Development and Characterization of a Mouse Model for Marburg Hemorrhagic Fever

Abstract

The lack of a mouse model has hampered an understanding of the pathogenesis and immunity of Marburg hemorrhagic fever (MHF), the disease caused by marburgvirus (MARV), and has created a bottleneck in the development of antiviral therapeutics. Primary isolates of the filoviruses, i.e., ebolavirus (EBOV) and MARV, are not lethal to immunocompetent adult mice. Previously, pathological, virologic, and immunologic evaluation of a mouse-adapted EBOV, developed by sequential passages in suckling mice, identified many similarities between this model and EBOV infections in nonhuman primates. We recently demonstrated that serially passaging virus recovered from the liver homogenates of MARV-infected immunodeficient (SCID) mice was highly successful in reducing the time to death in these mice from 50 to 70 days to 7 to 10 days after challenge with the isolate MARV-Ci67, -Musoke, or -Ravn. In this study, we extended our findings to show that further sequential passages of MARV-Ravn in immunocompetent mice caused the MARV to kill BALB/c mice. Serial sampling studies to characterize the pathology of mouse-adapted MARV-Ravn revealed that this model is similar to the guinea pig and nonhuman primate MHF 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 and thrombocytopenia. Sequencing the mouse-adapted MARV-Ravn strain revealed differences in 16 predicted amino acids from the progenitor virus, although the exact changes required for adaptation are unclear at this time. This mouse-adapted MARV strain can now be used to develop and evaluate novel vaccines and therapeutics and may also help to provide a better understanding of the virulence factors associated with MARV.

Post-exposure treatments for Ebola and Marburg virus infections

“…Small animals including mice, hamsters and guinea pigs have been used as animal models of filovirus haemorrhagic fever [226][227][228][229][230][231][232][233][234] . Mice and guinea pigs were historically used to screen post-exposure interventions against filoviruses, but these models have often failed to predict efficacy of candidate therapies in the more robust non-human primate (NHP) models 8,9 .…”

“…Importantly, filovirus isolates obtained from humans or NHPs do not cause severe disease in rodents upon initial exposure. Serial adaptation of filoviruses is required to produce a uniformly lethal infection in rodents, and the resulting viruses often have a number of mutations in viral genes associated with inhibition of the type I interferon host response 226,227,230,232,235 . Rodent models of filovirus haemorrhagic fever also do not fully display the coagulation disorders that are hallmark features of disease in filovirus-infected humans and NHPs 77,236 .…”

Aerosol Exposure to the Angola Strain of Marburg Virus Causes Lethal Viral Hemorrhagic Fever in Cynomolgus Macaques

“…These models have been described in several primary and review articles. 6,9,12,19,23,28,34,35,71,72,[88][89][90] The features of disease in these models depend on a variety of factors, including virus strain, dose and route of administration, and the age, species, and strain of animal involved. Whereas NHPs are often susceptible to lethal infection by wild-type strains of EBOV and MARV, immunocompetent adult mice and guinea pigs are not; they are susceptible to some attenuated strains, however.…”

A bioluminescent imaging mouse model for Marburg virus based on a pseudovirus system

“…Serial passages of the original MARV endue it lethal infection capacity to rodents, whereas the disease course still differs from that of humans. 22 The major limitation of all of these models is their dependence on BSL-4 environments. In our MARV bioluminescence imaging mouse model, we used pseudovirus only capable of single round replication that lacked any virulent viral components other than GP, ensuring it is safe for use in BSL-2 laboratories.…”