Mouse Immune System Modulation of DENV Genetic Diversity

Justification/Summary

Our overall research goal is to identify viral and host factors that modulate DENV infection and disease in an animal model.  Studies in human populations have furnished important information but can only be descriptive in nature; to address mechanistic questions, an animal model is essential.  Primates can be infected with DENV but do not develop disease, plus they are impractical and too costly for routine work.  A mouse model is attractive due to the availability of reagents (transgenic mice in well-defined genetic backgrounds and antibodies against mouse immune cells and molecules) to explore murine immunology. Paralysis is the dominant clinical phenotype of susceptible mouse strains.  In contrast, humans with DENV infection do not develop paralysis; most manifest clinical depression, and few develop encephalopathy. Despite the paralytic phenotype, we have been developing new mouse models of primary DENV infection using a variety of gene-targeted mice in the C57BL/6 or 129/Sv genetic background and novel DENV strains that are derived via alternate passaging between mosquito cells and mice.  Employing new mouse models that exhibit symptoms resembling key features of the human disease, we have been dissecting the host and viral determinants of primary DENV infection in mice and have begun to address longstanding questions about the virology and immunology of DENV infection in vivo.  Specifically, we have started to identify sites of viral replication and characterize protective versus pathogenic mechanisms of the immune system during primary DENV infection. This knowledge is essential for understanding the biology and pathogenic potential of DENV in vivo, creating a more relevant mouse model for the human disease, and developing and testing DENV-specific therapies and vaccines.

People

Principal External Collaborator

Sujan Shresta - Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA

Funding

Funding for this sequencing project was provided by the National Institute of Allergy and Infectious Diseases.

Cohort Description

MPV - DEN2 virus isolates derived by alternately passaging the non-mouse adapted DENV2 strain PL046 (a Taiwanese human isolate) between mosquito cells and non-neuronal tissues (i.e. serum) of AG129 mice (mice lacking receptors for both IFN-α/β and IFN-γ )