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Investigación
Adaptation of pathogenic fungi to the host and development of new antifungal therapies
Líneas de investigación
Content with Investigacion .
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.
Proyectos de investigación
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: 2021-2024
Funding: 117,000 €.
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
Publicaciones destacadas
Long-range dispersal moved Francisella tularensis into Western Europe from the East
Dwibedi, Chinmay; Birdsell, Dawn; Larkeryd, Adrian; Myrtennas, Kerstin; Ohrman, Caroline; Nilsson, Elin; Karlsson, Edvin; Hochhalter, Christian; Rivera, Andrew; Maltinsky, Sara; Bayer, Brittany; Keim, Paul; Scholz, Holger C; Tomaso, Herbert; Wittwer, Matthias; Beuret, Christian; Schuerch, Nadia; Pilo, Paola; Hernandez Perez, Marta; Rodriguez-Lazaro, David; Escudero, Raquel; Anda, Pedro; Forsman, Mats; Wagner, David M; Larsson, Par; Johansson, Anders. Long-range dispersal moved Francisella tularensis into Western Europe from the East. Microbial genomics. 2 - 12, pp. e000100. 01/01/2016.
PUBMED DOIFrancisella species in ticks and animals, Iberian Peninsula
Lopes de Carvalho, I.; Toledo, A.; Carvalho, C. L.; Barandika, J. F.; Respicio-Kingry, L. B.; Garcia-Amil, C.; Garcia-Perez, A. L.; Olmeda, A. S.; Ze-Ze, L.; Petersen, J. M.; Anda, P.; Nuncio, M. S.; Escudero, R. Francisella species in ticks and animals, Iberian Peninsula. Ticks and Tick-Borne Diseases. 7 - 1, pp. 159 - 165. Elsevier GMBH, Urban & Fischer Verlag, 01/01/2016.
PUBMED DOIStable levels of Coxiella burnetii prevalence in dairy sheep flocks but changes in genotype distribution after a 10-year period in northern Spain
Álvarez-Alonso R, Barandika JF, Ruiz-Fons F, Ortega-Araiztegi I, Jado I, Hurtado A, García-Pérez AL. Stable levels of Coxiella burnetii prevalence in dairy sheep flocks but changes in genotype distribution after a 10-year period in northern Spain. Acta Vet Scand. 2018 Nov 20;60(1):75.
PUBMED DOIEvidence for Suppression of Onchocerciasis Transmission in Bioko Island, Equatorial Guinea
Moya L, Herrador Z, Ta-Tang TH, Rubio JM, Perteguer MJ, Hernandez-González A, García B, Nguema R, Nguema J, Ncog P, Garate T, Benito A, Sima A and Aparicio P. Evidence for Suppression of Onchocerciasis Transmission in Bioko Island, Equatorial Guinea.PLoS Negl Trop Dis, 2016; 10(7): e0004829.
PUBMED DOILAMP kit for diagnosis of non-falciparum malaria in Plasmodium ovale infected patients
Cuadros J, Martin Ramírez A, González IJ, Ding XC, Perez Tanoira R, Rojo-Marcos G, Gómez-Herruz P, Rubio JM. LAMP kit for diagnosis of non-falciparum malaria in Plasmodium ovale infected patients. Malar J. 2017 Jan 7;16(1):20.
PUBMED DOIPlasmodium species differentiation by non-expert on-line volunteers for remote malaria field diagnosis
Ortiz-Ruiz A, Postigo M, Gil-Casanova S, Cuadrado D, Bautista JM, Rubio JM, Luengo-Oroz M, Linares M. Plasmodium species differentiation by non-expert on-line volunteers for remote malaria field diagnosis. Malar J. 2018 Jan 30;17(1):54.
PUBMED DOIStudy of the diagnostic accuracy of microbiological techniques in the diagnosis of malaria in the immigrant population in Madrid
Martín-Díaz A, Rubio JM, Herrero-Martínez JM, Lizasoain M, Ruiz-Giardin JM, Jaqueti J, Cuadros J, Rojo-Marcos G, Martín-Rabadán P, Calderón M, Campelo C, Velasco M, Pérez-Ayala A. Study of the diagnostic accuracy of microbiological techniques in the diagnosis of malaria in the immigrant population in Madrid. Malar J. 2018 Aug 29;17(1):314.
PUBMED DOIpective comparative multi-centre study on imported Plasmodium ovale wallikeri and Plasmodium ovale curtisi infections.
Rojo-Marcos G, Rubio-Muñoz JM, Angheben A, Jaureguiberry S, García-Bujalance S, Tomasoni LR, Rodríguez-Valero N, Ruiz-Giardín JM, Salas-Coronas J, Cuadros-González J, García-Rodríguez M, Molina-Romero I, López-Vélez R, Gobbi F, Calderón-Moreno M, Martin-Echevarría E, Elía-López M, Llovo-Taboada J; TropNet Plasmodium ovale investigator group. Prospective comparative multi-centre study on imported Plasmodium ovale wallikeri and Plasmodium ovale curtisi infections. Malar J. 2018 Oct 30;17(1):399.
PUBMED DOIImported and autochthonous malaria in West Saudi Arabia: results from a reference hospital
Soliman RH, Garcia-Aranda P, Elzagawy SM, Hussein BE, Mayah WW, Martin Ramirez A, Ta-Tang TH, Rubio JM. Imported and autochthonous malaria in West Saudi Arabia: results from a reference hospital. Malar J. 2018 Aug 7;17(1):286.
PUBMED DOICryptosporidium hominis genotypes involved in increased incidence and clusters of cases, Navarra, Spain, 2012.
Fuentes, I., Martín, C., Beristain, X; Mazón,A, Saugar, JM, Blanco, A; García M, Cenoz, Valle-Cristia, Ezpeleta, C., Castilla, J. 2015. Cryptosporidium hominis genotypes involved in increased incidence and clusters of cases, Navarra, Spain, 2012. Epidemiology and Infection; 143:1033-6
PUBMED DOIMolecular genotyping of Giardia duodenalis isolates from symptomatic individuals attending two major public hospitals in Madrid, Spain.
Lucio A, Martínez-Ruiz R, Merino FJ, Bailo B, Aguilera M, Fuentes I, Carmena D. 2015. Molecular genotyping of Giardia duodenalis isolates from symptomatic individuals attending two major public hospitals in Madrid, Spain. PLoS One. 10 (12): e0143981.
PUBMED DOIOccurrence and subtype distribution of Blastocystis sp. in humans, dogs, and cats sharing household in northern Spain and assessment of zoonotic transmission risk.
Paulos S, Köster PC, de Lucio A, Hernández-de-Mingo M, Cardona GA, Fernández-Crespo JC, Stensvold RC, Carmena D. 2018. Occurrence and subtype distribution of Blastocystis sp. in humans, dogs, and cats sharing household in northern Spain and assessment of zoonotic transmission risk. Zoonoses and Public Health, 65:993-1002.
PUBMED DOIPhlebotomine sand fly survey in the focus of leishmaniasis of Madrid, Spain (2012–2014): seasonal dynamics, Leishmania infantum infection rates and blood meal preferences.
González E, Jiménez M, Hernández S, Martín-Martín I, Molina R. Phlebotomine sand fly survey in the focus of leishmaniasis of Madrid, Spain (2012–2014): seasonal dynamics, Leishmania infantum infection rates and blood meal preferences. Parasit Vectors 2017, 10:368.
PUBMED DOIMethods in Sand Fly Research
Molina R, Jiménez M, Alvar J, González E, Hernández-Taberna S, Martín-Martín Inés. 2017. Methods in Sand Fly Research (R. Molina, M. Jiménez & J. Alvar, edits.). Servicio de Publicaciones Universidad de Alcalá de Henares. ISBN: 978-84-16978-28-1
Factors associated with Leishmania asymptomatic infection: results from a cross-sectional survey in highland northern Ethiopia
Custodio E, Gadisa E, Sordo L, Cruz I, Moreno J, Nieto J, Chicharro C, Aseffa A, Abraham Z, Hailu T, Cañavate C. Factors associated with Leishmania asymptomatic infection: results from a cross-sectional survey in highland northern Ethiopia. PLoS Negl Trop Dis. 2012;6(9):e1813.
PUBMED DOICytokine Release Assays as Tests for Exposure to Leishmania, and for Confirming Cure from Leishmaniasis, in Solid Organ Transplant Recipients.
Carrillo E, Carrasco-Antón N, López-Medrano F, Salto E, Fernández L, San Martín JV, Alvar J, Aguado JM, Moreno J. Cytokine Release Assays as Tests for Exposure to Leishmania, and for Confirming Cure from Leishmaniasis, in Solid Organ Transplant Recipients. PLoS Negl Trop Dis. 2015 Oct 23;9(10):e0004179.
PUBMED DOIContent with Investigacion .
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Óscar Zaragoza Hernández
Research Professor
ORCID code: 0000-0002-1581-0845
Dr. Oscar Zaragoza graduated in Biology from the Complutense University of Madrid in 1995 and obtained his PhD from the Autonomous University of Madrid. He completed his doctoral thesis (2000) at the CSIC under the direction of Dr. Juana María Gancedo on the topic of glucose catabolite repression in Saccharomyces cerevisiae. During this period, he was also tutored by Dr. Carlos Gancedo in collaborative projects, that allowed him to start working with the pathogenic yeast Candida albicans.
After a brief postdoctoral stay in the same laboratory, in 2001, he joined the laboratory of Dr. Arturo Casadevall (Albert Einstein College of Medicine, New York), where he specialized in research into virulence mechanisms of pathogenic fungi, mainly Cryptococcus neoformans. In 2006 he joined the National Center for Microbiology of the ISCIII thanks to a “Ramón y Cajal” contract and he became staff scientist in 2009. Currently, he occupies the rank of Research Professor of the OPIs.
During his career, he has published more than 140 articles, 4 book chapters and a popular book ("Microscopic fungi: Friends or Enemies?"). He has obtained public and private projects, and participates as CoIP of a CIBERINFEC group. He has supervised seven doctoral theses, and numerous master's thesis projects.
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Alba Torres Cano
PhD student (FPI contract)
ORCID code: 0009-0008-3151-1803
Alba Torres Cano has a degree in Health Biology from the University of Alcalá de Henares (UAH), and completed the master's degree "Microbiology Applied to Public Health and Infectious Diseases" from the UAH. He completed his master's thesis at the CNM under the direction of Dr. Zaragoza in 2022, focusing on pathogenic yeasts. In that year, he joined the ISCIII with an FPI predoctoral contract under the direction of Dr. Óscar Zaragoza.
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Alejandra Lora Plaza
PhD student (FPI contract)
ORCID code: 0009-0004-4344-1583
Alejandra Lora Plaza graduated in Health Biology and completed the Master in Applied Microbiology in Public Health and Infectious Diseases Research (2021) at the University of Alcalá in both cases. She joined the Department of Microbiology of the Faculty of Biology of the University of Barcelona to carry out her internship and her final degree work. Subsequently, she did her Master's thesis at the Microbiology Laboratory of the Hospital Universitario Príncipe de Asturias. In 2022 she joined the Public Health and Epidemiology group at the Marqués de Valdecilla Research Institute (IDIVAL), Santander, as a research support technician. In 2024 he joined Dr. Concha Gil's group in the Department of Microbiology and Parasitology at the Faculty of Pharmacy of the Complutense University of Madrid focusing on yeasts.
In 2025 she joined ISCIII with a predoctoral FPI fellowship under the direction of Dr. Óscar Zaragoza.
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