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Research Lines
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Mechanisms of pathogenic fungal host adaptation: Morphogenesis in Cryptococcus neoformans
One of the main mechanisms by which fungi are able to cause disease in humans is their ability to evade the immune response and adapt to the environmental conditions found in the host. In this regard, one of the yeasts that has the greatest ability to adapt to the host is Cryptococcus neoformans. This fungus is found in the environment, and is acquired by inhalation, although the most typical picture is meningitis in immunocompromised patients, mainly HIV+. The main phenotypic characteristic is the presence of a polysaccharide capsule surrounding the cell, which is considered a virulence factor. In addition, C. neoformans is able to increase cell size significantly forming “titan” cells, which can reach a diameter of more than 70 microns. In the laboratory, we are interested in the role of these titan cells in the virulence of C. neoformans. Recently, we have described in vitro media in which C. neoformans forms pseudo-titan cells, which has allowed us to identify new factors and pathways involved in this process.
Mechanisms of action of antifungals
In parallel, we have a line whose main objective is to characterize the mechanisms of action of antifungals. Specifically, we have focused our work on the effect of Amphotericin B (AmB). For decades it has been thought that this antifungal causes cell death after binding to ergosterol and pore formation. Our results indicate that this antifungal also induces strong oxidative stress in the cell, which occurs before cell integrity is lost. Furthermore, we have shown that oxidative stress is necessary for the fungicidal action of AmB. These results open the door to design new strategies to improve its efficiency in patients.
New therapeutic strategies
Work with AmB has led to research aimed at improving antifungal therapies. In particular, we have used the strategy of “off-patent” drug repositioning to search for new activities. Using this approach, we have identified several drugs that increase the effectiveness of AmB against major pathogenic yeasts, such as the antibiotic erythromycin. This approach has allowed us to identify drugs with antifungal activity against emerging pathogens, such as Candida auris.
Research projects
Content with Investigacion .
Projects with public funding
TITLE: Virulence factors of pathogenic yeasts and their influence on the host.
FUNDING ENTITY: Ministry of Education and Science.
POSITION HELD: Principal Investigator, Contracted “Ramón y Cajal”.
START/FINISH: 2006-2007
AMOUNT: 15,000 EUROS
TITLE: Characterization of fungal giant cells and their role during infection in mammals.
FINANCING ENTITY: Instituto de Salud Carlos III
POSITION HELD: Principal Investigator, Contracted “Ramón y Cajal”.
START/FINISH: 2006-2007
AMOUNT: 55,000 EUROS
TITLE: Search and identification of genes involved in the resistance to antifungal agents in
Cryptococcus neoformans
FUNDING ENTITY: Ministry of Science and Innovation.
POSITION HELD: Principal Investigator, Contracted “Ramón y Cajal”.
START/FINISH: 2008-2010
AMOUNT: 25,000 EUROS
COLLABORATORS: Juan Luis Rodríguez Tudela (National Center of Microbiology, ISCIII. Madrid); Manuel Cuenca Estrella (National Center of Microbiology, ISCIII. Madrid); Maria Jose Gianinni (Faculdade de Ciências Farmacêuticas-UNESP). Brazil
TITLE: Role of morphological changes of the pathogenic yeast Cryptococcus neoformans during host infection.
FUNDING ENTITY: Ministry of Science and Innovation. National Plan Program “Non-oriented Fundamental Research”, area of Biomedicine, SAF2008-03761.
POSITION HELD: Principal Investigator, Contracted “Ramón y Cajal”.
START/END: 2009-2011
AMOUNT: 46,000 EUROS
PROJECT TITLE: Identification of the molecular mechanisms involved in the morphogenesis of Cryptococcus neoformans and study of their function during infection.
FUNDING ENTITY: Ministry of Science and Innovation, National Plan for Non-Oriented Fundamental Research, Biomedicine Area, Referencia: SAF2011-25140
DURATION FROM: January 2012 UNTIL: December 2014
PRINCIPAL INVESTIGATOR: Oscar Zaragoza Hernández
This project has an FPI grantee granted.
SUBSIDY: 90.000 euros
TITLE: Importance of morphogenesis in the virulence of pathogenic yeast Cryptococcus neoformans and improvement of amphotericin B-based cryptococcosis therapy. Reference: SAF2014-25140
FUNDING ENTITY: MINECO (Call for R+D+I Projects “RETOS INVESTIGACION)
POSITION HELD: Principal Investigator
START/FINISH: 2015-2017
Funding: 100.000 €.
TITLE: Study of the molecular basis and factors inducing morphological changes in Cryptococcus neoformans and characterization of new therapeutic strategies. Reference: SAF2017-86912-R
FUNDING ENTITY: MINECO (Call for R+D+I Projects “RETOS INVESTIGACION)
POSITION HELD: Principal Investigator
START/END: 2018-2020
Funding: 106.000 €.
TITLE: Mechanisms of adaptation of the pathogenic yeast Cryptococcus neoformans to the lung. Reference: PID2020-114546RB
FUNDING ENTITY: Ministry of Science and Innovation, State Research Agency (Call “Proyectos I+D+I” 2020 - Modalities “Research Challenges” and “Knowledge Generation”).
POSITION HELD: Principal Researcher
START/END: 01/09/2021-31/05/2025
Funding: 143,990 €.
TITLE: Precision medicine against antimicrobial resistance. MePRAM Project.
FUNDING ENTITY: Research Projects on Precision Personalized Medicine of the Strategic Action in Health 2021-2023, under the PERTE for Vanguard Health and charged to the European funds of the Recovery, Transformation and Resilience Plan.
POSITION: Collaborator (Principal Investigator: Jesús Oteo Iglesias)
START/FINISH: 2023-2025
Funding: 4.339.500 €.
TITLE: Centre for Biomedical Research in Network. Infectious Diseases Area (CIBERINFEC)
Funding Agency: Insituto de Salud Carlos III. Reference: CB21/13/00105
Dates: 2022-2026 Funding: 85.000 € (first year)
PI: Emilia Mellado Terrado / CoPI: Óscar Zaragoza Hernández
TITLE: Study of the genetic, metabolic and cellular determinants that influence titan cell formation in the fungal pathogen Cryptococcus neoformans and correlation with antifungal exposure.
CALL FOR PROJECTS: Knowledge Generation Projects.
FUNDING ENTITY. State Research Agency. Ministry of Science, Innovation and Universities.
REFERENCE: Project PID2023-148686OB-I00 Project funded by MICIU/AEI/10.13039/501100011033 and by FEDER, EU.
PRINCIPAL INVESTIGATOR: Oscar Zaragoza Hernández
START/END: 2024-2027
FUNDING: 180.000 €.
TITLE: Characterization of azole-resistant Candida parapsilosis isolates associated with hospital outbreaks: New strategies for their detection and treatment.
CALL: Strategic Action in Intramural Health.
FUNDING ENTITY. Carlos III Health Institute.
REFERENCE: AESI-2024 PI24CIII/00051
PRINCIPAL RESEARCHER: Oscar Zaragoza Hernández / Laura Alcázar Fuoli
START/FINISH: /01/012025-31/12/2027
FUNDING: 70.000 €.
Projects financed by biotechnology companies
PROJECT TITLE: Amphores. Evaluation of the induction of oxidative damage by Amphoterin B in susceptible and resistant yeast species.
FUNDING ENTITY: Gilead
DURATION FROM: 2011 TO: 2012
PRINCIPAL INVESTIGATOR: Oscar Zaragoza Hernández
GRANT: 55,000 euros
TITLE: Fungomics. Evaluation of the activity of amphotericin B and other antifungals against human pathogenic fungi.
FINANCING ENTITY: Gilead
POSITION HELD: Principal Investigator
START/END: 2019-2020
TITLE: Antifungal susceptibility testing of a set of Candida spp to CD101 and anidulafungin in five microdilution plates.
FUNDING ENTITY: Cidara
POSITION HELD: Principal Investigator
START/END: 2018
TITLE: Cidara MultiCentre EUCAST study
FUNDING ENTITY: Cidara
POSITION HELD: Principal Investigator
START/END: 2016
TITLE: Characterization of triazole-resistant Candida parapsilosis isolates from Spanish hospitals
FUNDING ENTITY: Gilead Science
POSITION HELD: Principal Investigator
START/END: 2022-2023
TITLE: EUCAST multicentre MIC testing of manogepix meeting EUCAST ECOFF setting criteria
FUNDING ENTITY: Pfizer
POSITION HELD: Principal Investigator
START/END: 2023
Publications
Prevalence and genotype identification of Toxoplasma gondii in wild animals from southwestern Spain.
8. Calero-Bernal R, Saugar JM, Frontera E, Pérez-Martín JE, Habela MA, Serrano FJ, Reina D, Fuentes I. 2015. Prevalence and genotype identification of Toxoplasma gondii in wild animals from southwestern Spain. J Wildl Dis, 51:233-8.
PUBMED DOIHigh SARS-CoV-2 Viral Load and Low CCL5 Expression Levels in the Upper Respiratory Tract Are Associated With COVID-19 Severity.
4. Pérez-García F, Martin-Vicente M, Rojas-García RL, Castilla-García L, Muñoz-Gomez MJ, Hervás-Fernández I, González-Ventosa V, Vidal-Alcántara EJ, Cuadros-González J, Bermejo-Martin JF (‡), Resino S (‡ *), Martínez I (‡). High SARS-CoV-2 Viral Load and Low CCL5 Expression Levels in the Upper Respiratory Tract Are Associated With COVID-19 Severity. J Infect Dis 2022; 225(6):977-982 (A; FI= 7.76; Q1, Infectious Diseases; JCR 2021). PMID: 34910814 DOI: 10.1093/infdis/jiab604.
PUBMED DOIMetabolomic changes after DAAs therapy are related to the improvement of cirrhosis and inflammation in HIV/HCV-coinfected patients.
5. Virseda-Berdices A, Rojo D, Martínez I, Berenguer J, González-García J, Brochado-Kith O, Fernández-Rodríguez A, Díez C, Hontañon V, Pérez-Latorre L, Micán R, Barbas C, Resino S (‡ *), Jiménez-Sousa MA (‡ *). Metabolomic changes after DAAs therapy are related to the improvement of cirrhosis and inflammation in HIV/HCV-coinfected patients. Biomed Pharmacother 2022, 147: 112626. (A; FI= 7.42; D1, Pharmacology & Pharmacy; JCR 2021).
PUBMED DOIBlood microbiome is associated with changes in portal hypertension after successful direct-acting antiviral therapy in patients with HCV-related cirrhosis.
7. Virseda-Berdices A, Brochado-Kith O, Díez C, Hontañon V, Berenguer J, González-García J, Rojo D, Fernández-Rodríguez A, Ibañez-Samaniego L, Llop-Herrera E, Olveira A, Perez-Latorre L, Barbas C, Rava M (‡), Resino S (‡ *), Jiménez-Sousa MA (‡ *). Blood microbiome is associated with changes in portal hypertension after successful direct-acting antiviral therapy in patients with HCV-related cirrhosis. J Antimicrob Chemoth 2022; 77 (3): 719–726 (A; FI= 5.76; Q1, Pharmacology & Pharmacy; JCR 2020).
PUBMED DOIA Q Fever Outbreak with a High Rate of Abortions at a Dairy Goat Farm: Coxiella burnetii Shedding, Environmental Contamination, and Viability
3. Álvarez-Alonso R, Basterretxea M, Barandika JF, Hurtado A, Idiazabal J, Jado I, Beraza X, Montes M, Liendo P, García-Pérez AL. A Q Fever Outbreak with a High Rate of Abortions at a Dairy Goat Farm: Coxiella burnetii Shedding, Environmental Contamination, and Viability. Appl Environ Microbiol. 2018 Oct 1;84(20).
PUBMED DOIIrruptive mammal host populations shape tularemia epidemiology.
4. Luque-Larena, Juan J.; Mougeot, Francois; Arroyo, Beatriz; Dolors Vidal, Ma; Rodriguez-Pastor, Ruth; Escudero, Raquel; Anda, Pedro; Lambin, Xavier. Irruptive mammal host populations shape tularemia epidemiology. Plos Pathogens. 13 - 11, Public Library Science, 01/11/2017.
PUBMED DOIEnvironmental sampling coupled with real-time PCR and genotyping to investigate the source of a Q fever outbreak in a work setting.
5. Hurtado A, Alonso E, Aspiritxaga I, López Etxaniz I, Ocabo B, Barandika JF, Fernández-Ortiz DE Murúa JI, Urbaneja F, Álvarez-Alonso R, Jado I, García-Pérez AL. Environmental sampling coupled with real-time PCR and genotyping to investigate the source of a Q fever outbreak in a work setting. Epidemiol Infect. 2017 Jul;145(9):1834-1842.
PUBMED DOIDensity-Dependent Prevalence of Francisella tularensis in Fluctuating Vole Populations, Northwestern Spain
6. Rodriguez-Pastor, Ruth; Escudero, Raquel; Vidal, Dolors; Mougeot, Francois; Arroyo, Beatriz; Lambin, Xavier; Maria Vila-Coro, Ave; Rodriguez-Moreno, Isabel; Anda, Pedro; Luque-Larena, Juan J.Density-Dependent Prevalence of Francisella tularensis in Fluctuating Vole Populations, Northwestern Spain. Emerging Infectious Diseases. 23 - 8, pp. 1377 - 1379. Centers Disease Control, 01/08/2017.
PUBMED DOIGenotypes of Coxiella burnetii in wildlife: disentangling the molecular epidemiology of a multi-host pathogen
7. González-Barrio D, Jado I, Fernández-de-Mera IG, Del Rocio Fernández-Santos M, Rodríguez-Vargas M, García-Amil C, Beltrán-Beck B, Anda P, Ruiz-Fons F. Genotypes of Coxiella burnetii in wildlife: disentangling the molecular epidemiology of a multi-host pathogen. Environ Microbiol Rep. 2016 Oct;8(5):708-714.
PUBMED DOIDevelopment of Improved Serodiagnostics for Tularemia by Use of Francisella tularensis Proteome Microarrays
8. Nakajima, Rie; Escudero, Raquel; Molina, Douglas M.; Rodriguez-Vargas, Manuela; Randall, Arlo; Jasinskas, Algis; Pablo, Jozelyn; Felgner, Philip L.; AuCoin, David P.; Anda, Pedro; Davies, D. Huw. Towards Development of Improved Serodiagnostics for Tularemia by Use of Francisella tularensis Proteome Microarrays. Journal of Clinical Microbiology. 2016 Jul;54(7):1755-1765.
PUBMED DOIInterruption of onchocerciasis transmission in Bioko Island: Accelerating the movement from control to elimination in Equatorial Guinea
5. Herrador Z, Garcia B, Ncogo P, Perteguer MJ, Rubio JM, Rivas E, Cimas M, Ordoñez G, de Pablos S, Hernández-González A, Nguema R, Moya L, Romay-Barja M, Garate T, Barbre K, Benito A. Interruption of onchocerciasis transmission in Bioko Island: Accelerating the movement from control to elimination in Equatorial Guinea. PLoS Negl Trop Dis. 2018 May 3;12(5):e0006471.
PUBMED DOILAMP kit for diagnosis of non-falciparum malaria in Plasmodium ovale infected patients
7. Thuy-Huong Ta-Tang, Sergio L. B. Luz, Francisco J. Merino, Isabel de Fuentes, Rogelio López-Vélez, Tatiana A. P. Almeida, Marta Lanza, Cláudia M. M. Abrahim, and José M. Rubio (2016). Atypical Mansonella ozzardi Microfilariae from an Endemic Area of Brazilian Amazonia. Am. J. Trop. Med. Hyg 95(3), 2016, pp. 633–636.
PUBMED DOIComparison of Imported Plasmodium ovale curtisi and P. ovale wallikeri Infections among Patients in Spain, 2005-2011.
9. Rojo-Marcos G, Rubio-Muñoz JM, Ramírez-Olivencia G, García-Bujalance S, Elcuaz-Romano R, Díaz-Menéndez M, Calderón M, García-Bermejo I, Ruiz-Giardín JM, Merino-Fernández FJ, Torrús-Tendero D, Delgado-Iribarren A, Ribell-Bachs M,Arévalo-Serrano J, Cuadros-González J (2014). Comparison of Imported Plasmodium ovale curtisi and P. ovale wallikeri Infections among Patients in Spain, 2005-2011. Emerg Infect Dis. 2014 Mar;20(3):409-16.
PUBMED DOIArbovirus surveillance: first dengue virus detection in local Aedes albopictus mosquitoes in Europe, Catalonia, Spain, 2015.
1. C Aranda; MJ Martínez; T Montalvo; R Eritja; J Navero-Castillejos; E Herreros; E Marqués; R Escosa; I Corbella; E Bigas; L Picart; M Jané; I Barrabeig; N Torner; S Talavera; Ana Vázquez; María Paz Sánchez-Seco; Nuria Busquets. Arbovirus surveillance: first dengue virus detection in local Aedes albopictus mosquitoes in Europe, Catalonia, Spain, 2015.Eurosurveillance. 23 - 47, 2018.
PUBMED DOIPhylogenetic Characterization of Crimean-Congo Hemorrhagic Fever Virus, Spain
2. Eva Ramírez de Arellano; Lourdes Hernández; M José Goyanes; Marta Arsuaga; Ana Fernández Cruz; Anabel Negredo; María Paz Sánchez Seco. Phylogenetic Characterization of Crimean-Congo Hemorrhagic Fever Virus, Spain. Emerging infectious diseases. 23 - 12, pp. 2078 - 2080. 12/2017. ISSN 1080-6059
PUBMED DOIToscana virus infection in Catalonia (Spain).
4. Neus Cardeñosa; Diana Kaptoul; Pedro Fernández Viladrich; Carles Aranda; Fernando de Ory; Jordi Niubó; Pere Plans; Angela Domínguez; Giovanni Fedele; Antonio Tenorio; María Paz Sánchez Seco. Toscana virus infection in Catalonia (Spain). Vector borne and zoonotic diseases (Larchmont, N.Y.). 13 - 4, pp. 273 - 278. 04/2013. ISSN 1557-7759
PUBMED DOI. Autochthonous Crimean-Congo Hemorrhagic Fever in Spain
5. Anabel Negredo; Fernando de la Calle Prieto; Eduardo Palencia Herrejón; Marta Mora Rillo; Jenaro Astray Mochales; María P Sánchez Seco; Esther Bermejo Lopez; Javier Menárguez; Ana Fernández Cruz; Beatriz Sánchez Artola; Elena Keough Delgado; Eva Ramírez de Arellano; Fátima Lasala; Jakob Milla; Jose L Fraile; Maria Ordobás Gavín; Amalia Martinez de la Gándara; Lorenzo López Perez; Domingo Diaz Diaz; M Aurora López García; Pilar Delgado Jimenez; Alejandro Martín Quirós; Elena Trigo; Juan C Figueira; Jesús Manzanares; Elena Rodriguez Baena; Luis Garcia Comas; Olaia Rodríguez Fraga; Nicolás García Arenzana; Maria V Fernández Díaz; Victor M Cornejo; Petra Emmerich; Jonas Schmidt Chanasit; Jose R Arribas. Autochthonous Crimean-Congo Hemorrhagic Fever in Spain.The New England journal of medicine. 377 - 2, pp. 154 - 161. 13/07/2017. ISSN 1533-4406
PUBMED DOIZika Virus Screening among Spanish Team Members After 2016 Rio de Janeiro, Brazil, Olympic Games
6. Natalia Rodriguez Valero; Alberto M Borobia; Mar Lago; Maria Paz Sánchez Seco; Fernando de Ory; Ana Vázquez; Jose Luis Pérez Arellano; Cristina Carranza Rodríguez; Miguel J Martínez; Alicia Capón; Elias Cañas; Joaquin Salas Coronas; Arkaitz Azcune Galparsoro; Jose Muñoz. Zika Virus Screening among Spanish Team Members After 2016 Rio de Janeiro, Brazil, Olympic Games. Emerging infectious diseases. 23 - 8, pp. 1426 - 1428. 08/2017. ISSN 1080-6059
PUBMED DOIProlonged Zika Virus Viremia during Pregnancy
7. Anna Suy; Elena Sulleiro; Carlota Rodó; Élida Vázquez; Cristina Bocanegra; Israel Molina; Juliana Esperalba; María P Sánchez Seco; Hector Boix; Tomás Pumarola; Elena Carreras. Prolonged Zika Virus Viremia during Pregnancy. The New England journal of medicine. 375 - 26, pp. 2611 - 2613. 29/12/2016. ISSN 1533-4406
PUBMED DOIContent with Investigacion .
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Almudena Cascajero Díaz
Técnico de laboratorio
ORCID code: 0000-0002-9654-3100
Técnico Superior de Actividades Técnicas y Profesionales (Unidades de Inmunopatología del SIDA y Legionella, Centro Nacional de Microbiología). Clinical Diagnostic Laboratory Technician by IES Renacimiento de Madrid.
Experience in cloning techniques and characterization of neutralizing antibodies and participation in different projects on the pathogenesis of HIV by studying the viral envelope and the mechanisms of resistance to antiretroviral drugs. This experience has subsequently allowed me to participate in 5 multicenter clinical studies studying the immune response against different variants of SARS-CoV-2.
Since 2021, I also participate as a laboratory technician in the Legionella Unit as a support to the Spanish National Health System through the microbiological surveillance of the disease to contribute to the prevention and control of legionellosis.
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Laura del Estal Gómez
Ayudante de investigación
ORCID code: 0009-0000-2773-8986
Graduada en Biología Sanitaria por la Universidad de Alcalá. Máster Universitario en Microbiología Aplicada a la Salud Pública e Investigación en Enfermedades Infecciosas.
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Caroline Stephanie Crisóstomo Vergara
Técnico de Laboratorio
ORCID code: 0009-0008-0525-1737
Técnico de Laboratorio. Técnico superior de Laboratorio Clínico y Biomédico por la Escuela Técnica de Enseñanzas Especializadas de Madrid. Máster en Microbiología Clínica por el Instituto Europeo de Química, Física y Biología de Madrid.
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Fernando González Camacho
Científico Titular
ORCID code: 0000-0003-3175-9004
Licenciado en Ciencias Biológicas por la Universidad de Salamanca y Doctor por la Universidad Autónoma de Madrid. Actualmente, es Científico Titular de plantilla en el Centro Nacional de Microbiología (CNM) del Instituto de Salud Carlos III (ISCIII). Responsable de la Unidad de Legionella del Laboratorio de Referencia e Investigación en Enfermedades Bacterianas transmitidas por agua y alimentos.
A nivel europeo es sustituto (Alternate) al National Focal Point para la enfermedad del legionario en el ECDC y es OCP (Operational Contact Point) en microbiología para la legionelosis en la European Legionnaires' Disease Surveillance Network (ELDSNet).
Coordina las líneas de investigación del laboratorio que se desarrollan en tres perspectivas diferentes: en las instalaciones colonizadas, estudios sobre la resistencia a los tratamientos y su persistencia; en la clínica, sobre factores de virulencia y su interacción con el sistema inmune; y en la vigilancia microbiológica, sobre la mejorar de los métodos de caracterización del microorganismo.
Es Investigador Principal en el proyecto “Búsqueda de biomarcadores de patogenicidad en Legionella spp con interés predictivo de riesgo de infección".
Es miembro de distintas sociedades científicas como son la Sociedad Española de Salud Ambiental (SESA), Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC) y la European Society of Clinical Microbiology and Infectious Diseases (ESCMID).
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Juana María González Rubio
Científica Titular
ORCID code: 0000-0001-6979-2964
La Dra. Juana María González Rubio es Licenciada en Bioquímica por la Universidad de Salamanca y Doctora por la Facultad de Medicina de la Universidad Autónoma de Madrid. Actualmente, es Científico Titular de plantilla en el Centro Nacional de Microbiología del Instituto de Salud Carlos III (ISCIII), donde trabaja en la Unidad de Legionella del Laboratorio de Referencia e Investigación en Enfermedades Bacterianas transmitidas por agua y alimentos.
Dentro del laboratorio, realiza las actividades propias del Programa de Vigilancia Microbiológica de Legionella, y lleva las líneas de investigación del laboratorio sobre la caracterización de biofilms y la puesta a punto de nuevas técnicas para la caracterización de Legionella. También forma parte del equipo investigador del proyecto “Búsqueda de marcadores de patogenicidad para el análisis de riesgos en las instalaciones".
Anteriormente, ha trabajado en la Unidad de Biomonitorización humana del Centro Nacional de Sanidad Ambiental (ISCIII) participando en diferentes proyectos de investigación relacionados con la Sanidad Ambiental, siendo el último más destacado el proyecto “HBM4EU" en el que ha trabajado hasta junio de 2023.
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