Golden Syrian hamsters offer certain advantages over the use of other rodents in the study of a number of human diseases. In the context of cancer research, the histological and cytogenetic changes in the development of pancreatic cancers are similar in humans and hamsters, but not in mice. Hamsters are also the model species of choice for studying oncolytic adenoviruses, as they are the only rodents found to be permissive to adenovirus replication. In studying hypercholesterolemia, the hamster is favored over the mouse and the rat for the unique similarities between hamster and human lipid metabolism pathways. Specifically, the cholesteryl ester transfer protein (CETP) plays a central role in lipid metabolisms both in humans and hamsters but does not exist in either mice or rats. In modeling viral diseases, hamsters, when compared to mice, develop hemorrhagic disease manifestations more representative of human disease following exposure to Ebola virus (EBOV). Moreover, they are the only rodent species reported to be susceptible to Andes virus infection resulting in hantavirus pulmonary syndrome-like disease similar to that observed in humans. The Wang laboratory has recently established gene-targeting technologies in the hamster opening the door for the development of genetically engineered hamsters for use in modeling human diseases, especially diseases in which mouse models fail to recapitulate cardinal features of disease. To demonstrate the value of this pioneering technology, STAT2 knock-out (KO) hamsters have been created based on the potential of these animals to serve multiple fields of study wherein STAT2 has been implicated in a variety of disease processes. The ultimate goal of the proposed research is to demonstrate the value of the STAT2 KO hamsters in modeling filovirus disease using non-rodent adapted virus isolates to produce hemorrhagic and other notable human disease features. The Specific Aims of Phase I are to: 1) determine the susceptibility of STAT2 KO hamsters to multiple isolates of Marburg virus (MARV), and 2) to characterize the natural history of disease in STAT2 KO hamsters infected with MARV. For Specific Aim 1, the lethality of four wild-type (WT) MARV isolates in STAT2 KO hamsters will be investigated. Based on preliminary data with WT EBOV, we anticipate that most of the MARV isolates will cause lethal hemorrhagic disease in the STAT2 KO hamsters. Specific aim 2 will be accomplished through a detailed characterization of the clinical, virologica and pathological events in infected STAT2 KO hamsters and comparing the findings to reported data from human, nonhuman primate, and other rodent filovirus models. The expectation is that disease evolution in the novel MARV hamster model will be more representative of human disease compared to the existing mouse models, which would greatly enhance efforts towards the development of anti-MARV therapeutics and vaccines. Considering the involvement of STAT2 in the pathogenesis of a number of human diseases, the genetically engineered STAT2 KO hamsters will find broad application across multiple fields of study.