Referencia

PMID: 23133388 doi: 10.1371/journal.ppat.1003005

Autores

Marc Torrent, David Pulido, Maria VictòriaNogués, Ester Boix.

Resumen

Antimicrobial proteins and peptides (AMPs) are important effectors of the innate immune system that play a vital role in the prevention of infections. Recent advances have highlighted the similarity between AMPs and amyloid proteins. Using the Eosinophil Cationic Protein as a model, we have rationalized the structure-activity relationships between amyloid aggregation and antimicrobial activity. Our results show how protein aggregation can induce bacteria agglutination and cell death. Using confocal and total internal reflection fluorescence microscopy we have tracked the formation in situ of protein amyloid-like aggregates at the bacteria surface and on membrane models. In both cases, fibrillar aggregates able to bind to amyloid diagnostic dyes were detected. Additionally, a single point mutation (Ile13 to Ala) can suppress the protein amyloid behavior, abolishing the agglutinating activity and impairing the antimicrobial action. The mutant is also defective in triggering both leakage and lipid vesicle aggregation. We conclude that ECP aggregation at the bacterial surface is essential for its cytotoxicity. Hence, we propose here a new prospective biological function for amyloid-like aggregates with potential biological relevance.

Descripción

Las infecciones bacterianas están clasificadas como enfermedades graves que causan millones de muertes al año en todo el mundo. Los antibióticos son fármacos efectivos contra este tipo de infecciones pero, desafortunadamente, los microorganismos están desarrollando mecanismos de resistencia a una velocidad alarmante. Es por esta razón que las proteínas y péptidos propios del sistema inmunitario innato están captandointerésen el desarrollo de fármacos alternativos. Entre estas proteínas se encuentra la Proteína Catiónica de Eosinófilos (ECP), proteína secretada por los eosinófilos en los focos de infección, que presenta una elevadaactividad antimicrobiana y una capacidad excepcional de aglutinar las células bacterianas. En este artículo mostramos como el mecanismo de aglutinación de la ECP está basado en la agregación amiloideade la proteína en la superficie de las bacterias. Estas observaciones establecen un nuevo paradigma de cómo la naturaleza puede utilizar los agregados de tipo amiloideo para combatir las infecciones bacterianas. Los resultados presentados en este artículo no solo nos pueden servir para entender mejor la relación entre los mecanismos infecciosos y las enfermedades neurodegenerativas sino también para inspirar el desarrollo de nuevos fármacos basados en proteínas y péptidosantimicrobianos.

imagen junio

REFERENCIA DEL GRUPO INVESTIGADOR

Las ribonucleasas humanas forman parte del sistema inmunitario innato y son modelos interesantes para el desarrollo de fármacos alternativos para el tratamiento de infecciones y problemas inflamatorios.Nuestro grupo investiga, principalmente, el mecanismo de acción antimicrobiano de lasribonucleasashumanas, especialmente la Proteína Catiónica de Eosinófilos (ECP) y la ribonucelasa de piel (o Ribonucleasa 7). En este contexto, pretendemos caracterizar las relaciones estructura-función de estas ribonucleasas para identificar sus dominios funcionales y aplicar nuestros descubrimientos al desarrollo de nuevos agentes antimicrobianos.

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