ADAR1 haploinsufficiency and sustained picornaviral RdRp dsRNA synthesis synergize to dysregulate RNA editing and...

Area of Science:

• Immunology
• Virology
• Genetics

Background:

• MDA5 senses viral double-stranded RNA (dsRNA), initiating interferon-stimulated gene (ISG) expression.
• Persistent MDA5 activation typically leads to ISG upregulation but can cause autoimmunity.
• ADAR1 enzyme is crucial for RNA editing and preventing autoimmune responses.

Purpose of the Study:

• To investigate the consequences of chronic MDA5 activation by viral dsRNA in the absence of autoimmune complications.
• To explore the role of ADAR1 in modulating MDA5-driven inflammation and preventing autoimmunity.
• To establish a model for studying dsRNA-induced interferonopathies.

Main Methods:

• Transgenic mice expressing picornaviral RNA-dependent RNA polymerase (RdRp) for persistent dsRNA synthesis.
• Generation of Adar heterozygous knockout (Adar+/-) RdRp transgenic mice.
• Analysis of ISG expression, A-to-I RNA editing, and autoimmune phenotypes.

Main Results:

• Lifelong MDA5 activation in RdRp mice conferred viral resistance without autoimmunity.
• Adar+/- RdRp mice developed severe disease resembling interferonopathies, despite wild-type MDA5.
• A-to-I editing was dysregulated and increased in Adar+/- RdRp mice, indicating impaired RNA surveillance.
• The study uncoupled chronic MDA5 hyperactivity from autoinflammatory disease in ADAR1-intact models.

Conclusions:

• Viral polymerase-derived dsRNA can drive interferonopathy pathogenesis via MDA5.
• ADAR1 plays a critical role in preventing autoimmunity by regulating RNA editing in the context of chronic dsRNA sensing.
• The Adar+/- RdRp model provides insights into the mechanisms of interferonopathies and the protective function of ADAR1.