Critical role of TLR activation in viral replication, persistence, and pathogenicity of Theiler’s virus

Abstract

Theiler’s murine encephalomyelitis virus (TMEV) establishes persistent viral infections in the central nervous system and induces chronic inflammatory demyelinating disease in susceptible mice. TMEV infects dendritic cells, macrophages, B cells, and glial cells. The state of TLR activation in the host plays a critical role in initial viral replication and persistence. The further activation of TLRs enhances viral replication and persistence, leading to the pathogenicity of TMEV-induced demyelinating disease. Various cytokines are produced via TLRs, and MDA-5 signals linked with NF-κB activation following TMEV infection. In turn, these signals further amplify TMEV replication and the persistence of virus-infected cells. The signals further elevate cytokine production, promoting the development of Th17 responses and preventing cellular apoptosis, which enables viral persistence. Excessive levels of cytokines, particularly IL-6 and IL-1β, facilitate the generation of pathogenic Th17 immune responses to viral antigens and autoantigens, leading to TMEV-induced demyelinating disease. These cytokines, together with TLR2 may prematurely generate functionally deficient CD25-FoxP3+ CD4+ T cells, which are subsequently converted to Th17 cells. Furthermore, IL-6 and IL-17 synergistically inhibit the apoptosis of virus-infected cells and the cytolytic function of CD8+ T lymphocytes, prolonging the survival of virus-infected cells. The inhibition of apoptosis leads to the persistent activation of NF-κB and TLRs, which continuously provides an environment of excessive cytokines and consequently promotes autoimmune responses. Persistent or repeated infections of other viruses such as COVID-19 may result in similar continuous TLR activation and cytokine production, leading to autoimmune diseases.

The Contribution of Microglia and Brain-Infiltrating Macrophages to the Pathogenesis of Neuroinflammatory and Neurodegenerative Diseases during TMEV Infection of the Central Nervous System

“…Mechanisms such as bystander activation, molecular mimicry, and epitope spreading have been proposed to explain how viral infections lead to demyelinating disease [ 166 , 167 , 168 ], and chronic CNS inflammation due to the persistent viral infection is believed to be a significant driver of the immune-mediated demyelination [ 42 , 144 , 145 , 169 , 170 ]. During TMEV infection of the CNS, the continuous activation of innate and adaptive immune responses and peripheral immune cell infiltration into the CNS influences the pathogenesis of the demyelinating disease [ 64 , 171 ].…”

The Role of Natural Products from Herbal Medicine in TLR4 Signaling for Colorectal Cancer Treatment

“…TLRs contribute to the immune response, detecting microbial patterns and initiating signaling pathways for pro-inflammatory gene transcription [ 30 ]. Dimerization of TLRs is a crucial mechanism for their functional regulation and a necessary step for activation, thereby initiating downstream signaling pathways and triggering immune responses.…”