Pathogenic role of CD4+ T cells in the progression of neurotropic mouse hepatitis virus induced neuroinflammation

Abstract

Neurotropic Mouse hepatitis virus (MHV) induced demyelination serves as a model to understand the mechanisms of demyelination and concomitant axonal loss in CNS, which mimics the pathological symptoms of the human neurological disease Multiple Sclerosis (MS). Inflammation triggered by MHV consists of mixed population of inflammatory cells, predominantly microglia/macrophages, which differs from autoimmune model of MS, where infiltrating T cells are the major contributors to the pathology. Though the acute phase of MHV inflammation is controlled by microglia/microglia, the role of T and B cells in viral induced axonal degeneration and demyelination is controversial. In order to explore the role of CD4+ T cells during transition from an early protective innate response to a highly regulated adaptive response following MHV infection, MHV-infected CD4−/− mice were compared with MHV-infected CD4+/+ (wildtype) mice at days 5/6, 10, 15 and 30 post infection. Viral titre estimation and nucleocapsid gene amplification confirm enhanced replication of the virions in the absence of functional CD4 + T cells in brain tissue. Viral anti-nucleocapsid antigen staining further shows the persistence of virus at day 30 p.i. in CD4−/− mice unlike CD4+/+ mice. Moreover, histopathological analysis of liver, brain and spinal cord showed an elevated susceptibility of CD4−/− mice to encephalitis and axonal degeneration with augmented progression of acute poliomyelitis, bulbar vacuolation, and dorsal root ganglionic inflammation rarely observed in CD4+/+ infected mice. In summary, current study suggests that CD4 T cell is critical for viral clearance, resolving microglial activation, and controlling chronic progressive axonal degeneration.