Tesis doctoral de Marta Galán Díez
Candida albicans is a major agent of opportunistic infections especially among immunocompromised patients. As this yeast is a normal commensal of human microbiota, the ultimate challenge in c. Albicans antifungal therapy is to identify novel targets to improve protective host responses to invasive candidiasis. In the work herein presented, we found that cek1 map kinase blockade in c. Albicans caused cell wall !- glucan unmasking and render the fungus ¿visible¿ to the pathogen recognition receptor dectin-1. innate immunity to candida albicans depends upon recognition of molecular patterns on the fungal cell wall. However, masking of major components such as !- glucan seems to be a mechanism that fungi have evolved to avoid immune-cell recognition through dectin-1-receptor. Although the role of c. Albicans mitogenactivated protein kinase (mapk) pathways as virulence determinants has been previously established in animal models, the mechanism involved in this behaviour is largely unknown. In this study we demonstrate that disruption of the c. Albicans erklike- 1 (cek1)-mediated mapk pathway causes enhanced cell-wall !-Glucan exposure triggering immune responses more efficiently than wild-type yeast, as measured by dectin-1-mediated specific binding, human dendritic cell (hdc)- and macrophagemediated phagocytosis, killing and activation of intracellular signaling-pathways. At the molecular level, disruption of cek1 resulted in altered spleen tyrosine kinase (syk)-, raf-1- and erk1/2- activation together with i-«b degradation on hdc and increased dectin-1-dependent ap-1 activation on transfected cells. In addition, concurring with these altered pathways, we detected increased reactive oxygen species production and cytokine secretion. in conclusion, this study demonstrates that the cek1-mediated mapk pathway is involved in !-Glucan exposure in a fungal pathogen, hence influencing dectin-1- dependent immune-cell recognition. Consequently, drugs targeting this fungalconserved map kinase pathway may provide new tools for fighting fungal infections, and help lay the groundwork for the development of novel anti-candida strategies.
Datos académicos de la tesis doctoral «Papel del receptor dectin-1 humano en la respuesta inmune frente a candida albicans: implicación de la ruta mediada por la map quinasa fúngica cek1«
- Título de la tesis: Papel del receptor dectin-1 humano en la respuesta inmune frente a candida albicans: implicación de la ruta mediada por la map quinasa fúngica cek1
- Autor: Marta Galán Díez
- Universidad: Autónoma de Madrid
- Fecha de lectura de la tesis: 02/07/2010
Dirección y tribunal
- Director de la tesis
- Elena Fernandez Ruiz
- Tribunal
- Presidente del tribunal: María no Sánchez crespo
- esteban Veiga chacon (vocal)
- m. mar Alonso monge rebeca (vocal)
- david Sancho Madrid (vocal)