Tuesday, 23 February 2021 15:42

Descubren el mecanismo por el que las enterobacterias se adaptan a nuestro organismo

Imagen al microscopio de Salmonella enterica serovar Typhimurium. Imagen al microscopio de Salmonella enterica serovar Typhimurium. Volker Brinkmann, Max Planck Institute for Infection Biology
  • Un grupo de investigación con participación del Instituto de Biomedicina de Valencia (IBV) y del Centro Nacional de Biotecnología de Madrid (CNB), ambos del CSIC, realiza la mejor caracterización del sistema que permite a la bacteria Salmonella sobrevivir en el cuerpo humano
  • El hallazgo abre la puerta a diseñar nuevos fármacos antimicrobianos

Un grupo de investigación donde participan científicos del Instituto de Biomedicina de Valencia (IBV) y del Centro Nacional de Biotecnología (CNB), ambos del Consejo Superior de Investigaciones Científicas (CSIC), junto a la Universitat de València (Instituto Universitario Biotecmed) y la Universidad Autónoma de Madrid, han aclarado el mecanismo que emplea la bacteria patógena Salmonella para controlar la expresión de cientos de sus genes, entre ellos los que controlan la adaptación a nuestro organismo y, por tanto, su capacidad para infectarnos. El hallazgo, publicado en la revista Nucleic Acids Research, abre la puerta a diseñar nuevos fármacos antimicrobianos.

El trabajo describe con precisión el mecanismo de funcionamiento de la proteína RcsB de Salmonella para controlar la expresión de un número elevado de genes. RcsB es una proteína que se une al ADN para controlar la expresión de genes cuyos productos son necesarios para reorganizar la arquitectura de la envuelta celular en respuesta a daños externos. Esta proteína recibe señales de otras proteínas dispuestas en la envuelta y que actúan de antenas, formando todas ellas el denominado ‘sistema Rcs’, conservado en la familia de las enterobacterias (Enterobacteriaceae). Esta familia está formada por más de 100 géneros bacterianos que incluyen especies y serovares como Salmonella enterica serovar Typhi (S. typhi) o Shigella dysenteriae, causantes de la fiebre tifoidea y la disentería en humanos.

Entre los procesos controlados por el sistema Rcs se incluyen el movimiento de la bacteria y la formación de una cápsula protectora. En este trabajo se ha visualizado a nivel atómico como RcsB reconoce y se une su ADN diana, lo que ha permitido identificar su secuencia de reconocimiento y así explicar su especificidad de unión. Esta secuencia (denominada ‘caja’ en el argot) se ha buscado en todo el genoma de Salmonella, encontrándose más de 200 sitios de unión y estando más de la mitad de ellos en regiones con información de codificación de proteínas.

20210223 GPortillo

“Mediante este trabajo hemos realizado la mejor caracterización hasta la fecha del sistema Rcs de Salmonella, descubriendo que gestiona más genes de los que pensábamos, hasta un centenar, entre ellos algunos fundamentales para la supervivencia de la bacteria en nuestro organismo”, explica Alberto Marina, investigador del Instituto de Biomedicina de Valencia (IBV-CSIC) y uno de los coautores del estudio.

“Además, hemos realizado un análisis de secuenciación masiva de ARN con distintas variantes mutantes de RcsB en residuos catalíticos que modulan su fosforilación. Así, se han observado cambios en los niveles de expresión de cientos de genes, algunos relacionados con el metabolismo del hierro y desconocidos con anterioridad como controlados por RscB”, apunta Patricia Cansino, investigadora de la Universitat de València y coautora del estudio.

Para el investigador del CNB-CSIC Francisco García-Portillo, coautor del trabajo "una de las sorpresas del trabajo ha sido encontrar potenciales sitio de unión a ADN de este regulador en regiones que codifican a proteína además de las clásicas regiones promotoras". "Será interesante conocer en un futuro si a unión a estos sitios intragénicos la realiza RcsB de forma autónoma o con otros co-reguladores como ocurre en algunas regiones promotoras por las que muestra afinidad"

Finalmente, se cruzaron los datos obtenidos mediante el análisis de RNAseq y el mapeo genómico validando la unión de RcsB a dichas regiones. Los nuevos hallazgos han sido obtenidos mediante aproximaciones estructurales y funcionales combinadas con transcriptómica y bioinformática. El estudio ha permitido arrojar luz sobre cómo RcsB podría controlar la expresión de un número tan elevado de genes en respuesta a daños en la envuelta, y desvelar nuevos genes regulados por esta potencial diana de antimicrobianos.

 

 

Referencia:

Huesa J, Giner-Lamia J, Pucciarelli MG, Paredes-Martíınez F, García-del Portillo F, Marina A and Casino P. Structure-based analyses of Salmonella RcsB variants unravel new features of the Rcs regulon, Nucleic Acids Research 2021,DOI: 10.1093/nar/gkab060

 

Casa de la Ciencia. Delegación del CSIC en la Comunidad Valenciana

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