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Investigation
Hepatitis C and VIH/VHC coinfection
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 .
1. RTC2019-007023-1, Desarrollo de kits diagnósticos mediante PCR multiplex en tiempo real en formato líquido y gelificado para detección enfermedades víricas y sepsis. Ministerio de Ciencia e Innovación. Investigación. Retos. Inmaculada Casas Flecha. (Instituto de Salud Carlos III). 01/01/2021-31/12/2023. 1.685.803 €. DTA: I. colaborador.
2. AESI2020 PI20CIII/00005, Diagnóstico virológico por secuenciación masiva de casos de meningitis y encefalitis sin filiación etiológica AESI Investigación en salud. Mª Dolores Fernández García. (Instituto de Salud Carlos III). 01/01/2021- 31/12/2023. 74.600 €. DTA:I colaborador.MDF: I. principal.
3. PI-0216-2019, Junta de Andalucía. Aplicación de la secuenciación masiva para el diagnóstico de infecciones neurológicas de origen vírico no filiadas. IMIBIC (Instituto Maimónides de Investigación Biomédica de Córdoba). 23/12/2019- 22/06/2022. 59.540,56 €.MDF: I. principal. DTA: I. colaborador.
4. PI19CIII/00041 /MPY 513/19, Estudio del fallo vacunal en enfermedades víricas inmunoprevenibles AESI2019 Investigación en Salud. Aurora Fernández García. (Instituto de Salud Carlos III). 01/01/2020-31/12/2022. 102.497,27 €. DTA: I. colaborador.
5. PI20CIII/00009, Caracterización de la respuesta inmune de anticuerpos en pacientes con trasplante para el desarrollo de una vacuna AESI Investigación en Salud. (Instituto de Salud Carlos III). 01/01/2021-31/12/2023. 92.000 €. DTA: I. colaborador.
6. DTS18CIII/00006, Desarrollo preclínico de vacunas de ADN frente a CMV a través de análisis inmunogénico del proteoma completo de CMV AESI2018 Desarrollo Tecnológico en Salud. (Instituto de Salud Carlos III). 01/01/2019- 31/12/2020. 98.400 €. DTA: I. colaborador.
7. MPY1372/12, Investigación genético molecular en virus de la familia herpesviridae. Ayudas a Grupos de Investigación Emergentes. David Tarragó Asensio. (Instituto de Salud Carlos III). 01/01/2013-31/12/2015. 63.100 €. DTA: I. principal.
Referencia Virológica en Infecciones Producidas por Virus Herpes
El grupo de investigación ofrece y realiza actividades de diagnóstico y referencia a través de la cartera de servicios del Centro Nacional de Microbiología a todo el sistema nacional de salud. Estas actividades son realizadas por los técnicos del grupo y diseñadas, supervisadas y validados sus resultados de forma facultativa por el responsable del grupo.
Estos servicios incluyen:
Detección de virus herpes (virus herpes simple 1 y 2, virus de la varicela zóster) y enterovirus (genérico) en infecciones del sistema nervioso central, infecciones respiratorias, infecciones del tracto intestinal e infecciones sistémicas.
Detección de virus herpes (CMV, EBV, HHV6, HHV7 y HHV8) y determinación de carga viral de citomegalovirus y virus de Epstein Barr en infecciones sistémicas, del sistema nervioso central, respiratorias y del tracto intestinal.
Determinación de cepas salvajes versus cepas resistentes a antivirales en CMV
Determinación de cepa salvaje versus cepa vacunal del virus de la varicela zóster.
Publications
OLFM4 polymorphisms predict septic shock survival after major surgery. Eur J Clin Invest.
Pérez-García F; Resino S; Gómez-Sánchez E; et al; Jiménez-Sousa MÁ (10/10). OLFM4 polymorphisms predict septic shock survival after major surgery. Eur J Clin Invest. 2021. 51(4):e13416. doi: 10.1111/eci.13416.
Alcazar-Fuoli L, Mellado E, Garcia-Effron G, Buitrago MJ, Lopez JF, Grimalt JO, Cuenca-Estrella JM, Rodriguez-Tudela JL. Aspergillus fumigatus C-5 sterol desaturases Erg3A and Erg3B: role in sterol biosynthesis and antifungal drug susceptibility. Antimicrob Agents Chemother. 2006 Feb
Alcazar-Fuoli L, Mellado E, Garcia-Effron G, Buitrago MJ, Lopez JF, Grimalt JO, Cuenca-Estrella JM, Rodriguez-Tudela JL. Aspergillus fumigatus C-5 sterol desaturases Erg3A and Erg3B: role in sterol biosynthesis and antifungal drug susceptibility. Antimicrob Agents Chemother. 2006 Feb;50(2):453-60. doi: 10.1128/AAC.50.2.453-460.2006. PMID: 16436696; PMCID: PMC1366924.
PUBMED14. Alcazar-Fuoli L, Mellado E, Alastruey-Izquierdo A, Cuenca-Estrella M, Rodriguez-Tudela JL. Aspergillus section Fumigati: antifungal susceptibility patterns and sequence-based identification. Antimicrob Agents Chemother. 2008 Apr
Alcazar-Fuoli L, Mellado E, Alastruey-Izquierdo A, Cuenca-Estrella M, Rodriguez-Tudela JL. Aspergillus section Fumigati: antifungal susceptibility patterns and sequence-based identification. Antimicrob Agents Chemother. 2008 Apr;52(4):1244-51. doi: 10.1128/AAC.00942-07. Epub 2008 Jan 22. PMID: 18212093; PMCID: PMC2292508.
PUBMED DOIAlcazar-Fuoli L, Mellado E, Alastruey-Izquierdo A, Cuenca-Estrella M, Rodriguez-Tudela JL. Species identification and antifungal susceptibility patterns of species belonging to Aspergillus section Nigri. Antimicrob Agents Chemother. 2009 Oct
Alcazar-Fuoli L, Mellado E, Alastruey-Izquierdo A, Cuenca-Estrella M, Rodriguez-Tudela JL. Species identification and antifungal susceptibility patterns of species belonging to Aspergillus section Nigri. Antimicrob Agents Chemother. 2009 Oct;53(10):4514-7. doi: 10.1128/AAC.00585-09. Epub 2009 Jul 27. PMID: 19635955; PMCID: PMC2764190.
PUBMED DOIAlcazar-Fuoli L, Mellado E, Cuenca-Estrella M, Sanglard D. Probing the role of point mutations in the cyp51A gene from Aspergillus fumigatus in the model yeast Saccharomyces cerevisiae. Med Mycol. 2011 Apr
Alcazar-Fuoli L, Mellado E, Cuenca-Estrella M, Sanglard D. Probing the role of point mutations in the cyp51A gene from Aspergillus fumigatus in the model yeast Saccharomyces cerevisiae. Med Mycol. 2011 Apr;49(3):276-84. doi: 10.3109/13693786.2010.512926. Epub 2010 Sep 10. PMID: 20831364.
PUBMED DOIAlcazar-Fuoli L, Cuesta I, Rodriguez-Tudela JL, Cuenca-Estrella M, Sanglard D, Mellado E. Three-dimensional models of 14α-sterol demethylase (Cyp51A) from Aspergillus lentulus and Aspergillus fumigatus: an insight into differences in voriconazole interaction. Int J Antimicrob Agents. 2011 Nov
Alcazar-Fuoli L, Cuesta I, Rodriguez-Tudela JL, Cuenca-Estrella M, Sanglard D, Mellado E. Three-dimensional models of 14α-sterol demethylase (Cyp51A) from Aspergillus lentulus and Aspergillus fumigatus: an insight into differences in voriconazole interaction. Int J Antimicrob Agents. 2011 Nov;38(5):426-34. doi: 10.1016/j.ijantimicag.2011.06.005. Epub 2011 Aug 25. PMID: 21871783.
PUBMED DOIAlcazar-Fuoli L, Mellado E. Ergosterol biosynthesis in Aspergillus fumigatus: its relevance as an antifungal target and role in antifungal drug resistance.
Alcazar-Fuoli L, Mellado E. Ergosterol biosynthesis in Aspergillus fumigatus: its relevance as an antifungal target and role in antifungal drug resistance. Front Microbiol. 2013 Jan 10;3:439. doi: 10.3389/fmicb.2012.00439. PMID: 23335918; PMCID: PMC3541703.
PUBMED DOIBernal-Martínez L, Alcazar Fuoli L, Miguel-Revilla B, Carvalho A, Cuétara Garcia MS, Garcia-Rodriguez J, Cunha C, Gómez-García de la Pedrosa E, Gomez-Lopez A. High-Resolution Melting Assay for Genotyping Variants of the CYP2C19 Enzyme and Predicting Voriconazole Effectiveness. Antimicrob Agents Chemother. 2019 May 24
Bernal-Martínez L, Alcazar Fuoli L, Miguel-Revilla B, Carvalho A, Cuétara Garcia MS, Garcia-Rodriguez J, Cunha C, Gómez-García de la Pedrosa E, Gomez-Lopez A. High-Resolution Melting Assay for Genotyping Variants of the CYP2C19 Enzyme and Predicting Voriconazole Effectiveness. Antimicrob Agents Chemother. 2019 May 24;63(6):e02399-18. doi: 10.1128/AAC.02399-18. PMID: 30910893; PMCID:PMC6535561.
PUBMED DOI