Coronavirus JHM induced demyelinating disease: specific domains on the E2-protein are associated with neurovirulence.
Infections of rodents by murine coronaviruses can lead to chronic diseases of the central nervous system. These infections are interesting systems to study mechanisms which could be relevant for the pathogenesis of certain human diseases. One major factor influencing the outcome of infection is related to the virus. To understand the virological basis for neurovirulence we compared JHM-virus isolates with different biological properties. JHM-Wt causes only acute disease, JHM-Ts43 a demyelinating encephalomyelitis and a virus shedded from persistently infected cells (JHM-Pi) is not virulent at all. The spread of these viruses in glial cell cultures reflects their different neurovirulence for animals. The peplomer E2 of these viruses reveals structural and antigenic differences. We characterised the epitopes of E2 with a panel of monoclonal antibodies. Four epitopes are associated with regions important for neutralisation, cell fusion and attachment. More than five epitopes are not related to such functions. Epitopes differ in their location and accessibility on the E2 protein subunits between JHM-Wt, JHM-Ts43 and JHM-Pi. To identify epitopes in regions important for pathogenesis, we performed animal studies with variants selected by monoclonal antibodies. Variants changed in a defined epitope (E2-Ba) induce in Balb/c mice a chronic disease. Variants changed in only one of the other three neutralisation epitopes induce acute disease. These results support and extend the observation that the peplomer protein E2 is a major determinant for virulence and antigenic variability of coronaviruses 1,4,5,6,8,10,17,19,22,23. Increasing evidence had been obtained that certain structural features of this protein are important for the cell tropism of the virus. Furthermore, this protein influences strongly the type and specificity of immune responses against viral and host antigens. The highly advanced knowledge on structure and replication of coronaviruses will be of great value to analyze further mechanisms leading to inflammatory demyelinating diseases associated with a persistent virus infection.
D000818:Animals; D000956:Antigens, Viral / Q000235:genetics; D003333:Coronaviridae Infections / Q000209:etiology*; D003711:Demyelinating Diseases / Q000209:etiology*; D004679:Encephalomyelitis / Q000209:etiology; D000939:Epitopes / Q000235:genetics; D014644:Genetic Variation; D051379:Mice; D006517:Murine hepatitis virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D051381:Rats; D014764:Viral Proteins / Q000276:immunology / Q000502:physiology*; D015678:Viral Structural Proteins; D014774:Virulence
D000956:Antigens, Viral; D000939:Epitopes; D014764:Viral Proteins; D015678:Viral Structural Proteins