TLR3 Deficiency in Patients with Herpes Simplex Encephalitis

TLDR

Toll‑like receptors protect against experimental infections, yet their role in natural host defense is unclear, and human TLR3 is largely redundant for most microbes but essential for immunity to HSV‑1 in the CNS, implying neurotropic viruses drive its evolutionary maintenance. TLR3 is expressed in the CNS, where it controls HSV‑1 spread via cranial nerves, and also in epithelial and dendritic cells that employ TLR3‑independent pathways to limit HSV‑1 dissemination and resist other pathogens in TLR3‑deficient patients. A dominant‑negative TLR3 allele was identified in otherwise healthy children with HSV‑1 encephalitis, confirming that TLR3 is essential for CNS immunity to HSV‑1 while remaining largely redundant for other microbes.

Abstract

Some Toll and Toll-like receptors (TLRs) provide immunity to experimental infections in animal models, but their contribution to host defense in natural ecosystems is unknown. We report a dominant-negative TLR3 allele in otherwise healthy children with herpes simplex virus 1 (HSV-1) encephalitis. TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1, which spreads from the epithelium to the CNS via cranial nerves. TLR3 is also expressed in epithelial and dendritic cells, which apparently use TLR3-independent pathways to prevent further dissemination of HSV-1 and to provide resistance to other pathogens in TLR3-deficient patients. Human TLR3 appears to be redundant in host defense to most microbes but is vital for natural immunity to HSV-1 in the CNS, which suggests that neurotropic viruses have contributed to the evolutionary maintenance of TLR3.