Transgenic mouse core

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ABSTRACT – Core A, Bournazos The ability of an IgG antibody to mediate biological effects in vivo, such as protection from viral infection, results from its bispecific nature. The Fab region of an antibody recognizes epitopes on the viral spike and may interfere with virus binding to target cells, while the Fc domain mediates diverse immunomodulatory activities through specific interactions with Fcγ receptors (FcγRs) expressed by effector leukocytes. Studies on several infectious pathogens have shown that Fc-FcγR interactions have the capacity to mediate a wide spectrum of opposing functions – from viral opsonization and clearance of infected cells (protective) to enhanced viral infection and disease severity (pathogenic). Understanding the precise mechanisms by which IgG antibodies mediate protective or pathogenic functions necessitates the use of well-defined in vivo experimental systems that reflect the unique complexity of effector leukocytes that participate in an immune response. Indeed, although in vitro assays using cell lines or primary effector cells represent well-established approaches for characterizing the function of IgG antibodies, such assays provide limited information on the precise molecular mechanisms that drive human immunity during infection or upon vaccination. We will provide a Core that will maintain, characterize, and distribute a series of genetically-engineered humanized mouse strains to the Center investigators in support of the proposed studies on the characterization of the pathogenic activity of anti-flavivirus antibodies that confer susceptibility to dengue disease, as well as on the evaluation of the protective antiviral function of neutralizing antibodies against hepatitis B viruses. Through specific deletions of key immune signaling pathways or reconstitution with human primary cells that represent the natural viral host cell type, these engineered mouse strains support the infection and replication of flaviviruses and hepatitis viruses in vivo, thereby facilitating the study of viral disease pathogenesis, as well as the characterization of the molecular mechanisms that contribute to the IgG antibody activity during viral infection.