Murine Coronavirus Receptors Are Differentially Expressed in the Central Nervous System and Play Virus Strain-Dependent Roles in Neuronal Spread

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Abstract
Coronavirus infection of the murine central nervous system (CNS) provides a model for studies of viral encephalitis and demyelinating disease. Mouse hepatitis virus (MHV) neurotropism varies by strain: MHV-A59 causes mild encephalomyelitis and demyelination, while the highly neurovirulent strain JHM.SD (MHV-4) causes fatal encephalitis with extensive neuronal spread of virus. In addition, while neurons are the predominant CNS cell type infectedin vivo, the canonical receptor for MHV, the carcinoembryonic antigen family member CEACAM1a, has been demonstrated only on endothelial cells and microglia. In order to investigate whether CEACAM1a is also expressed in other cell types,ceacam1amRNA expression was quantified in murine tissues and primary cells. As expected, among CNS cell types, microglia expressed the highest levels ofceacam1a, but lower levels were also detected in oligodendrocytes, astrocytes, and neurons. Given the low levels of neuronal expression ofceacam1a, primary neurons from wild-type andceacam1aknockout mice were inoculated with MHV to determine the extent to which CEACAM1a-independent infection might contribute to CNS infection. While both A59 and JHM.SD infected small numbers ofceacam1aknockout neurons, only JHM.SD spread efficiently to adjacent cells in the absence of CEACAM1a. Quantification of mRNA for theceacam1a-related genesceacam2andpsg16(bCEA), which encode proposed alternative MHV receptors, revealed lowceacam2expression in microglia and oligodendrocytes andpsg16expression exclusively in neurons; however, only CEACAM2 mediated infection in human 293T cells. Therefore, neither CEACAM2 nor PSG16 is likely to be an MHV receptor on neurons, and the mechanism for CEACAM1a-independent neuronal spread of JHM.SD remains unknown.