Murine theiloviruses : characterization and pathogenesis of enteric and disseminated disease

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Rat theilovirus (RTV), a member of the Theilovirus (ThV) species and closely related to Theiler's murine encephalomyelitis virus (TMEV), is a prevalent viral pathogen infecting research rats. A novel isolate of RTV, designated RTV-1, was isolated, cultivated in vitro and its full genome sequenced. Experimental inoculation studies revealed distinct differential susceptibilities, as exhibited by varied fecal shedding patterns and serologic responses, between immunocompetent and immunocompromised rats infected with RTV1 by gastric gavage. In addition, immunohistochemical analysis revealed enterocytes of the proximal small intestine as cellular tropisms of RTV. These studies present a rat model to further study Theilovirus pathogenesis and highlight an important role of the adaptive immune response to control RTV infection at the level of the intestinal mucosa. Inbred SJL/J mice were shown to be susceptible to neurologic disease following gastric gavage with the GDVII strain of TMEV and vascular endothelial cells of the central nervous system were identified as a site for viral replication. We identified downregulation of type I interferons in the intestines and mesenteric lymph nodes of mice at an early time point following alimentary exposure to GDVII and further identified that resistant, C57BL/6 congenic mice were more susceptible to GDVII infection when the type I interferon response was not functional. In addition, interferon alpha receptor knockout mice harbored infective virus in multiple tissues throughout the body compared to wild type mice. These studies highlight an inbred mouse model to further study the natural pathogenesis of ThV and demonstrate the important role type I interferons have in controlling TMEV infections.