The Level of Viral Infection of Antigen-Presenting Cells Correlates with the Level of Development of Theiler's Murine Encephalomyelitis Virus-Induced Demyelinating Disease

Abstract

Intracerebral infection with Theiler's murine encephalomyelitis virus (TMEV) induces immune-mediated demyelinating disease in susceptible SJL/J mice but not in resistant C57BL/6 mice. Previous studies have indicated that the major histocompatibility complex (MHC) genes play the most prominent role in the development of TMEV-induced demyelinating disease. In this study, we used C57BL/6.S (B6.S) congenic mice, which carry H-2 s MHC genes instead of H-2 b MHC genes in conjunction with the C57BL/6 (B6) background genes. Our data show that virus-infected B6.S mice are free from disease and have significantly lower viral loads than susceptible SJL mice, particularly in the spinal cord. A strong protective Th1-type T helper response with virtually no pathogenic Th17 response was detected in B6.S mice, in contrast to the reduced Th1-and robust Th17-type responses in SJL mice. Notably, lower levels of viral infectivity in B6.S antigen-presenting cells (APCs) correlated with the disease resistance and T-cell-type response. In vitro studies using APCs from B6.S and SJL mice show that TLR2, -3, -4, and -7, but not TLR9, signaling can replace viral infection and augment the effect of viral infection in the differentiation of the pathogenic Th17 cell type. Taken together, these results strongly suggest that the viral replication levels in APCs critically affect the induction of protective versus pathogenic Th cell types via the signaling of pattern recognition receptors for innate immune responses. Our current findings further imply that the levels of viral infectivity/replication and TLR-mediated signaling play critical roles in the pathogenesis of chronic viral diseases. Intracerebral infection of susceptible mice with Theiler's murine encephalomyelitis virus (TMEV) induces an immune-mediated, progressive inflammatory demyelinating disease (IDD) that is similar to a progressive form of human multiple sclerosis (MS) (1, 2). Histopathology and clinical similarities between TMEVinduced disease and human disease make this a relevant model to investigate the mechanisms underlying demyelinating diseases (3). Different inbred mouse strains exhibit different levels of susceptibility to the demyelinating disease induced by TMEV (TMEV-IDD). For example, SJL/J (H-2 s ), SWR (H-2 q ), RIII (H-2 r ), PL/J (H-2 u ), and DBA/2 (H-2 d ) mice are highly susceptible, AKR/J (H-2 k ) and C3H/J (H-2 k ) mice are moderately susceptible, and C57BL/6 (H-2 b ), C57BL/10 (H-2 b ), and BALB/c (H-2 d ) mice are resistant to the development of demyelinating disease (4). One of the most important susceptibility loci is linked to the H-2D gene complex (5, 6). In addition, a locus on chromosome 6 near the Tcrb locus and a locus on chromosome 3 were identified as susceptibility-linked loci for the development of demyelinating disease (7,8). However, the viral persistence level in the central nervous system (CNS) is associated with a locus on chromosome 10, a locus (or possible two loci) on chromosome 14, and a locus on chromosome 18 (9-11). Nevert...

Rapid Expansion of Virus-Specific CD4+ T Cell Types in the CNS of Susceptible Mice Infected with Theiler’s Virus

“…Previous studies have indicated that antigen-presenting cells infected with live TMEV preferentially induce pathogenic Th17 responses, while cells treated with UV-inactivated TMEV or peptide preferentially induce protective Th1 responses [ 13 , 15 ]. Our results in this study indicate that the presence of a high level of initial virus-reactive CD4 + T cells exacerbates the development of TMEV-induced demyelinating disease ( Figure 1 ).…”

“…Recent studies indicated that a higher level of initial viral replication in various antigen presenting cells, including dendritic cells, macrophages, microglia and astrocytes in susceptible SJL mice compared to resistant B6 mice determines the level and type of early T cell responses affecting the protection from or pathogenesis of viral demyelinating disease [ 12 , 15 ]. High levels of viral replication in these antigen presenting cells provide strong innate immunity signaling via TLRs [ 15 , 16 , 17 ] and MDA5 [ 18 ] for the production of various chemokines and cytokines, which, in turn, steer the differentiation of T cell types and modify their effector functions. In addition, activation of the NLRP3 inflammasome and the downstream PGE 2 promote the pathogenesis of TMEV-induced demyelinating disease by enhancing the production of IL-17 [ 19 , 20 ].…”

“…In addition, a high level of IL-6 promotes the expression of PD-1 and PD-L1, which inhibit the protective function of CD8 + T cells [ 24 , 25 ]. Indeed, viral infection of DCs and other antigen-presenting cells showed the preferential induction of pathogenic Th17 cells over protective Th1 cells, whereas UV-inactivate TMEV or viral peptides preferentially induced Th1 cells over Th17 cells [ 13 , 15 ]. In addition, the potential role of vitamin D in the pathogenesis of viral demyelinating disease would be intriguing because Vitamin D appears to play important roles in enhancing innate immune responses and steering the development of T cell subpopulations in MS [ 26 ].…”

Transgenic expression of non-structural genes of Theiler’s virus suppresses initial viral replication and pathogenesis of demyelination

“…It is conceivable that some host pattern-recognizing molecules (e.g., TLRs such as TLR7/8 and TLR9) recognize either the viral proteins or nucleic acids encoded by the P2/P3 region and consequently trigger innate cytokine production [ 34 ]. We previously showed that TMEV infection triggers TLR-mediated innate cytokine production in mice via interaction with viral double-stranded RNA (dsRNA) replication intermediates [ 35 – 37 ]. In addition, we demonstrated that TMEV infection triggers innate immunity in the host via melanoma differentiation-associated 5 (MDA-5) protein [ 38 ], which involves a group of intracellular responders, the retinoic acid-inducible gene I-like receptors (RLR) [ 39 ].…”

Dl-3-n-butylphthalide is effective for demyelination: A case-combined study

“…Genetics [2], infectious agents [3], drugs [4], or autoimmune reactions [5] can lead to demyelinating diseases. The basal treatment of demyelinating diseases including using high-dose intravenous methyl-prednisolone [6], immunoglobulin or others [7], but the curative effect varies from person to person.…”