Awarded grant in 2011

IL-1 Receptor-associated Kinase 4 (IRAK4) Epigentically Modulates Nod2- and MDA5- dependent Protection in Viral Myocarditis

Dr. Alan Valaperti of the University of Health Network at the University of Toronto in Canada

“First we observed that the major cell population infiltrating into the inflamed heart of Coxsackie virus B3 (CVB3)-inoculated IRAK4 deficient mice were macrophages. We were able to show that upon in vitro infection with Coxackievirus B3 (CVB3), IRAK4 down-regulated IFN-α and IFN-γ, but not IFN-β, exclusively in macrophages, but not in myeloid dendritic cells or plasmacytoid dendritic cells. Simultaneous down-regulation of IFN-α and IFN-γ, which means up-regulation of IFN-α and IFN-γ in IRAK4 deficient cells, was enough to dramatically reduce viral replication in infected macrophages.”

“In addition, IRAK4 showed unique functions that were only partially shared with its upstream molecule MyD88. In particular, IRAK4 deficiency showed better stability of MDA5, which is an important cytoplasmic receptor to recognize Coxackievirus genome to mount an interferon-dependent anti-viral response. On the contrary, CVB3-infected wild-type macrophages showed a relevant degradation of MDA5 few hours after infection, whereas MyD88 deficient cells showed degradation of MDA5 in a later stage. This resulted in higher viral protection in IRAK4 deficient cells compared to wild-type or MyD88 deficient counterparts.”

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