2005 Experimental Models of Multiple Sclerosis __ Coronavirus-Induced Demyelination and Spontaneous Remyelination

Chapter C8 CORONAVIRUS-INDUCED DEMYELINATION AND SPONTANEOUS REMYELINATION Growth factor expression and function Regina C. Armstrong 12, Jeffrey M. Redwine 23, and Donna J. Messersmith 14 1Department of Anatomy, Physiology, and Genetics, and 2Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814-4799; rarmstrong usuhs.mil 3Current affiliation: Neurome Inc., La Jolla, CA 92037 4Current affiliation: National Center for Biotechnology Information, Bethesda, MD 20894 Abstract: Key words: MHV-A59 coronavirus infection produces a transient episode of demyelination that is followed by spontaneous remyelination. This paradigm provides a complex lesion environment to examine cellular and molecular mechanisms involved in successful CNS remyelination. Our work in this model has focused on the roles of platelet-derived growth factor and fibroblast growth factor 2 in regulating oligodendrocyte progenitor responses required for remyelination. platelet-derived growth factor, fibroblast growth factor, estrous cycle, gender, demyelinating disease, remyelination, coronavirus, cuprizone . INTRODUCTION Insufficient remyelination results in prolonged neurological impairment in demyelinating disease states, such as multiple sclerosis. A critical determinant of remyelination is regulation of oligodendrocyte lineage responses. Surviving and/or newly generated oligodendrocyte lineage cells must be recruited to appropriate sites within demyelinated tissues and induced to differentiate and form myelin. Each of these oligodendrocyte lineage cell responses appears to be regulated by signals within the lesion environment, such as growth factors, cytokines, and cell-cell interactions. The pathology of multiple sclerosis (MS) lesions is heterogeneous between patients, with at least four fundamentally different patterns of 794 Chapter C8 demyelination (12). Therefore, analysis of experimental models of demyelination with distinct mechanisms of pathogenesis is warranted. In addition, different experimental models have advantages for examining specific aspects within the course of demyelinating diseases. The mouse model of murine hepatitis strain A59 (MHV-A59) coronavirus infection serves as a relevant model for analyzing the cellular and molecular components involved in spontaneous remyelination. The complexity of MHV-A59 lesions includes infiltration of CD8+ and CD4+ T cells, B lymphocytes producing immunoglobulins, macrophages, and reactive glial cells (15,21). These lesion components are variably exhibited among categories of MS lesions. The potential function of molecules that can promote remyelination in MS lesions, such as growth factors, is ideally analyzed in the context of a complex lesion environment due to contributing effects of cytokines, chemokines, infiltrating lymphocytes, and reactive cells. However, this complex lesion milieu can also make it difficult to delineate effects that are specific to the remyelination process. For this purpose, analysis of oligodendrocyte lineage responses is facilitated by comparison with a simpler lesion model, such as ingestion of cuprizone (14). Growth factor effects common to experimental lesions of diverse pathogenesis, such as MHV-A59 and cuprizone models, are most likely to be applicable more generally to demyelinating diseases. This chapter will review recent findings of the expression and function of specific growth factors in MHV-A59 and cuprizone models of spontaneous remyelination. In addition, the complexity of the MHV-A59 model will be exemplified by discussion of the modulation of the disease course in correlation with gender and estrous cycle status. This modulation of the MHV-A59 disease course is also relevant to modulation of MS disease activity. . DISEASE SEVERITY IN THE MHV-A59 MODEL Intracranial infection of female C57B1/6 mice at 28 days of age with 1000 plaque forming units (PFU) of MHV-A59 virus produces a characteristic progression of demyelinating disease. Demyelination begins within the first week post-injection (wpi), with more extensive areas of myelin degeneration by 2 wpi (1,9). During this progression of demyelination, mice exhibit loss of motor function, and virus is present in cells of the white matter (9). In subsequent weeks, clearance of virus and myelin debris occurs, remyelination is initiated, and recovery of motor function proceeds (9,21). However, among mice similarly infected with MHV-A59, there is variability in the proportion of mice that exhibit distinct results from asymptomatic, C8. coronavirus-induced demyelination and spontaneous remyelination 795 mild paresis, severe paralysis, to mortality. Early studies reported mortality rates that ranged from 11% (1) to 70% (11). To take advantage of knockout mice for the analysis of growth factors and cellular components involved in spontaneous remyelination in this model, we needed to optimize the reproducibility of the MHV