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

Byung S Kim1

  • 1Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States.

Frontiers in Immunology
|May 8, 2023
PubMed

Insights

Theiler

Area of Science:

  • Neurovirology
  • Immunology
  • Molecular Biology

Background:

  • Theiler's murine encephalomyelitis virus (TMEV) causes persistent central nervous system infections and chronic inflammatory demyelinating disease in mice.
  • TMEV infects various immune and glial cells, with Toll-like receptor (TLR) activation critical for viral replication and persistence.
  • TLR signaling pathways, including MDA-5 and NF-κB, amplify TMEV replication and promote viral persistence.

Purpose of the Study:

  • To elucidate the role of TLR activation and associated cytokine production in TMEV-induced demyelinating disease pathogenesis.
  • To investigate how TMEV manipulates host immune responses, including Th17 cell differentiation and apoptosis, to ensure viral persistence.
  • To explore the potential link between TMEV-induced mechanisms and autoimmune disease development.

Main Methods:

  • Analysis of TMEV infection in susceptible mouse models.
  • Investigation of TLR activation, cytokine profiles (IL-6, IL-1β), and immune cell populations (CD4+, CD8+, T regulatory cells).
  • Assessment of NF-κB signaling, apoptosis, and Th17 cell responses in the context of viral persistence.

Main Results:

  • TLR activation enhances TMEV replication and persistence, driving disease pathogenicity.
  • TMEV infection leads to elevated cytokine production (IL-6, IL-1β), promoting pathogenic Th17 responses and inhibiting apoptosis.
  • Cytokines and TLR2 signaling contribute to the generation of deficient CD4+ T cells, which convert to Th17 cells, further promoting viral survival and autoimmune responses.

Conclusions:

  • Persistent TMEV infection relies on TLR-mediated cytokine production to promote Th17 responses and inhibit apoptosis, ensuring viral persistence.
  • The mechanisms driving TMEV-induced demyelinating disease, involving sustained TLR activation and cytokine storms, may mirror pathways in other persistent viral infections like COVID-19, potentially leading to autoimmune conditions.
  • Understanding these pathways is crucial for developing therapeutic strategies against TMEV-induced neurological disorders and related autoimmune diseases.
Keywords:
TLRsapoptosisautoimmunitychronic viral infectioninflammation

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