Toll-like Receptors in Viral Encephalitis

Abstract

Viral encephalitis is a rare but serious syndrome. In addition to DNA-encoded herpes viruses, such as herpes simplex virus and varicella zoster virus, RNA-encoded viruses from the families of Flaviviridae, Rhabdoviridae and Paramyxoviridae are important neurotropic viruses. Whereas in the periphery, the role of Toll-like receptors (TLR) during immune stimulation is well understood, TLR functions within the CNS are less clear. On one hand, TLRs can affect the physiology of neurons during neuronal progenitor cell differentiation and neurite outgrowth, whereas under conditions of infection, the complex interplay between TLR stimulated neurons, astrocytes and microglia is just on the verge of being understood. In this review, we summarize the current knowledge about which TLRs are expressed by cell subsets of the CNS. Furthermore, we specifically highlight functional implications of TLR stimulation in neurons, astrocytes and microglia. After briefly illuminating some examples of viral evasion strategies from TLR signaling, we report on the current knowledge of primary immunodeficiencies in TLR signaling and their consequences for viral encephalitis. Finally, we provide an outlook with examples of TLR agonist mediated intervention strategies and potentiation of vaccine responses against neurotropic virus infections.

Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use

“…They can be localized on the surface of the cell (TLR1, 2, 4, 6, 10) or in intracellular compartments (TLR3, 7, 8, 9, 11, 12, 13) [ 36 ]. In brief, TLR-signaling induces recruitment of specific adaptor molecules, leading to activation of the transcription factors, which stimulate production of inflammatory mediators, including cytokines and chemokines, such as TNF-α, IL-1α, IL-1β, IL-6, IL-8, IL-12, IL-23, macrophage inflammatory protein (MIP)-1α, and MIP-1β [ 37 , 38 , 39 ].…”

“…TLRs sense PAMPs and DAMPs through their outer leucine-rich repeat domain (LRR). Upon ligand binding, this ectodomain undergoes homo- or heterodimerization, activating intracellular TLR’s Toll/IL-1 receptor domain (TIR) which induces a downstream signaling pathway [ 39 ]. It starts with recruitment of intracellular adaptor proteins, namely myeloid differentiation primary response protein (MyD88), MyD88-adopter-like protein (MAL, also known as TIR domain-containing adaptor protein- TIRAP), Toll/interleukin-1-receptor domain-containing adaptor-inducing interferon β (TRIF) and TRIF-related adaptor molecule (TRAM) [ 38 ].…”

“…When TLR4 is expressed on the cell surface, MyD88-dependent signaling occurs. However, TLR4 also has the ability to be endocytosed upon ligand binding [ 39 ]. After internalization into endosome, TLR4 signals via a TRIF-dependent signaling cascade which moreover can reinforce NF-κB and AP-1 response.…”

Molecular Mechanisms in the Genesis of Seizures and Epilepsy Associated With Viral Infection

“…Microglia expresses various pattern recognition receptors (PRRs) that recognize viral signatures called pathogen-associated molecular patterns (PAMPs) ( Bachiller et al, 2018 ; Gern et al, 2021 ). Upon stimulation by PAMPs, microglia release several pro- and anti-inflammatory cytokines such as monocyte chemoattractant protein 1 (MCP1 aka CCL2), interleukin (IL)-1β, type I interferon (IFN), IFNγ, and tumor necrosis factor-α (TNF-α) ( O’Shea et al, 2013 ).…”

Influences of Magnetic Resonance Imaging Superresolution Algorithm-Based Transition Care on Prognosis of Children with Severe Viral Encephalitis

“…It is the commonest disease among children [1,2]. Viral encephalitis is featured with sudden onset, rapid development, and high mortality, especially severe viral encephalitis (SVE) [3]. Children with SVE usually suffer from epilepsy, mental retardation, paralysis, dyskinesia, and other sequelae, which cause huge burden to families.…”