The neuroimmunology of encephalitis in a mouse model of Dengue virus infection

Abstract

Dengue (DENV) has increasingly been reported as being associated with neurological manifestations. Using a non-lethal mouse encephalitis model, we found that either soluble DENV2-derived or APC-processed antigen can drain from the parenchyma of infected brain to the draining cervical lymph node (CLN) within 24h post intracranial infection. Cognate T cells exit from the CLN and gain entry into the infected brains initially at d3 p.i., correlating with increased CXCL10, CCL5, CCL3, and CCL2 mRNA expression. Cytotoxic CD8+ T cells (CTL) were shown to be able to efficiently perform their immune tasks in vivo, contributing to clearance of infection, notwithstanding a temporal mismatch of T cell infiltration with early virus eradication in infected brains. After the resolution of infection, CTL remained in the brain as long-lived memory resident CD103+ T cells, as indicated by their differential CD62L and CX3CR1 expression, and expression of Granzyme B, rapidly expanding and lysing target cells following reinfection in vivo. In addition, we found two distinct differentiation patterns of bone marrow–derived monocytes (BMM) infiltrating virus-infected brains. During non-lethal DENV encephalitis, BMM gave rise to Ly6ChiCD11chiMHC-IIhi dendritic cells (DC), while in lethal WNV encephalitis, BMM differentiated into Ly6ChiCD11clowMHC-IIint inflammatory macrophages. At the gene expression level, the transforming growth factor-beta (TGF-β)-signalling (i.e., anti-inflammatory/healing) pathway is activated to a much greater degree in DENV-infected than WNV-infected brains. Manipulating these mediators may allow us to control the severity of CNS inflammation, highlighting the potential therapeutic opportunities.