Immune cells promote paralytic disease in mice infected with enterovirus D68

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Abstract

Enterovirus D68 (EV-D68) is associated with acute flaccid myelitis (AFM), a poliomyelitis-like illness causing paralysis in young children. However, the mechanisms of paralysis are unclear, and antiviral therapies are lacking. To better understand EV-D68 disease, we inoculated newborn mice intracranially to assess viral tropism, virulence, and immune responses. WT mice inoculated intracranially with a neurovirulent strain of EV-D68 showed infection of spinal cord neurons and developed paralysis. Spinal tissue from infected mice revealed increased levels of chemokines, inflammatory monocytes, macrophages, and T cells relative to those in controls, suggesting that immune cell infiltration influences pathogenesis. To define the contribution of cytokine-mediated immune cell recruitment to disease, we inoculated mice lacking CCR2, a receptor for several EV-D68–upregulated cytokines, or RAG1, which is required for lymphocyte maturation. WT, Ccr2–/–, and Rag1–/– mice had comparable viral titers in spinal tissue. However, Ccr2–/– and Rag1–/– mice were significantly less likely to be paralyzed relative to WT mice. Consistent with impaired T cell recruitment to sites of infection in Ccr2–/– and Rag1–/– mice, antibody-mediated depletion of CD4+ or CD8+ T cells from WT mice diminished paralysis. These results indicate that immune cell recruitment to the spinal cord promotes EV-D68–associated paralysis and illuminate potential new targets for therapeutic intervention.

Authors

Mikal A. Woods Acevedo, Jie Lan, Sarah Maya, Jennifer E. Jones, Isabella E. Bosco, John V. Williams, Megan Culler Freeman, Terence S. Dermody