Gain-of-function mutations in the viral dsRNA sensor
melanoma differentiation-associated protein 5 (MDA5) lead to autoimmune IFNopathies, including
Singleton-Merten syndrome (SMS) and Aicardi-Goutières syndrome. However, much remains unclear regarding the mechanism of
disease progression and how external factors such as
infection or immune stimulation with vaccination can affect the immune response. With this aim, we generated mice with human MDA5 bearing the SMS-associated mutation R822Q (hM-R822Q). hM-R822Q transgenic (Tg) mice developed SMS-like heart
fibrosis, aortic valve enlargement, and aortic calcification with a systemic IFN-stimulated gene signature resulting in the activation of the adaptive immune response. Although administration of the viral dsRNA mimic
polyinosinic-polycytidylic acid [
poly(I:C)] did not have remarkable effects on the cardiac phenotype, dramatic
inflammation was observed in the intestines where IFN production was most elevated.
Poly(I:C)-injected hM-R822Q Tg mice also developed lethal
hypercytokinemia marked by massive
IL-6 levels in the serum. Interrupting the IFN signaling through mitochondrial
antiviral signaling
protein or IFN-α/β receptor alleviated hM-R822Q-induced
inflammation. Furthermore, inhibition of JAK signaling with
tofacitinib reduced
cytokine production and ameliorated mucosal damage, enabling the survival of
poly(I:C)-injected hM-R822Q Tg mice. These findings demonstrate that the MDA5 R822Q mutant introduces a critical risk factor for uncontrollable
inflammation on
viral infection or vaccination.