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Errores congénitos de la OAS-RNasa L en el síndrome inflamatorio multisistémico relacionado con el SARS-CoV-2 en

Danyel Lee^1,2,3, Jérémie Le Pen⁴, Ahmad Yatim¹

¹St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.

Science (New York, N.Y.)

|December 20, 2022

Resumen

Los defectos genéticos en OAS1, OAS2 o RNASEL causan síndrome inflamatorio multisistémico severo en niños (MIS-C) después de COVID-19. Estas deficiencias conducen a una producción excesiva de citoquinas inflamatorias, subyacente a la patogénesis de MIS-C.

Área de la Ciencia:

Inmunología
La genética
Virología

Sus antecedentes:

El síndrome inflamatorio multisistémico en niños (MIS-C) es una afección grave después de la infección por SARS-CoV-2.
Los fundamentos genéticos precisos de MIS-C siguen siendo incompletamente entendidos.

Objetivo del estudio:

Investigar la base genética de MIS-C en niños afectados.
Para aclarar los mecanismos moleculares que vinculan las deficiencias genéticas a la inflamación excesiva.

Principales métodos:

Análisis genético de cinco niños no relacionados diagnosticados con MIS-C.
Estudios in vitro con líneas celulares monocíticas y células mieloides primarias.
Estimulación con ARN de doble cadena (dsRNA) y SARS-CoV-2.
Evaluación de la producción de citoquinas y análisis de la vía (MDA5, RIG-I, MAVS).

Principales resultados:

Se identificaron deficiencias autosómicas recesivas en OAS1, OAS2 o RNASEL en todos los pacientes con MIS-C estudiados.
Las células con estas deficiencias exhibieron una liberación excesiva de citoquinas inflamatorias al ser estimuladas por dsRNA o SARS-CoV-2.
La vía OAS-RNasa L, que involucra la señalización MAVS, fue crucial para la producción de citoquinas desencadenadas por SARS-CoV-2 en fagocitos mononucleares.

Conclusiones:

Las deficiencias recesivas en la vía OAS-RNasa L predisponen a las personas a la MIS-C grave.
La desregulación de esta vía de detección inmune innata contribuye a la patogénesis de MIS-C.
Comprender estos factores genéticos ofrece información sobre el desarrollo de MIS-C y posibles objetivos terapéuticos.

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