Development and Characterization of a Mouse Model for Marburg Hemorrhagic Fever

摘要

The lack of a mouse model has hampered understanding of the pathogenesis and immunity, and created a bottleneck in the development of antiviral therapeutics for marburgvirus (MARV). Primary isolates of the filoviruses, ebolavirus (EBOV) and MARV are not lethal to immunocompetent adult mice. Previously, a lethal mouse-adapted EBOV was developed by sequential passage in suckling mice. Pathologic, virologic, and immunologic evaluation of mouse-adapted, EBOV-infected mice identified many similarities between this model and EBOV infections in nonhuman primates. We recently demonstrated that serially passaging the livers from MARV-infected immunodeficient mice was highly successful in reducing the time to death in SCID mice from 50-70 days to 7-10 days after MARV-Ci67, -Musoke, or -Ravn challenge. Here, we extended our findings to show that further sequential passage of these viruses in immunocompetent mice allowed the MARV to cause lethality in both BALB/c and C57BL/6 mice. Serial sampling studies to characterize the pathology of the mouse-adapted MARV-Ravn revealed that the mouse-adapted MARV model has many similar properties as the guinea pig and nonhuman primate MARV models. Infection of BALB/c mice with mouse-adapted MARV-Ravn caused uncontrolled viremia and high viral titers in the liver, spleen, lymph node, and other organs; profound lymphopenia; destruction of lymphocytes within the spleen and lymph nodes; and marked liver damage. This mouse-adapted MARV can now be used for developing and evaluating novel vaccines and therapeutics and may also help to provide a better understanding of the virulence factors associated with MARV.