T cell infiltration associated with neurodegeneration and Zika virus control in the CNS of immunocompetent, neonatal mice.

Abstract

Abstract The recent spread of Zika virus (ZIKV) and its association with neurological disorders as well as congenital defects has created an urgent need to develop animal models that allow the elucidation of pathogenesis following ZIKV infection and to develop and test therapeutic agents that will prevent or eliminate CNS disease. We have developed a novel model of ZIKV infection in mice, using B6 WT, neonatal mice that are susceptible to contemporary ZIKV (PRVABC59) CNS infection following peripheral, subcutaneous inoculation at P1. Immunocompetent B6 WT mice develop a discrete neurological disease that includes: unsteady gait, kinetic tremors, severe ataxia and seizures by 12–15 dpi that gradually resolve. Gene expression and immunohistochemistry demonstrate inflammation in the CNS of ZIKV infected B6 WT mice starting after 9 dpi and infiltration of immune cells into the parenchyma of the CNS beginning concomitantly. At the peak of disease (15 dpi), immune cell infiltrates in the CNS consisted primarily of T cells, particularly CD8+ T cells. Gene expression analysis indicated an upregulation of genes consistent with this infiltration. Immunohistochemistry of the CNS indicates a concomitant increase in apoptosis and neurodegeneration after 9 dpi in the CNS particularly in the granular and Purkinje cell layers of the cerebellum. The role of T cells in the control of ZIKV infection in the CNS and the periphery will be explored.