a mouse model for studying viscerotropic disease caused by yellow fever virus infection研究嗜内脏型疾病的小鼠模型由黄热病病毒感染引起的.pdfVIP

A Mouse Model for Studying Viscerotropic Disease Caused by Yellow Fever Virus Infection Kathryn C. Meier, Christina L. Gardner, Mikhail V. Khoretonenko, William B. Klimstra, Kate D. Ryman* Department of Microbiology Immunology and Center for Molecular Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, United States of America Abstract Mosquito-borne yellow fever virus (YFV) causes highly lethal, viscerotropic disease in humans and non-human primates. Despite the availability of efficacious live-attenuated vaccine strains, 17D-204 and 17DD, derived by serial passage of pathogenic YFV strain Asibi, YFV continues to pose a significant threat to human health. Neither the disease caused by wild- type YFV, nor the molecular determinants of vaccine attenuation and immunogenicity, have been well characterized, in large part due to the lack of a small animal model for viscerotropic YFV infection. Here, we describe a small animal model for wild-type YFV that manifests clinical disease representative of that seen in primates without adaptation of the virus to the host, which was required for the current hamster YF model. Investigation of the role of type I interferon (IFN-a/ b) in protection of mice from viscerotropic YFV infection revealed that mice deficient in the IFN-a/ b receptor (A129) or the STAT1 signaling molecule (STAT129) were highly susceptible to infection and disease, succumbing within 6–7 days. Importantly, these animals developed viscerotropic disease reminiscent of human YF, instead of the encephalitic signs typically observed in mice. Rapid viremic dissemination and extensive replication in visceral organs, spleen and liver, was associated with severe pathologies in these tissues and dramatically elevated MCP-1 and IL-6 levels, suggestive of a cytokine storm.