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.
Highlights
Division of Infectious Diseases and Geographic Medicine, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
In the context of CNS infection, TLR2−/− primary astrocytes showed lower Theiler’s murine encephalomyelitis virus (TMEV)-induced nuclear factor-κB (NF-κB) activity than WT cells [176]. These experiments demonstrated that TLR2 is crucial for NF-κB activation, leading to downstream cellular activation and cytokine production in astrocytes following TMEV infection
Similar to the rhabdoviral N protein, the influenza A virus (IAV) NS1 coats dsRNA, and hides the viral genome from detection through pattern recognition receptors (PRRs) [229]. These data demonstrate how Toll-like receptors (TLR) are directly involved in sensing viral components [86,170,180,205] and through which evasion strategies of TLR signaling virus sensing is impaired by neurotropic viruses such as herpes simplex virus type 1 (HSV-1), dengue virus (DENV), West Nile virus (WNV), Rabies virus (RABV) [214,215,216,217,218,219,220,221,222,223,224,225]
Summary
Among DNA viruses, the members of the Herpesviridae family herpes simplex virus and Varicella-zoster virus are the most relevant pathogens that account for the majority of sporadic encephalitis cases in humans worldwide. Advanced age and immunosuppression favor VZV reactivation in the dorsal nerve ganglia causing viral spread in a centripetal pattern (towards the brain), a centrifugal pattern (towards the skin) or both directions in an anterograde manner [13,14]. NiV cases are more frequent with approximately 700 human cases in Southeast Asia reported until 2018 [29] Both viruses are leading to serious illness in humans with a case-fatality rate of 60% for HeV infection [30], and 53% for NiV infection while NiV is highly neurotropic and affects several regions of the brain [29]
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