Replication of Theiler's virus requires NF‐κB‐activation: Higher viral replication and spreading in astrocytes from susceptible mice

Hou

et al. 2015

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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...

Section: B6s Mice Infected With Tmev Do Not Develop Demyelinating DIsupporting

confidence: 91%

Section: B6s Mice Infected With Tmev Do Not Develop Demyelinating DImentioning

confidence: 98%

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

Hou

et al. 2015

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“…The initial level of IL-6 production appears to be determined by the susceptibility of the cells to viral infection, which is associated with genetic background. Cells from susceptible mice are dramatically more permissive to TMEV infection (31,39) and, consequently, the infected cells from susceptible mice antibody (n ϭ 3/group) were quantified using plaque assays at 8 days postinfection. (C) Levels of infectious virus in the CNS of WT and IL-6 KO mice infected with TMEV in PBS or 100 ng IL-17 (n ϭ 3/group) were quantified using plaque assays at 7 days postinfection.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 (IL-6) and IL-17 Synergistically Promote Viral Persistence by Inhibiting Cellular Apoptosis and Cytotoxic T Cell Function

Hou

et al. 2014

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127

125

Interleukin-6 (IL-6) plays an important role in the development and progression of inflammatory responses, autoimmune diseases, and cancers. Many viral infections, including Theiler's murine encephalomyelitis virus (TMEV), result in the vigorous production of IL-6. However, the role of IL-6 in the development of virus-induced inflammatory responses is unclear. The infection of susceptible mice with TMEV induces the development of chronic demyelinating disease, which is considered a relevant infectious model for multiple sclerosis. In this study, we demonstrate that resistant C57BL/6 mice carrying an IL-6 transgene (IL-6 Tg) develop a TMEV-induced demyelinating disease accompanied by an increase in viral persistence and an elevated Th17 cell response in the central nervous system. Either IL-6 or IL-17 induced the expression of Bcl-2 and Bcl-xL at a high concentration. The upregulated expression of prosurvival molecules in turn inhibited target cell destruction by virus-specific CD8 ؉ T cells. More interestingly, IL-6 and IL-17 synergistically promoted the expression of these prosurvival molecules, preventing cellular apoptosis at a much lower (<5-fold) concentration. The signals involved in the synergy appear to include the activation of both STAT3 and NF-B via distinct cytokine-dependent pathways. Thus, the excessive IL-6 promotes the generation of Th17 cells, and the resulting IL-6 and IL-17 synergistically promote viral persistence by protecting virus-infected cells from apoptosis and CD8؉ T cell-mediated target destruction. These results suggest that blocking both IL-6 and IL-17 functions are important considerations for therapies of chronic viral diseases, autoimmune diseases, and cancers. IMPORTANCEThis study indicates that an excessive level of IL-6 cytokine produced following viral infection promotes the development of IL-17-producing pathogenic helper T cells. We demonstrate here for the first time that IL-6 together with IL-17 synergistically enhances the expression of survival molecules to hinder critical host defense mechanisms removing virus-infected cells. This finding has an important implication in controlling not only chronic viral infections but also autoimmune diseases and cancers, which are associated with prolonged cell survival.

“…Interestingly, however, the viral message level in F1 macrophages was higher than that in B6 macrophages, suggesting an intermediate permissiveness to the viral infection. Since F1 cells are less permissive to TMEV infection and consequently produce lower levels of proinflammatory cytokines, including IL-6 (not shown), similarly to B6 cells (20,21), the lower level of Th17 development by F1 cells appears to reflect their relative resistance to the viral infection. These results suggest that a combination of low levels of viral loads and pathogenic Th17 cells and a high level of protective Th1 cells in the CNS of F1 mice compared to susceptible SJL mice leads to the resistance to pathogenesis in F1 mice.…”

mentioning

confidence: 97%

Preferential Induction of Protective T Cell Responses to Theiler's Virus in Resistant (C57BL/6 × SJL)F1 Mice

Mohindru

et al. 2011

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