Vulnerability of rat and mouse brain cells to murine hepatitis virus (JHM‐strain): Studies in vivo and in vitro

Abstract

The pathogenicity and cell tropism of mouse hepatitis virus (MHV-JHM-strain) in the developing mouse (Balb/c) and rat (Wistar and Lewis) brain were analysed. Intracranial infection of Balb/c mice at postnatal day 5 induced a lethal encephalitis in all animals. Of Wistar rats infected at day 2 or 5 after birth, 30 to 70%, respectively, survived. The distribution of viral antigen was studied in frozen brain sections of animals that died after infection; astrocytes were found to be the major virus-infected cell type throughout the central nervous system. More than 75% of the surviving rat pups developed paralysis, but viral antigen was detected in only few brain cells and not in astrocytes. The cell tropism of MHV-JHM was examined further in virus-infected glial cell cultures derived from brains of rats or mice. In the glial cultures derived from Wistar rats, only oligodendrocytes were infected, whereas in cultures derived from mouse or Lewis rat brain viral antigen was detected in both astrocytes and oligodendrocytes. Infection of astrocytes led to the formation of syncytia and degradation of the cytoskeleton. Infected rat oligodendrocytes gradually disappeared from the cultures because of cell death. These phenomena indicate that, besides an indirect autoimmune response triggered by infected astrocytes, direct virus-induced injury to astrocytes or to oligodendrocytes can have a dominant role in the neuropathogenicity of mouse hepatitis virus. The present results underscore the importance of species and developmental stage of experimental animals in the neurotropism and pathogenicity of MHV-JHM.

Infection by coronavirus JHM of rat neurons and oligodendrocyte-type-2 astrocyte lineage cells during distinct developmental stages

“…In this regard, MTCM and ACM which promoted mitogenesis and presumably blocked or delayed differentiation also caused a reduction of 10to 100-fold in virus yields relative to those in unconditioned 01/T3 medium. These findings are consistent with a brief mention (67) of resistance to JHMV among A2B5+ 0-2A progenitors in primary dissociated cultures from Wistar rats. Our assumption that 0-2A glia in mixed cultures are made nonpermissive by factors released into the medium by other cell types was supported by demonstrating that PDGF and bFGF, while prolonging the mitotically active, undifferentiated state, also conferred reversible resistance to JHMV.…”

Distinct Roles for Sialoside and Protein Receptors in Coronavirus Infection

“…Notably, neural cell membranes are known for their abundant sialic acid content (72). These findings, combined with evidence that cell-tocell syncytial spread correlates with pathogenesis in several infection models (30,62,63,(73)(74)(75), prompts a hypothesis that JHM-CoV sialic acid binding potential accounts for an interneuronal syncytial spread that is rapidly lethal. A prediction is that variants of JHM-CoV exhibiting enhanced sialic acid affinity will have unusually high neurovirulence.…”

Mechanisms of Immunopathology in Murine Models of Central Nervous System Demyelinating Disease

“…MHV infects and replicates within oligodendrocytes, the myelin-synthesizing cells of the CNS (61,62), and it can be argued that oligodendrocyte damage or death is the major mechanism of demyelination (63,64). However, mice exposed to immunosuppressive doses of irradiation following JHM strain of mouse hepatitis virus infection showed little demyelination despite the presence of virus in oligodendrocytes and reconstituting irradiated mice with splenocytes from unirradiated-infected mice restored demyelination (65).…”