Impaired STING activation due to a variant in the E3 ubiqitin ligase AMFR in a patient with severe VZV infection and hemophagocytic lymphohistiocytosis

Abstract

Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus exclusively infecting humans, where it causes two distinct pathologies: varicella (chickenpox) upon primary infection and herpes zoster (shingles) following reactivation. In susceptible individuals, VZV can give rise to more severe clinical manifestations, including disseminated infection, pneumonitis, encephalitis, and vasculopathy. Here we describe a 3-year-old boy with severe VZV infection involving the central nervous system, subsequently triggering longstanding hemophagocytic lymphohistiocytosis (HLH). We found that the patient carries a rare monoallelic variant in autocrine motility factor receptor AMFR encoding an ubiquitin ligase involved in innate cytosolic DNA sensing and interferon (IFN) production through the cyclic GMP-AMP synthase – stimulator of IFN genes (cGAS-STING) pathway. Peripheral blood mononuclear cells (PBMCs) from the patient exhibited impaired signaling downstream of STING in response to the cGAS agonists 2’3’-cGAMP and dsDNA, as well as decreased IFN induction in response to herpes virus. VZV replication in patient PBMCs was found to be slightly increased compared to healthy controls. Overexpression of the variant AMFR p.R594C resulted in decreased K27-linked STING ubiquitination compared to expression of WT AMFR. This work links defective AMFR-STING signaling to severe VZV disease and hyperinflammation and suggests a direct role for cGAS-STING in control of viral infections in humans.