Development of a STAT2 knock-out hamster model for wild-type filovirus infections

DESCRIPTION provided by applicant 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 STAT knock out KO hamsters have been created based on the potential of these animals to serve multiple fields of study wherein STAT has been implicated in a variety of disease processes The ultimate goal of the proposed research is to demonstrate the value of the STAT 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 determine the susceptibility of STAT KO hamsters to multiple isolates of Marburg virus MARV and to characterize the natural history of disease in STAT KO hamsters infected with MARV For Specific Aim the lethality of four wild type WT MARV isolates in STAT 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 STAT KO hamsters Specific aim will be accomplished through a detailed characterization of the clinical virologica and pathological events in infected STAT 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 STAT in the pathogenesis of a number of human diseases the genetically engineered STAT KO hamsters will find broad application across multiple fields of study PUBLIC HEALTH RELEVANCE The proposed research will build upon our recent success in creating the first genetically engineered golden Syrian hamsters and demonstrate their value as the basis of a novel model system for wild type Marburg virus MARV infection Completion of the proposed research will lead to the establishment of a new animal model for MARV infection for use in the development of vaccines and antiviral therapies Moreover this work will highlight the value of genetically engineered hamsters as a powerful technology for the development of model systems broadly applicable to both infectious and non infectious diseases for which other rodents do not serve as representative models of human diseases