Encephalitis and poor neuronal death–mediated control of herpes simplex virus in human inherited RIPK3 deficiency, 2023, ZHIYONG LIU et al

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.

Abstract
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.

https://www.science.org/doi/10.1126/sciimmunol.ade2860