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Las pantallas CRISPR de todo el genoma revelan factores de huésped críticos para la infección por SARS-CoV-2
Jin Wei1, Mia Madel Alfajaro1, Peter C DeWeirdt2
1Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
Cell
|November 4, 2020
Resumen
Los investigadores identificaron genes huéspedes clave para la infección por SARS-CoV-2 utilizando pantallas CRISPR. Estos hallazgos revelan nuevos objetivos terapéuticos y vías críticas para los coronavirus, incluidos el HMGB1 y el complejo SWI/SNF.
Área de la Ciencia:
- Virología
- La genética
- Inmunología
Sus antecedentes:
- El coronavirus 2 del síndrome respiratorio agudo severo (SARS-CoV-2) causa COVID-19, lo que requiere la identificación de los factores de acogida para el desarrollo terapéutico.
- Comprender las interacciones huésped-patógeno es crucial para combatir las infecciones virales y la patogénesis.
Objetivo del estudio:
- Identificar los genes huéspedes esenciales para la infección por SARS-CoV-2 utilizando pantallas CRISPR de todo el genoma.
- Descubrir nuevos objetivos terapéuticos y comprender la patogénesis de la enfermedad por coronavirus 2019 (COVID-19).
- Para explorar el linaje específico del SARS y los factores de hospedaje del pan-coronavirus.
Principales métodos:
- Las pantallas CRISPR de todo el genoma se realizaron en células Vero-E6 utilizando SARS-CoV-2, MERS-CoV y virus diseñados.
- Se realizó una validación funcional de los factores del huésped identificados, incluido el HMGB1.
- Se probó la eficacia de los antagonistas de moléculas pequeñas contra la infección por SARS-CoV-2.
Principales resultados:
- Se identificaron factores de huésped conocidos como ACE2 y Cathepsin L.
- Se descubrieron nuevos genes pro-virales, incluidos el HMGB1 y el complejo SWI/SNF.
- Se demostró que HMGB1 regula la expresión de ACE2 y es crítico para la entrada de múltiples coronavirus.
- Los inhibidores de moléculas pequeñas dirigidos a genes identificados redujeron la infección por SARS-CoV-2 en primates y células humanas.
Conclusiones:
- El estudio identifica genes huéspedes esenciales para el SARS-CoV-2 y otros coronavirus, ofreciendo objetivos terapéuticos potenciales.
- HMGB1 y el complejo SWI/SNF representan factores clave específicos del linaje del SARS y del pancoronavirus, respectivamente.
- La inhibición de los factores de huésped identificados demuestra una estrategia terapéutica viable contra el SARS-CoV-2.
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