Contrasting effects of immunosuppression on herpes simplex virus type I (HSV I) induced central nervous system (CNS) demyelination in mice

Abstract

We previously reported that lip inoculation of Herpes simplex virus type I (HSV I) in specific strains of mice would induce multifocal brain demyelination (MBD). The mechanisms mediating the development of MBD are unknown. In this study, five inbred strains of mice (C57BL/6J, Balb/cByJ, A/J, SJL/J, PL/J) immunosuppressed with either irradiation (IR), cyclophosphamide (CY), or cyclosporin A (CP) along with three immune deficient strains (C57BL/6J nu/nu, Balb/cByJ nu/nu, C57BL/6J bg/bg) were lip inoculated with HSV I to determine the effect of immunosuppression on viral spread throughout the brain and the development of demyelination during the acute stage of infection. Mortality increased in all groups when compared with controls but was greatest in A/J, SJL/J, and PL/J strains, where all mice died before day 6 PI. In contrast with immunocompetent C57BL/6J mice where virus is restricted to the brainstem, virus spread throughout the brain of immunosuppressed C57BL/6J, C57BL/6J nu/nu, and C57BL/6J bg/bg mice. Despite viral spread throughout the brain of immunosuppressed C57BL/6J, C57BL/6J nu/nu, Balb/cByJ and Balb/cByJ nu/nu mice, MBD did not develop. MBD did develop however, in both HSV I infected C57BL/6J bg/bg and CP treated Balb/cByJ mice. Immunosuppression of HSV I infected Balb/cByJ mice prevents the development of demyelination at the trigeminal root entry zone (TREZ) of the brainstem while in Balb/cByJ nu/nu mice, the extent of demyelination at TREZ was reduced and delayed when compared with immunocompetent controls. These results suggest that the immune system plays an important role in limiting viral spread in the brain as well as in the development of demyelination at TREZ and of MBD throughout the brain during the acute phase of infection. Virus alone does not induce MBD in this animal model of virus induced CNS demyelination but is a prerequisite for its development.