Abstract
The attenuated rabies virus (RV) strain Challenge Virus Standard (CVS)-F3 and a highly pathogenic strain associated with the silver-haired bats (SHBRV) can both be cleared from the central nervous system (CNS) tissues by appropriate antiviral immune mechanisms if the effectors are provided access across the blood-brain barrier (BBB). In the case of SHBRV infection, antiviral immunity develops normally in the periphery but fails to open the BBB, generally resulting in a lethal outcome. To determine whether or not an absence in the CNS targeted immune response is associated with the infection with other pathogenic RV strains, we have assessed the development of immunity, BBB permeability, and immune cell infiltration into the CNS tissues of mice infected with a variety of RV strains, including the dog variants responsible for the majority of human rabies cases. We demonstrate that the lethal outcomes of infection with a variety of known pathogenic RV strains are indeed associated with the inability to deliver immune effectors across the BBB. Survival from infection with certain of these viruses is improved in mice prone to CNS inflammation. The results suggest that competition between the activity of the immune effectors reaching CNS tissues and the inherent pathological attributes of the virus dictates the outcome and that intervention to deliver RV-specific immune effectors into CNS tissues may have general therapeutic value in rabies.
Acknowledgements
The authors thank Dr. Charles E. Rupprecht and his colleagues at the Center for Disease Control and Prevention, Atlanta, GA, and Dr. Bernard Dietzschold of Thomas Jefferson University, Philadelphia, PA, for the provision of the virus strains used in this study. The authors also thank Rhonda B. Kean and Fatu Badiane for helpful contribution to this work. This work was supported by National Institute of Health grants AI 077033 and AI 060005. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.