The purpose of this core is to support the proposed projects by generating and maintaining animal models for in vivo studies investigating how anti-influenza antibodies regulate host immunity during virus infection.
The first aim of the animal core will be to maintain transgenic lines of mice for use by each project. Our recent studies have demonstrated that interactions between the Fc constant region of broadly neutralizing antibodies (bNAbs) and Fc receptors (FcRs) are required for optimal neutralization of influenza viruses in vivo. However, the human (hu) FcR system differs from that of mice in expression patterns, the affinities of each human IgG Fc subclass for each huFcR, and which huFcRs and effector cells dominate in vivo. Therefore, in order to address the functional contributions of huFcRs during in vivo viral neutralization with human bNAbs, we have recently generated FcR-humanized mice, which express the full array of huFcRs on a background lacking all mouse FcRs and with the capacity to elicit human IgG mediated Fc responses. FcyR-humanized mice recapitulate the unique expression profile of huFcyRs and function to mediate the inflammatory, immunomodulatory and cytotoxic activities of hulgG antibodies in vivo. These animals will be vital for investigating in vivo neutralization by human bNAbs, understanding the mechanism of neutralization in vivo, and investigating methods to enhance neutralization in vivo by manipulating Fc-FcR interactions. This core will also support the maintenance of mouse lines lacking specific FcIRs and lines in which specific FcR are conditionally deleted in specific cell subsets. These mouse strains will be crucial to support studies investigating the mechanisms by which bNAbs neutralize virus in vivo, and this animal core will support the maintenance of these mouse lines for use by all investigators in this project. Passive administration of hulgG bNAbs to mice results in an anti-huIgG response which clears the human bNAb. This clearance of passively-transferred human bNAb precludes long-term in vivo studies with human bNAbs in mice. Therefore, the second aim of the animal core will be to generate a knock-in mouse line in which the hulgGI constant region replaces the mouse lgG2a constant region. Thus, this mouse will express hulgGI as a self-protein and be tolerized to passive human bNAb administration. This line will be crossed to the FcR-humanized mouse line, thereby generating a superior in vivo model in which long-term studies of human IgG bNAbs can be performed in the context of human FcR effector function.
Influenza viruses remain a formidable global health concern. Through the studies supported by this core, we will investigate mechanisms by which antibodies neutralize influenza viruses. These studies will inform on the design of protective antibodies for use as therapeutics and the development of novel vaccines and vaccination protocols.
|Wohlbold, Teddy John; Krammer, Florian (2014) In the shadow of hemagglutinin: a growing interest in influenza viral neuraminidase and its role as a vaccine antigen. Viruses 6:2465-94|
|Ellebedy, Ali H; Krammer, Florian; Li, Gui-Mei et al. (2014) Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans. Proc Natl Acad Sci U S A 111:13133-8|
|Tan, Gene S; Lee, Peter S; Hoffman, Ryan M B et al. (2014) Characterization of a broadly neutralizing monoclonal antibody that targets the fusion domain of group 2 influenza A virus hemagglutinin. J Virol 88:13580-92|
|Nachbagauer, Raffael; Wohlbold, Teddy John; Hirsh, Ariana et al. (2014) Induction of broadly reactive anti-hemagglutinin stalk antibodies by an H5N1 vaccine in humans. J Virol 88:13260-8|