Forty-Five Years of Marburg Virus Research

Brauburger, Kristina; Hume, Adam J.; Mühlberger, Elke; Olejnik, Judith

To date four different animal models have been established for MARV infection: NHPs, mice, guinea pigs, and hamsters. The NHP model best reflects the symptoms and pathology observed in human cases (described in 5. Clinical Manifestations and reviewed in [46, 48] ) with uniform lethality in cynomolgus and rhesus macaques as well as African green monkeys [12, 14, 26, 193, 194, 206, [218] [219] [220] . The disease symptoms are generally the same for all types of NHPs. The animals develop febrile illness with high fever, anorexia, weight loss and unresponsiveness. Death is observed after 6-13 days and thrombocytopenia, lymphopenia, blood coagulation abnormalities and hemorrhages are observed. Squirrel monkeys have also been successfully infected with MARV, showing typical disease symptoms [206] . Recently, a small NHP model using marmosets has been developed recapitulating the features of human infections except for the typical maculopapular rash development that is observed in other NHPs and humans infected with MARV [221] . Rodents with an intact immune system do not develop disease after infection with MARV. MARV variants Musoke and Ci67 and RAVV variant Ravn were adapted to severe-combined immunodeficiency (scid) mice by serial passaging, reducing the time to death from 50-70 days to 7-10 days for all tested virus variants [195] . Further passaging of the scid mouse-adapted marburgviruses in immunocompetent mice was used to establish mouse models for RAVV Ravn and MARV Ci67 [130, 131] . Successful adaptation by serial passaging was also used to generate lethal infection models for both guinea pig [218, 222] and hamster [206, 208] . Coagulation abnormalities, typical rash development, and hemorrhagic manifestations (especially in mice) are not as pronounced as in the NHP model [130] ; (reviewed in [223] ). Neuropathogenicity, recapitulating the CNS involvement described during the first human MVD outbreak in Germany [41, 224, 225] , has only been observed in the hamster model [208] . It is not clear if CNS pathology is developed in other animal models as no brain pathology has been observed in mice [195] and cynomolgus macaques [14] . Nevertheless, virus has been isolated from brain from MARV-infected marmosets, showing micro-hemorrhages [221] .