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The immune response in the CNS in Theiler’s virus induced demyelinating disease switches from an early adaptive response to a chronic innate-like response

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Abstract

Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is an important model of the progressive disability caused by irreversible CNS tissue injury, and provides an example of how a CNS pathogen can cause inflammation, demyelination, and neuronal damage. We were interested in which molecules, especially inflammatory mediators, might be upregulated in the CNS throughout TMEV-IDD. We quantitated by a real-time RT-PCR multi-gene system the expression of a pathway-focused panel of genes at 30 and 165 days post infection, characterizing both the early inflammatory and the late neurodegenerative stages of TMEV-IDD. Also, we measured 32 cytokines/chemokines by multiplex Luminex analysis in CSF specimens from early and late TMEV-IDD as well as sham-treated mice. Results indicate that, in the later stage of TMEV-IDD, activation of the innate immune response is most prominent: TLRs, type I IFN response genes, and innate immunity-associated cytokines were highly expressed in late TMEV-IDD compared to sham (p ≤ 0.0001) and early TMEV-IDD (p < 0.05). Conversely, several molecular mediators of adaptive immune response were highly expressed in early TMEV-IDD (all p ≤ 0.001). Protein detection in the CSF was broadly concordant with mRNA abundance of the corresponding gene measured by real-time RT-PCR in the spinal cord, since several cytokines/chemokines were increased in the CSF of TMEV-IDD mice. Results show a clear shift from adaptive to innate immunity from early to late TMEV-IDD, indicating that adaptive and innate immune pathways are likely involved in the development and progression of the disease to different extents. CSF provides an optimal source of biomarkers of CNS neuroinflammation.

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Acknowledgments

The authors thank the staff of the Center for Comparative Medicine and Research (CCMR) at Dartmouth for their expert care of the mice used for this study. The authors also acknowledge Joanna Hamilton and Carol Ringelberg for their technical assistance with microarray experiments and analyses, as well as Emily Clough for her excellent administrative support.

Conflict of interest

FG has received research support from Biogen Idec. ARP has received personal compensation for activities with Biogen Idec, EMD Serono, Novartis, Hoffman-LaRoche, Schering AG, NovoNordisk, Biomonitor, and Teva Marion as a consultant. ARP has also received research support from Hoffman-LaRoche, Biogen Idec, and Sanofi-Aventis. LL is currently an employee of GenScript USA Inc.

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Authors and Affiliations

  1. Department of Neurology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA

    Francesca Gilli & Andrew R. Pachner

  2. Department of Neurology, University of Medicine and Dentistry-New Jersey Medical School, Newark, NJ, USA

    Libin Li & Andrew R. Pachner

  3. GenScript USA Inc, Piscataway, NJ, USA

    Libin Li

  4. Department of Neurology, Geisel School of Medicine at Dartmouth, 1 Medical Center Drive, Lebanon, NH, 03756, USA

    Francesca Gilli

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  1. Francesca Gilli
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Correspondence to Francesca Gilli.

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Gilli, F., Li, L. & Pachner, A.R. The immune response in the CNS in Theiler’s virus induced demyelinating disease switches from an early adaptive response to a chronic innate-like response. J. Neurovirol. 22, 66–79 (2016). https://doi.org/10.1007/s13365-015-0369-4

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  • DOI: https://doi.org/10.1007/s13365-015-0369-4

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