Activation of Astrocytes in the Spinal Cord of Mice Chronically Infected with a Neurotropic Coronavirus

Abstract

Mice infected with the neurotropic JHM strain of mouse hepatitis virus (MHV-JHM) develop a demyelinating encephalomyelitis several weeks after infection. Astrogliosis and infiltration of inflammatory cells are prominent findings in the brains and spinal cords of infected mice. In this report, astrocytes in infected spinal cords were analyzed for expression of three pleiotropic cytokines, TNF-alpha, IL-1 beta, and IL-6; Type 2 nitric oxide synthase (iNOS); and MHC class I and II antigen. The data show that all three cytokines and iNOS are expressed by astrocytes in chronically infected spinal cords. These activated astrocytes are localized to areas of virus infection and demyelination, although most of the astrocytes expressing these proteins are not MHV-infected. MHC class I and II antigen can be detected in these spinal cords as well, but not in cells with the typical morphology of astrocytes. TNF-alpha, IL-6, and iNOS are also evident in the brains of mice with MHV-induced acute encephalitis, but in marked contrast to the results obtained with the chronically infected mice, most of the cells expressing these cytokines or iNOS had the morphology of macrophages or other mononuclear cells and very few appeared to be astrocytes. Additionally, astrocytes and, most likely, oligodendrocytes are infected in the spinal cords of mice with chronic demyelination. These results are consistent with a role for both viral infection of glial cells and high localized levels of proinflammatory cytokines and nitric oxide in the demyelinating process in mice infected with MHV-JHM. They also show that analogously to the human demyelinating disease, multiple sclerosis, astrocytes are a major cellular source for these cytokines in mice with chronic, but not acute disease.

Critical Role for Protein Tyrosine Phosphatase SHP-1 in Controlling Infection of Central Nervous System Glia and Demyelination by Theiler's Murine Encephalomyelitis Virus

“…One is direct cytopathic effects of the virus on oligodendrocytes, and the second is an indirect immunopathologic response to the virus or autoantigens involving inflammation and oligodendrocyte pathology. Of particular note, the latter is often promoted by proinflammatory cytokine secretion and major histocompatibility complex expression induced by viruses in astrocytes (10,26,33,35,57,58). The relative contributions of these mechanisms to the demyelinating process in TMEV-infected motheaten mice are presently unknown.…”

“…These studies have indicated that damage to oligodendrocytes and myelin may occur by multiple distinct pathways. Depending on the particular virus, these pathways include direct cytopathic effects of the virus in oligodendrocytes, virus-induced inflammatory immune responses promoted by infected glia in the white matter, or molecular mimicry between virus and myelin antigens (43,56,57). In each of these responses, the activities of proinflammatory cytokines, interferons, and virus-induced genes play an important role in promoting or protecting against oligodendrocyte pathology (6,40,44,45,51,65).…”

Cytokine production in the nervous system of mice during acute and latent infection with herpes simplex virus type 1.

“…However, high levels of TNF-α and IL-6 persisted in astrocytes and other cells. Astrocytes produce TNF-α under a variety of circumstances, including virus infection (Joseph et al, 1993 ;Sun et al, 1995). It is noteworthy that production of these potent macrophage activators occurs at the site where such activation may play a key role in the demyelination associated with HSV-1 infection in the CNS (Townsend, 1981).…”

Bystander CD8 T Cell-Mediated Demyelination After Viral Infection of the Central Nervous System

“…This profile is identical with the profile of chemokines expressed in the CNS of immunocompetent C57BL/6 (B6) mice after MHV infection (27). Astrocytes are the source for cytokines such as TNF-␣ and IL-1␤, and chemokines such as CXCL10/IP-10, in B6 mice chronically infected with MHV (27,28). Similarly, astrocytes were also the source for a representative cytokine, TNF-␣, in MHV-infected RAG 1 Ϫ/Ϫ mice (Fig.…”