Encephalitis and poor neuronal death–mediated control of herpes simplex virus in human inherited RIPK3 deficiency.

Inborn errors of TLR3-dependent type I IFN immunity in cortical neurons underlie forebrain herpes simplex virus-1 (HSV-1) encephalitis (HSE) due to uncontrolled viral growth and subsequent cell death. We report an otherwise healthy patient with HSE who was compound heterozygous for nonsense (R422*) and frameshift (P493fs9*) RIPK3 variants. Receptor-interacting protein kinase 3 (RIPK3) is a ubiquitous cytoplasmic kinase regulating cell death outcomes, including apoptosis and necroptosis. In vitro, the R422* and P493fs9* RIPK3 proteins impaired cellular apoptosis and necroptosis upon TLR3, TLR4, or TNFR1 stimulation and ZBP1/DAI-mediated necroptotic cell death after HSV-1 infection. The patient's fibroblasts displayed no detectable RIPK3 expression. After TNFR1 or TLR3 stimulation, the patient's cells did not undergo apoptosis or necroptosis. After HSV-1 infection, the cells supported excessive viral growth despite normal induction of antiviral IFN-β and IFN-stimulated genes (ISGs). This phenotype was, nevertheless, rescued by application of exogenous type I IFN. The patient's human pluripotent stem cell (hPSC)–derived cortical neurons displayed impaired cell death and enhanced viral growth after HSV-1 infection, as did isogenic RIPK3-knockout hPSC-derived cortical neurons. Inherited RIPK3 deficiency therefore confers a predisposition to HSE by impairing the cell death–dependent control of HSV-1 in cortical neurons but not their production of or response to type I IFNs. Faulty cell death predisposes encephalitis: Susceptibility to childhood herpes simplex encephalitis (HSE) caused by HSV-1 infection has been attributed to inborn errors of immunity affecting production or sensing of type I interferon. Using whole-exome sequencing, Liu et al. identified a patient with HSE bearing compound heterozygous variants in RIPK3, a key cytoplasmic regulator of cell death. Patient-derived RIPK3 was less stable, resulting in RIPK3 deficiency and defects in apoptosis and necroptosis, without affecting production of type I interferon. Both patient-specific and RIPK3 knockout human pluripotent stem cell–derived cortical neurons displayed enhanced HSV-1 replication and resistance to virus-induced cell death. These results identify a previously undescribed genetic etiology of childhood HSE and demonstrate that cell death–dependent control is a critical component of antiviral defenses against HSV-1. —CO [ABSTRACT FROM AUTHOR]