Inflammation Unleashed in Viral-Induced Epileptogenesis

Abstract

Viral infection of the central nervous system increasingly places people at risk of developing life-threatening and treatment-resistant acute and chronic seizures (epilepsy). The emergence of new human viruses due to ongoing social, political, and ecological changes places people at risk more than ever before. The development of new preventative or curative strategies is critical to address this burden. However, our understanding of the complex relationship between viruses and the brain has been hindered by the lack of animal models that survive the initial infection and are amenable for long-term mechanistic, behavioral, and pharmacological studies in the process of viral-induced epileptogenesis. In this review, we focus on the Theiler’s murine encephalomyelitis virus (TMEV) mouse model of viral infection–induced epilepsy. The TMEV model has a number of important advantages to address the quintessential processes underlying the development of epilepsy following a viral infection, as well as fuel new therapeutic development. In this review, we highlight the contributions of the TMEV model to our current understanding of the relationship between viral infection, inflammation, and seizures.

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

“…It is also important to note that the consequences of pharmacological vs. genetic manipulation of monocyte invasion and microglia activation strikingly differed ( Table 3 ). Furthermore, the interplay between microglia and invading monocytes in this model is more complex than previously proposed by other groups ( Libbey and Fujinami, 2011 ; DePaula-Silva et al, 2017 , 2018 , 2021 ).…”

“…Upon viral invasion of the CNS, activation of the innate and adaptive immune response is critical to control viral replication and spread ( Libbey and Fujinami, 2014 ; Figure 3 ). However, an exuberant innate response to the infection may cause considerable acute bystander pathology, while failing to adequately control viral replication which may lead to persistent smoldering inflammation that results in chronic neuropathology ( DePaula-Silva et al, 2021 ; Figure 3 ). In general, as illustrated in Figure 5 , inflammation plays a prominent role in the mechanisms underlying increased neuronal excitability in both early and late seizures associated with virus infection ( Vezzani et al, 2016 ).…”

“…Based on a large series of subsequent studies of the groups of Robert S. Fujinami, H. Steve White, and Karen S. Wilcox at the University of Utah, which were reviewed by Libbey and Fujinami (2011) and DePaula-Silva et al (2017 , 2021) , it was suggested that infiltrating monocytes (CD45 hi CD11b + ) present in the brain of B6 mice at day 3 post-infection are an important source of IL-6, which critically contributes to the development of acute seizures in the TMEV-induced seizure model. Furthermore, the production of high levels of TNF-α by microglia during the acute phase of the infection was found to play a role ( Cusick et al, 2013 ).…”

“…When mice deficient in TNF receptors, TNF-α or IL-6 were infected with TMEV, the incidence of acute seizures was significantly decreased, whereas IL-1R1 deficient mice did not differ from wild-type controls ( Kirkman et al, 2010 ; Patel et al, 2017 ). From these data and the known effects of IL-6 and TNF-α on neuronal activity, it was suggested that IL-6 and TNF-α secreted in the brain by infiltrated monocytes and resident microglia during TMEV infection in B6 mice may contribute to enhanced glutamatergic excitation and decreased GABAergic inhibition and lead to a more seizure prone state ( DePaula-Silva et al, 2021 ). In support of this hypothesis, TMEV infection of B6 mice depleted of monocytes resulted in a significant decrease in the number of mice experiencing seizures, substantiating a role for infiltrating monocytes in the development of acute seizures in the TMEV-induced seizure model ( Cusick et al, 2013 ).…”

“…The potential role of blood-borne monocyte brain invasion for the seizure phenotype induced by TMEV infection of B6 mice suggested by the University of Utah groups ( Libbey and Fujinami, 2011 ; DePaula-Silva et al, 2017 , 2018 , 2021 ) prompted us to perform a series of studies using either genetic or pharmacological strategies. The outcome of these studies is summarized in Table 3 .…”