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Mx1 revela vías innatas para la resistencia antiviral y la enfermedad letal de la gripe

Padmini S Pillai¹, Ryan D Molony¹, Kimberly Martinod²

¹Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.

Science (New York, N.Y.)

|April 23, 2016

Resumen

Los adultos mayores con resistencia debilitada al virus de la influenza A (VIA) se enfrentan a un aumento de las infecciones bacterianas. La mortalidad está relacionada con la patología caspase-dependiente, no con la carga viral, en estas poblaciones vulnerables.

Área de la Ciencia:

Inmunología
Virología
Gerontología

Sus antecedentes:

El virus de la gripe A (IAV) causa una mortalidad anual significativa, afectando desproporcionadamente a los adultos mayores.
Los monocitos infectados por IAV en personas mayores presentan una disminución de la producción de interferón pero respuestas inflamatorias intactas.
La comprensión de la vulnerabilidad de los VAI relacionada con la edad requiere examinar las interacciones huésped-patógeno in vivo.

Objetivo del estudio:

Investigar las consecuencias in vivo de las respuestas antivirales alteradas en el contexto de la infección por VAI.
Determinar los mecanismos subyacentes al aumento de la mortalidad en adultos mayores durante la infección por VAI.
Esclarecer el papel de la coinfección bacteriana y la activación del inflamatorio en la patogénesis del VAI.

Principales métodos:

Se utilizaron ratones que expresaban un gen Mx funcional, un efector antiviral clave inducido por el interferón humano.
Empleando modelos de ratón con deficiencias en Mavs y Tlr7 para imitar la resistencia antiviral debilitada.
Carga viral evaluada, carga bacteriana, activación del inflamatorio (caspase-1/11) y daño del tejido dependiente de los neutrófilos.

Principales resultados:

Los ratones con resistencia debilitada (deficiencias de Mavs y Tlr7) mostraron una carga bacteriana respiratoria elevada.
La mortalidad fue independiente de la carga viral o de la señalización dependiente de MyD88.
La mortalidad fue críticamente dependiente de la carga bacteriana, la activación de la caspasa-1/11 y el daño tisular mediado por neutrófilos.

Conclusiones:

En individuos con defensas antivirales comprometidas, la susceptibilidad a la enfermedad IAV grave es impulsada por la patología caspase-dependiente, exacerbada por co-infecciones bacterianas.
Esto pone de relieve el papel crítico de la activación del inflamatorio y las infecciones bacterianas secundarias en la mortalidad relacionada con el VAI en poblaciones vulnerables.
La orientación de las vías dependientes de la caspasa puede ofrecer estrategias terapéuticas para mitigar los resultados graves en personas mayores durante los brotes de influenza.

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