ID: 55: Humans with loss-of-function mutations in ISG15 display gain-of-function in anti-viral immunity at the expense of increased susceptibility to mycobacteria and auto-immunity

ISG15 is an interferon (IFN)-α/β-inducible protein that exists as a free molecule and conjugated to target proteins (ISGylation). In vivo studies in mice have demonstrated a critical role for ISG15 in antiviral immunity. By contrast, in humans, ISG15 has been shown to have critical functions, but not in antiviral immunity. Extracellular ISG15 is essential in IFN-γ-dependent antimycobacterial immunity, and intracellular ISG15 is essential for the USP18-mediated downregulation of IFN-α/β signaling. We describe ISG15-deficient patients, who, unlike Isg15-deficient mice, display no enhanced susceptibility to viruses in vivo. On the contrary, patients fibroblasts displayed enhanced antiviral protection and transduction of ISG15 restored viral replication to control levels. Difference in antiviral immunity in absence of ISG15 in humans vs. mice is mechanistically explained by ISG15 stabilizing USP18 in humans but not in mice. Thus, ISG15-deficient individuals present with gain-of-function in antiviral immunity at the expense of increased susceptibility to mycobacteria and auto-immunity.