Date of Award
Doctor of Philosophy
Host and viral determinants influencing the outcome of coronavirus JHM infections of the CNS of rodents were investigated using intact animals and primary neural cell cultures. Two problems pertinent to the process of pathogenesis were addressed. The first was concerned with elucidating host factors responsible for controlling the age dependent nature for induction of the demyelinating form of disease in suckling rats. In the second, the basis of the relative resistance exhibited by inbred SJL/J mice to JHMV was examined in relation to both host and viral determinants.;Using primary, dissociated neural cultures from perinatal rats, several interesting aspects of host cell tropism having potential significance to the process of pathogenesis were found. Neurons were identified as important targets for both wt and neuroattenuated variants of JHMV. Moreover, immunofluorescent and electron microscopic analysis of infected neurons revealed that trafficking of viral structural proteins and virions occurs into neurites, consistent with the notion that transneuronal transport of virus takes place. Assessment of JHMV tropism for oligodendrocyte-type-2 astrocyte (O-2A) lineage cells, whcih are responsible for myeline formation within the CNS, revealed some provocative findings. Culture conditions that maintained these cells in a mitotically active, migratory, progenitor state correlated with virus non-permissiveness. By contrast, culture conditions that encouraged O-2A differentiation into oligodendrocytes correlated with a semi-permissive state for JHMV. These data, combined with the previous finding that JHMV does not replicate in terminally differentiated oligodendrocytes, suggest that permissiveness of O-2A cells for JHMV is restricted to a 'window' in their development. This coincides in vivo with the second and third weeks of postnatal life, when induction of demyelinating disease by this agent is optimal.;Finally, whole animals and primary neural cultures, in combination with viral spike protein variants were used to analyze virus-cell and virus-host interactions in relationship to the observed resistance of SJL/J mice to JHMV. Based on these studies, it was concluded that SJL/J resistance to JHMV-induced neurologic disease may result from the combination of inefficient cell-to-cell spread of the infection and protection by the cellular immune response.
Pasick, John M., "Host And Viral Determinants Influencing The Pathogenesis Of Coronavirus-induced Neurological Disease In Rodents" (1993). Digitized Theses. Paper 2217.