Early T cell response in the central nervous system in canine distemper virus infection

Abstract

The initial demyelinating lesions in canine distemper virus (CDV) infection develop during a period of severe immunosuppression in the absence of inflammation. In vitro and in vivo studies suggest that early demyelination is due to directly virus-induced oligodendroglial changes. In the present spatiotemporal study in experimentally CDV-infected dogs we observed diffuse up-regulation of T cells throughout the central nervous system (CNS) and T cell invasion in early demyelinating lesions. Invasion of T cells in the CNS occurred despite severe immunosuppression and without any perivascular cuffing. However, the major fraction of invading T cells correlated with sites of viral replication and coincided with the demonstration of an early immune response against the nucleocapsid protein of CDV. Activation of microglial cells was thought to have elicited the migration of T cells to the CNS by secretion of chemokines: marked IL-8 activity was found in the CSF of dogs with acute lesions. In areas of early demyelination, large numbers of CD3+ cells accumulated in the tissue in the absence of any morphological sign of inflammation. Whether the T cells at lesion sites contribute to the development of acute demyelination remains uncertain at this stage. Antiviral cytotoxicity was not apparent since viral clearance in demyelinating lesions is only effective when B cells and concurring antiviral antibody production appeared in the subacute and chronic inflammatory stage of the disease. CD3+ cells appear to persist for several weeks after infection since they were also found in recovered dogs that did not develop demyelination. Accumulation of immune cells, including a significant proportion of resting T cells (CD45RA+) in the CNS in the early stages of the disease may facilitate the later development of the intrathecal immune response and associated immunopathological complications.

Canine Distemper Virus Uses both the Anterograde and the Hematogenous Pathway for Neuroinvasion

“…The course of CDV in dogs initially follows the same pattern, including the infection of cells in locations consistent with hematogenous invasion (31). However, neutralizing antibodies are detected in up to 90% of the animals 2 to 3 weeks p.i., indicating the onset of an effective antiviral immune response that controls and then eliminates the infection and coincides with resolution of the disease signs (31,39,41). In the CNS, an inflammatory process characterized by lymphocyte invasion is observed, which results in a chronic demyelinating disease in 10 to 30% of the animals (52).…”

“…The CNS infection peaks 4 to 5 weeks after inoculation, when virus is detected in neurons and glial cells throughout white and gray matter in a focal fashion (23,45,52). Around 10% of dogs die at this time from acute encephalitis developing while their immune system fails to control the infection.In animals that mount an effective cellular and humoral immune response, perivascular cuffing and lymphocyte infiltration of the infected areas occur at the same time as the rash and other signs of disease recede, and CDV-specific neutralizing antibodies are detected in the serum and cerebrospinal fluid (CSF) (39,41,52). This immune response results in virus clearance from the CNS, but can be accompanied by continued demyelination, which is ultimately responsible for the development of neurological signs in a subset of animals several weeks after recovery from the acute infection (38,44).…”

“…Around 3 weeks after infection, CDV-positive glial cells and neurons are found in the white matter, and the beginning of demyelination is observed in these regions (41). The CNS infection peaks 4 to 5 weeks after inoculation, when virus is detected in neurons and glial cells throughout white and gray matter in a focal fashion (23,45,52).…”

“…In animals that mount an effective cellular and humoral immune response, perivascular cuffing and lymphocyte infiltration of the infected areas occur at the same time as the rash and other signs of disease recede, and CDV-specific neutralizing antibodies are detected in the serum and cerebrospinal fluid (CSF) (39,41,52). This immune response results in virus clearance from the CNS, but can be accompanied by continued demyelination, which is ultimately responsible for the development of neurological signs in a subset of animals several weeks after recovery from the acute infection (38,44).…”

Sentries at the gate: chemokines and the blood-brain barrier

“…Astrocytes expressed IP-10 in this model (Lane et al, 1998). Increased IL-8 activity was observed in CSF from dogs with acute and chronic stages of canine distemper virus (CDV) infection characterized by multifocal demyelination in the central nervous system (Tipold et al, 1999). Mouse adenovirus -type 1 (MAV-1) causes fatal haemorrhagic encephalopathy associated with increased expression of IP-10, MCP-1, MIP-1a, MIP-1b and RANTES in the CNS of C57BL/6 mice.…”