Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency

during which the vast majority of cases are a consequence of primary infection with HSV-1 (7-9). The pathogenesis of HSE, first described in 1941, remained elusive until the demonstration of an underlying role in this devastating disease, in at least some children, of autosomal recessive (AR) UNC-93B deficiency in 2006, autosomal dominant (AD) TLR3 deficiency in 2007, and, more recently, AD TNF receptor-associated factor 3 (TRAF3) and AR TLR3 deficiencies (10-13). Fibroblasts from patients with UNC-93B, TLR3, and TRAF3 deficiencies do not respond to stimulation with TLR3 agonists or infection with HSV-1 or vesicular stomatitis virus (VSV). HSE, together with other infectious diseases, was also reported in 2 children with mutations in STAT-1 and NEMO (10-15). These genetic deficiencies thus highlighted the importance of the TLR3-dependent production of IFN-/ and IFN- after infection of the CNS with HSV-1 (6, 16, 17). In fibroblasts from patients with Herpes simplex encephalitis (HSE) is the most common sporadic viral encephalitis of childhood. Autosomal recessive (AR) UNC-93B and TLR3 deficiencies and autosomal dominant (AD) TLR3 and TRAF3 deficiencies underlie HSE in some children. We report here unrelated HSE children with AR or AD TRIF deficiency. The AR form of the disease was found to be due to a homozygous nonsense mutation that resulted in a complete absence of the TRIF protein. Both the TLR3-and the TRIF-dependent TLR4 signaling pathways were abolished. The AD form of disease was found to be due to a heterozygous missense mutation, resulting in a dysfunctional protein. In this form of the disease, the TLR3 signaling pathway was impaired, whereas the TRIF-dependent TLR4 pathway was unaffected. Both patients, however, showed reduced capacity to respond to stimulation of the DExD/H-box helicases pathway. To date, the TRIF-deficient patients with HSE described herein have suffered from no other infections. Moreover, as observed in patients with other genetic etiologies of HSE, clinical penetrance was found to be incomplete, as some HSV-1-infected TRIF-deficient relatives have not developed HSE. Our results provide what we believe to be the first description of human TRIF deficiency and a new genetic etiology for HSE. They suggest that the TRIF-dependent TLR4 and DExD/H-box helicase pathways are largely redundant in host defense. They further demonstrate the importance of TRIF for the TLR3-dependent production of antiviral IFNs in the CNS during primary infection with HSV-1 in childhood.