertas MC, Mateos E, Salgado M, Navarro A, Sánchez-Conde M, Ambrosioni J, Cervero M, Wyen C, Hoffmann C, Miró JM, Alcamí J, Podzamczer D, García-Gutiérrez V, Martínez-Picado J, Briz V, Rosa López-Huertas M, Planelles V, Coiras M (AC). Biochem Pharmacol. 2021 Oct;192:114666. doi: 10.1016/j.bcp.2021.114666. PMID: 34186065.

PUBMED DOI

T-Cell-Specific Loss of the PI-3-Kinase p110α Catalytic Subunit Results in Enhanced Cytokine Production and Antitumor Response.

1. Aragoneses-Fenoll L, Ojeda G, Montes-Casado M, Acosta-Ampudia Y, Dianzani U, Portolés P, Rojo JM. T-Cell-Specific Loss of the PI-3-Kinase p110α Catalytic Subunit Results in Enhanced Cytokine Production and Antitumor Response. Front. Immunol. 2018 Feb 27;9:332.

PUBMED DOI

ETP-46321, a dual p110α/δ class IA phosphoinositide 3-kinase inhibitor modulates T lymphocyte activation and collagen-induced arthritis.

2. Aragoneses-Fenoll L, Montes-CasadoM, Ojeda G, Acosta YY, Herranz J, Martínez S, Blanco-Aparicio C, Criado G, Pastor J, Dianzani U, Portolés P, Rojo JM. ETP-46321, a dual p110α/δ class IA phosphoinositide 3-kinase inhibitor modulates T lymphocyte activation and collagen-induced arthritis. Biochem. Pharmacol. 2016 Apr 15;106:56-69. Epub 2016 Feb 13.

PUBMED DOI

Suppression of CD4+ T lymphocyte activation in vitro and experimental encephalomyelitis in vivo by the phosphatidyl inositol 3-kinase inhibitor PIK-75.

3. Acosta YY, Montes-Casado M, Aragoneses-Fenoll L, Dianzani U, Portoles P, Rojo JM. Suppression of CD4+ T lymphocyte activation in vitro and experimental encephalomyelitis in vivo by the phosphatidyl inositol 3-kinase inhibitor PIK-75. Int. J. Immunopathol. Pharmacol. 2014 Jan-Mar;27(1):53-67.

PUBMED DOI

Effects of 3D nanocomposite bioceramic scaffolds on the immune response

4. Cicuendez M., Portolés P., Montes-Casado M., Izquierdo-Barba I., Vallet-Regı M., and Portolés M.T. Effects of 3D nanocomposite bioceramic scaffolds on the immune response. J. Mater. Chem. B, 2014, 2 (22), 3469-3479.

DOI

Characteristics of TCR/CD3 complex CD3 chains of regulatory CD4+ T (Treg) lymphocytes: Role in Treg differentiation in vitro and impact on Treg in vivo.

5. Rojo, J. M., G. Ojeda, Y. Y. Acosta, M. Montes-Casado, G. Criado, and P. Portoles. Characteristics of TCR/CD3 complex CD3 chains of regulatory CD4+ T (Treg) lymphocytes: Role in Treg differentiation in vitro and impact on Treg in vivo. J. Leukoc. Biol. 2014, 95 (3): 441-450.

PUBMED DOI

Dissociation of actin polymerization and lipid raft accumulation by ligation of the Inducible Costimulator (ICOS, CD278)

6. Y. Acosta, G. Ojeda, M. P. Zafra, I. Seren-Bernardone, A. Sánchez, U. Dianzani, P. Portolés y J. M. Rojo. Dissociation of actin polymerization and lipid raft accumulation by ligation of the Inducible Costimulator (ICOS, CD278). Inmunología, 2012, 31 (1): 4-12.

DOI

Complement regulatory protein Crry/p65 costimulation expands natural Treg cells with enhanced suppressive properties in proteoglycan-induced arthritis.

7. Ojeda G., Pini E., Eguiluz C., Montes-Casado M., Broere F., van Eden W., Rojo J.M., and Portolés P. Complement regulatory protein Crry/p65 costimulation expands natural Treg cells with enhanced suppressive properties in proteoglycan-induced arthritis. Arthritis Rheum. 2011 Jun;63(6):1562-72.

PUBMED DOI

Biased binding of class IA phosphatidyl inositol 3-kinase subunits to inducible costimulator (CD278)

8. Acosta Y.Y., Zafra M.P., Ojeda G., Bernardone I.S., Dianzani U., Portolés P., Rojo J.M. Biased binding of class IA phosphatidyl inositol 3-kinase subunits to inducible costimulator (CD278). Cell. Mol. Life Sci. 2011 Sep;68(18):3065-79.

PUBMED DOI

Structure and Immunogenicity of the Human Metapneumovirus F Protein in the Postfusion Conformation.

5. Mas V, Rodriguez L, Olmedillas E, Cano O, Palomo C, Terron MC, et al. Engineering, Structure and Immunogenicity of the Human Metapneumovirus F Protein in the Postfusion Conformation. PLoS Pathog. 2016;12(9):e1005859.

PUBMED DOI

Essential in vitro diagnostics for advanced HIV and serious fungal diseases: international experts' consensus recommendations. Eur J Clin Microbiol Infect Dis. 2019 Sep

Bongomin F, Govender NP, Chakrabarti A, Robert-Gangneux F, Boulware DR, Zafar A, Oladele RO, Richardson MD, Gangneux JP, Alastruey-Izquierdo A, Bazira J, Boyles TH, Sarcarlal J, Nacher M, Obayashi T, Worodria W, Pasqualotto AC, Meya DB, Cheng B, Sriruttan C, Muzoora C, Kambugu A, Rodriguez Tudela JL, Jordan A, Chiller TM, Denning DW. Essential in vitro diagnostics for advanced HIV and serious fungal diseases: international experts' consensus recommendations. Eur J Clin Microbiol Infect Dis. 2019 Sep;38(9):1581-1584. doi: 10.1007/s10096-019-03600-4. PMID: 31175479.

PUBMED DOI

Godet C, Alastruey-Izquierdo A, Flick H, Hennequin C, Mikilps-Mikgelbs R, Munteanu O, Page I, Seidel D, Salzer HJF. A CPAnet consensus statement on research priorities for chronic pulmonary aspergillosis: a neglected fungal infection that requires attention. J Antimicrob Chemother. 2018 ​

Godet C, Alastruey-Izquierdo A, Flick H, Hennequin C, Mikilps-Mikgelbs R, Munteanu O, Page I, Seidel D, Salzer HJF. A CPAnet consensus statement on research priorities for chronic pulmonary aspergillosis: a neglected fungal infection that requires attention. J Antimicrob Chemother. 2018 Feb 1;73(2):280-286. doi: 10.1093/jac/dkx390. PMID: 29126309.​

PUBMED DOI

Genetic Characterization of Brucella spp.: Whole Genome Sequencing-Based Approach for the Determination of Multiple Locus Variable Number Tandem Repeat Profiles

Pelerito A, Nunes A, Grilo T, Isidro J, Silva C, Ferreira AC, Valdezate S, Núncio MS, Georgi E, Gomes JP. (2021) Genetic Characterization of Brucella spp.: Whole Genome Sequencing-Based Approach for the Determination of Multiple Locus Variable Number Tandem Repeat Profiles. 2021. Front Microbiol. 12;12:740068

PUBMED DOI

Saezia sanguinis gen. nov., sp. nov., a Betaproteobacteria member of order Burkholderiales, isolated from human blood

Medina-Pascual MJ, Monzón S, Villalón P, Cuesta I, González-Romo F, Valdezate S. (2020). Saezia sanguinis gen. nov., sp. nov., a Betaproteobacteria member of order Burkholderiales, isolated from human blood. Int J Syst Evol Microbiol.70:2016-25.

PUBMED DOI

Dynamics of a Sporadic Nosocomial Acinetobacter calcoaceticus-Acinetobacter baumannii Complex Population

Villalón P, Ortega M, Sáez-Nieto JA, Carrasco G, Medina-Pascual MJ, Garrido N, Valdezate S. (2019). Dynamics of a Sporadic Nosocomial Acinetobacter calcoaceticus-Acinetobacter baumannii Complex Population. 2019. Front Microbiol. 22;10:593

PUBMED DOI

Epidemiology and susceptibility to antimicrobial agents of the main Nocardia species in Spain.

Valdezate S, Garrido N, Carrasco G, Medina-Pascual MJ, Villalón P, Navarro AM, Saéz-Nieto JA. Epidemiology and susceptibility to antimicrobial agents of the main Nocardia species in Spain. J Antimicrob Chemother. 2017;72(3):754-761.

PUBMED DOI

Paenibacillus spp. isolated from human and environmental samples in Spain: detection of 11 new species.

Sáez-Nieto JA, Medina-Pascual MJ, Carrasco G, Garrido N, Fernandez-Torres MA, Villalón P, Valdezate S. Paenibacillus spp. isolated from human and environmental samples in Spain: detection of 11 new species. New Microbes New Infect. 2017. 24;19:19-27.

PUBMED DOI

Increase in isolation of Burkholderia contaminans from Spanish patients with cystic fibrosis.

Medina-Pascual MJ, Valdezate S, Carrasco G, Villalón P, Garrido N, Saéz-Nieto JA. (2015) Increase in isolation of Burkholderia contaminans from Spanish patients with cystic fibrosis. Clin Microbiol Infect. ;21(2):150-6

PUBMED DOI

Resistance gene pool to co-trimoxazole in non-susceptible Nocardia strains

Valdezate S, Garrido N, Carrasco G, Villalón P, Medina-Pascual MJ, Saéz-Nieto JA. (2015). Resistance gene pool to co-trimoxazole in non-susceptible Nocardia strains. Front Microbiol. 2015 Apr 28;6:376

PUBMED DOI

Genomic Background and Phylogeny of cfiA-Positive Bacteroides fragilis Strains Resistant to Meropenem-EDTA

Medina-Pascual MJ, Valdezate S, Carrasco G, Villalón P, Garrido N, Saéz-Nieto JA. (2015) Increase in isolation of Burkholderia contaminans from Spanish patients with cystic fibrosis. Clin Microbiol Infect. ;21(2):150-6.

PUBMED DOI

Content with Investigacion Inmunopatología del SIDA .

List of staff

Additional Information

Our objectives are research into well-established autochthonous viruses (Toscana, West Nile and Lymphocoriomeningitis), imported viruses with a vector in Spain (mainly Zika, Dengue and Chikungunya), and viruses that cause haemorrhagic fevers (such as Ebola, Lassa or Crimea Congo, which despite being autochthonous, we include in this category) without forgetting other viruses that, at any time, may become emerging viruses and cause public health alerts.

The group's main research objective is to identify and characterise the aforementioned viruses that cause disease and those circulating in our environment with pathogenic potential.

One of the cross-cutting objectives of the laboratory is to optimise methods for the detection of these viruses and their application to determine the incidence, prevalence and/or presence of the viruses in our environment.

However, in addition to methodological development, it is important to know the origin of the circulating viruses, their antigenic relationships with related viruses, the pathogenicity of the different isolates or the interactions of the agents with their host both in cell culture and in arthropod vectors when this is possible. The aim is to strengthen our role as a National Reference Laboratory for zoonoses through research.

Our objectives are research into well-established autochthonous viruses (Toscana, West Nile and Lymphocoriomeningitis), imported viruses with a vector in Spain (mainly Zika, Dengue and Chikungunya), and viruses that cause haemorrhagic fevers (such as Ebola, Lassa or Crimea Congo, which despite being autochthonous, we include in this category) without forgetting other viruses that, at any time, may become emerging viruses and cause public health alerts.

The group's main research objective is to identify and characterise the aforementioned viruses that cause disease and those circulating in our environment with pathogenic potential.

One of the cross-cutting objectives of the laboratory is to optimise methods for the detection of these viruses and their application to determine the incidence, prevalence and/or presence of the viruses in our environment.

However, in addition to methodological development, it is important to know the origin of the circulating viruses, their antigenic relationships with related viruses, the pathogenicity of the different isolates or the interactions of the agents with their host both in cell culture and in arthropod vectors when this is possible. The aim is to strengthen our role as a National Reference Laboratory for zoonoses through research.

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