We protect your health through science
Investigation
Medical Entomology
Research Lines
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.
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
Emergence of linezolid-resistant coagulase-negative staphylococci in an intensive care unit
2. Emergence of linezolid-resistant coagulase-negative staphylococci in an intensive care unit. Balandin B, Lobo B, Orden B, Román F, García E, Martínez R, Valdivia M, Ortega A, Fernández I, Galdos P. Infect Dis (Lond). 2016;48(5):343-9.
PUBMED DOIHorizontal gene transmission of the cfr gene to MRSA and Enterococcus: role of Staphylococcus epidermidis as a reservoir and alternative pathway for the spread of linezolid resistance.
3. Horizontal gene transmission of the cfr gene to MRSA and Enterococcus: role of Staphylococcus epidermidis as a reservoir and alternative pathway for the spread of linezolid resistance. Cafini F, Nguyen le TT, Higashide M, Román F, Prieto J, Morikawa K. J Antimicrob Chemother. 2016 Mar;71(3):587-92.
PUBMED DOIEmergence of cfr-Mediated Linezolid Resistance in a Methicillin-Resistant Staphylococcus aureus Epidemic Clone Isolated from Patients with Cystic Fibrosis.
4. Emergence of cfr-Mediated Linezolid Resistance in a Methicillin-Resistant Staphylococcus aureus Epidemic Clone Isolated from Patients with Cystic Fibrosis. de Dios Caballero J, Pastor MD, Vindel A, Máiz L, Yagüe G, Salvador C, Cobo M, Morosini MI, del Campo R, Cantón R; GEIFQ Study Group. Antimicrob Agents Chemother. 2015 Dec 14;60(3):1878-82.
PUBMED DOIThe dynamic changes of dominant clones of Staphylococcus aureus causing bloodstream infections in the European region: results of a second structured survey.
5. The dynamic changes of dominant clones of Staphylococcus aureus causing bloodstream infections in the European region: results of a second structured survey. Grundmann H, Schouls LM, Aanensen DM, Pluister GN, Tami A, Chlebowicz M, Glasner C, Sabat AJ, Weist K, Heuer O, Friedrich AW; ESCMID Study Group on Molecular Epidemiological Markers; European Staphylococcal Reference Laboratory Working Group. Euro Surveill. 2014 Dec 11;19(49).
PUBMED DOIPeptidoglycan recycling contributes to intrinsic resistance to fosfomycin in Acinetobacter baumannii.
6. Gil-Marqués ML, Moreno-Martínez P, Costas C, Pachón J, Blázquez J, McConnell M.J.* Peptidoglycan recycling contributes to intrinsic resistance to fosfomycin in Acinetobacter baumannii. Journal of Antimicrobial Chemotherapy. 2018 Nov 1;73(11):2960-2968.
PUBMED DOIImmunization with lipopolysaccharide-free outer membrane complexes protects against Acinetobacter baumannii infection.
7. Pulido MR, García-Quintanilla M, Pachón J, McConnell M.J.* Immunization with lipopolysaccharide-free outer membrane complexes protects against Acinetobacter baumannii infection. Vaccine. 2018 Jul 5;36(29):4153-4156.
PUBMED DOIInhibition of LpxC increases antibiotic susceptibility in Acinetobacter baumannii.
8. García-Quintanilla M, Caro-Vega JM, Pulido MR, Moreno-Martínez P, Pachón J, McConnell M.J.* Inhibition of LpxC increases antibiotic susceptibility in Acinetobacter baumannii. Antimicrobial Agents and Chemotherapy. 2016 Jul 22;60(8):5076-9.
PUBMED DOIImmunization with lipopolysaccharide-deficient whole cells provides protective immunity in an experimental mouse model of Acinetobacter baumannii infection.
9. García-Quintanilla M., Pulido M.R., Pachón J. and McConnell, M.J.* Immunization with lipopolysaccharide-deficient whole cells provides protective immunity in an experimental mouse model of Acinetobacter baumannii infection. PLOS One. 2014 Dec 8;9(12).
PUBMED DOIEncephalitis associated with human herpesvirus-7 infection in an immunocompetent adult.
M. Parra; A. Alcala; C. Amoros; A. Baeza; A. Galiana; D. Tarragó; M.Á. García-Quesada; V. Sánchez-Hellín. Encephalitis associated with human herpesvirus-7 infection in an immunocompetent adult. Virology Journal. 14 - 1, 2017.
PUBMED DOIMolecular epidemiology of enterovirus and parechovirus infections according to patient age over a 4-year period in Spain.
M. Cabrerizo; M. Díaz-Cerio; C. Muñoz-Almagro; N. Rabella; D. Tarragó; M.P. Romero; M.J. Pena; C. Calvo; S. Rey-Cao; A. Moreno-Docón; I. Martínez-Rienda; A. Otero; G. Trallero. Molecular epidemiology of enterovirus and parechovirus infections according to patient age over a 4-year period in Spain. J Med Virol. 2017 Mar;89(3):435-442.
PUBMED DOIViral epidemic outbreaks and public health alerts studied at the National Centre of Microbiology during a two-year period (2012-2013).
J.M. Echevarría Mayo; A.A. Avellón Calvo; M. Cabrerizo Sanz; I. Casas Flecha; J.E. Echevarría Mayo; Fd.eO. de Ory Manchón; A. Negredo Antón; F. Pozo Sánchez; M.P. Sánchez-Seco Fariñas; D. Tarragó Asensio; G. Trallero Masó. Viral epidemic outbreaks and public health alerts studied at the National Centre of Microbiology during a two-year period (2012-2013). Revista española de salud pública. 90, pp. E16 - E16. 2016
PUBMEDMolecular epidemiology of enterovirus 71, coxsackievirus A16 and A6 associated with hand, foot and mouth disease in Spain.
M. Cabrerizo; D. Tarragó; C. Muñoz-Almagro; E. del Amo; M. Domínguez-Gil; J.M.-S. Eiros; I. López-Miragaya; C. Pérez; J. Reina; A. Otero; I. González; J.E. Echevarría; G. Trallero. Molecular epidemiology of enterovirus 71, coxsackievirus A16 and A6 associated with hand, foot and mouth disease in Spain. Clinical Microbiology and Infection. 20 - 3, pp. O150 - O156. 2014.
PUBMED DOIMolecular epidemiology of the first Spanish enterovirus A71 outbreak associated with severe neurological diseases, 2016.
R Gonzalez-Sanz*, D Casas-Alba, C Launes, C Muñoz-Almagro, M Ruiz-García, MJ Gonzalez-Abad, M Alonso, G Megias, N Rabella, M del Cuerpo, M Gozalo-Margüello, A González-Praetorius, A Martínez-Sapiña, MJ Goyanes-Galán, MP Romero, C Calvo, A Antón, M Imaz, M Aranzamendi, Á Hernandez, A Moreno-Docón, S Rey Cao, A Navascuences, A Otero, M Cabrerizo. Molecular epidemiology of the first Spanish enterovirus A71 outbreak associated with severe neurological diseases, 2016. Euro Surveill. 2019 Feb;24(7).
PUBMED DOIAcute flaccid paralysis (AFP) surveillance: challenges and opportunities from 18 years’ experience, Spain, 1998 to 2015.
J Masa-Calles, N Torner, N López-Perea, MV Torres de Mier, B Fernández-Martínez, M Cabrerizo, V Gallardo-García, C Malo, M Margolles, M Portell, N Abadía, A Blasco, S García-Hernández, H Marcos, N Rabella, C Marín, A Fuentes, I Losada, A Nieto, V García Ortúzar, M García Cenoz, JM Arteagoitia, Á Blanco Martínez, A Rivas, D Castrillejo, Spanish AFP Surveillance Working Group. Acute flaccid paralysis (AFP) surveillance: challenges and opportunities from 18 years’ experience, Spain, 1998 to 2015. EuroSurveill 2018 23(47):pii=1700423.
PUBMED DOIRecommendations for enterovirus diagnostics and characterisation within and beyond Europe.
H Harvala, E Broberg, K Benschop, N Berginc, S Ladhani, P Susi, C Christiansen, J McKenna, D Allen, P Makiello, G McAllister, M Carmen, M Sveinsdottir, K Zakikhany, T Gunnarsdottir, R Dyrdak, X Nielsen, T Madsen, J Paul, C Moore, K von Eije, A Piralla , M Strutt, M Carileir, L Vanoverschelde, R Poelman, A Anton, X López-Labrador, C Galli, K Keeren, M Maier, H Cassidy, S Derdas, C Savolainen-Kopra, S Diedrich, S Nordbø, P Minor, J Buesa, H Yu, Q Liao, JL Bailly, F Baldanti, A MacAdam, N Grossly, A Mirand, S Dudman, I Schuffenecker, S Kadamba, n Neyts, M Griffiths, J Richter, C Margaretto, S Govind, U Morley, S Krokstad, J Dean, M Salort, B Prochazka, H-R Honkanen, M Cabrerizo, M Majumdar, L Pellegrinelli, G Nebbia, M Wiewel, S Cottrell, P Coyle, O Adams, J Martin, S Midgley, P Horby, K Wolthers, B Hubert Niesters, P Simmonds and TK Fischer. Recommendations for enterovirus diagnostics and characterisation within and beyond Europe. J Clin Virol 101: 11-17 (2018).
PUBMED DOIMolecular surveillance of norovirus, 2005-16: an epidemiological analysis of data collected from the NoroNet network.
4. J van Beek, M de Graaf, H Al-Hhello, DJ Allen, K Ambert-Balay, N Botteldoorn, M Brytting, J Buesa, M Cabrerizo, M Chan, F Cloak, I Di Bartolo, S Guix, J Hewitt, N Iritani, M Jin, R Johne, I Lederer, J Mans, V Martella, L Maunula, G McAllister, S Niendorf, HG Niesters, AT Podkolzin, M Poljsak-Prijatelj, L Dam Rasmussen, G Reuter, G Tuite, A Kroneman, H Vennema, MPG Koopmans, on behalf of NoroNet. Molecular surveillance of norovirus, 2005-16: an epidemiological analysis of data collected from the NoroNet network. Lancet Infect Dis 18:545-553 (2018)
PUBMED DOIFirst Cases of Severe Flaccid Paralysis Associated with Enterovirus D68 Infection in Spain, 2015-2016.
M Cabrerizo*, JP García-Iñiguez, F Munell, A Amado, P Madurga-Revilla, C Rodrigo, S Pérez, A Martínez-Sapiña, A Antón, G Suárez, N Rabella, V Del Campo, A Otero, J Masa-Calles. First Cases of Severe Flaccid Paralysis Associated with Enterovirus D68 Infection in Spain, 2015-2016. Pediatric Infect Dis J; 36: 1214-1216 (2017).
PUBMED DOIAdditional Information
The Medical Entomology Laboratory has accumulated extensive experience in this field, especially in entomological field studies, biology of arthropods of medical interest, vector competence and vector control. Also, in the molecular detection of Leishmania infantum promastigotes in naturally parasitized phlebotomine sand flies, in the molecular identification of blood ingested by hematophagous arthropods and in the study of the immunomodulatory properties of proteins present in the saliva of phlebotomine sand flies and mosquitoes. Our laboratory is currently co-leading the studies of vectors and wild reservoirs of leishmaniasis in the leishmaniasis focus of Fuenlabrada, Madrid. In this sense, we have studied the role of asymptomatic individuals as reservoirs in the outbreak by xenodiagnosis. On the other hand, we have participated since 2007 in the Entomological Surveillance Program in Airports and Ports against Potential Vectors of Exotic Infectious Diseases, a program that is allowing to develop the expansion map in Spain of Aedes albopictus. In 2016-2017, we carried out surveillance of Ae. albopictus in the Community of Castilla-La Mancha. On the other hand, we conducted studies on the role of patients with post-kala-azar dermal leishmaniasis (PKDL) in the transmission of the parasite in Bangladesh and Sudan. In addition, we participate in research studying ticks transmitting Crimean-Congo hemorrhagic fever in Spain.
Currently, it maintains confidentiality agreements with several companies participating in the evaluation of molecules with activity against pathogens in vectors (GSK), in the development of vector traps using artificial intelligence algorithms (Irideon, Spain), and in the evaluation of repellents against phlebotomine sand flies (IRSEA, France).
The laboratory actively participates in outreach activities such as the Science Week or the European Researchers' Night, among others, making medical entomology science available to the general population.
The Medical Entomology Laboratory has accumulated extensive experience in this field, especially in entomological field studies, biology of arthropods of medical interest, vector competence and vector control. Also, in the molecular detection of Leishmania infantum promastigotes in naturally parasitized phlebotomine sand flies, in the molecular identification of blood ingested by hematophagous arthropods and in the study of the immunomodulatory properties of proteins present in the saliva of phlebotomine sand flies and mosquitoes. Our laboratory is currently co-leading the studies of vectors and wild reservoirs of leishmaniasis in the leishmaniasis focus of Fuenlabrada, Madrid. In this sense, we have studied the role of asymptomatic individuals as reservoirs in the outbreak by xenodiagnosis. On the other hand, we have participated since 2007 in the Entomological Surveillance Program in Airports and Ports against Potential Vectors of Exotic Infectious Diseases, a program that is allowing to develop the expansion map in Spain of Aedes albopictus. In 2016-2017, we carried out surveillance of Ae. albopictus in the Community of Castilla-La Mancha. On the other hand, we conducted studies on the role of patients with post-kala-azar dermal leishmaniasis (PKDL) in the transmission of the parasite in Bangladesh and Sudan. In addition, we participate in research studying ticks transmitting Crimean-Congo hemorrhagic fever in Spain.
Currently, it maintains confidentiality agreements with several companies participating in the evaluation of molecules with activity against pathogens in vectors (GSK), in the development of vector traps using artificial intelligence algorithms (Irideon, Spain), and in the evaluation of repellents against phlebotomine sand flies (IRSEA, France).
The laboratory actively participates in outreach activities such as the Science Week or the European Researchers' Night, among others, making medical entomology science available to the general population.