Double-Stranded RNA Induces Mortality in an MDA5-Mediated Type I Interferonopathy Model

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Gain-of-function mutations in MDA5 cause autoimmune IFNopathies like Singleton-Merten syndrome (SMS).
• Mechanisms of disease progression and external factor influence remain unclear.

Purpose of the Study:

• To investigate the impact of the SMS-associated MDA5 R822Q mutation on disease development and response to immune stimulation.
• To explore therapeutic interventions for MDA5-mediated autoimmune conditions.

Main Methods:

• Generated transgenic mice expressing human MDA5 with the R822Q mutation (hM-R822Q Tg mice).
• Administered polyinosinic-polycytidylic acid [poly(I:C)] to stimulate the innate immune system.
• Interrupted interferon (IFN) signaling pathways and inhibited JAK signaling with tofacitinib.

Main Results:

• hM-R822Q Tg mice exhibited SMS-like cardiac fibrosis, valve enlargement, and calcification, with a systemic IFN-stimulated gene signature.
• Poly(I:C) induced severe intestinal inflammation and lethal hypercytokinemia (high IL-6) in hM-R822Q Tg mice.
• Interfering with IFN signaling or inhibiting JAK signaling ameliorated inflammation and improved survival.

Conclusions:

• The MDA5 R822Q mutation is a critical risk factor for uncontrollable inflammation during viral infection or vaccination.
• Targeting IFN and JAK signaling pathways offers potential therapeutic strategies for MDA5-associated autoimmune diseases.