Vaccine strategies to prevent invasive mucosal pathogens are being sought due to the fact that 80-90% of infectious diseases are initiated at mucosal surfaces. In addition, our ability to deliver vaccine antigens across the mucosal barrier for induction of the effective mucosal immunity is limited. The long-term goal of this proposal is to determine whether the FcRn-IgG transcellular pathway represents a novel delivery path for a subunit vaccine against mucosal pathogens. The neonatal Fc receptor (FcRn) was initially considered to transport maternal IgG to a fetus through the placenta or to newborns via the intestine. However, FcRn is expressed in a variety of tissues and cells in adult humans and animals, and mediates the bi-directional transport of IgG across polarized epithelial cell lines. Based on these evidences, we hypothesize that such IgG transport pathway may allow FcRn to deliver a viral antigen fused to an IgG-Fc across the mucosal barrier to the underlying mucosa-associated lymphoid tissue. The consequences of such transport could give way to immunogenicity. Herpes simplex virus type-2 (HSV-2) is a sexually-transmitted disease, and thus, the primary site of HSV-2 infection is the mucosa of the genital tract. The glycoprotein gD will be used to probe responses to immunization and to define protective immune responses.
The specific aim of this proposal is to determine the ability of FcRn to deliver gD-Fc antigen across the genital or the respiratory mucosal barrier to engender protective immunity against mucosally-administered virulent HSV-2 challenge. The results from this study will be relevant to understanding mucosal immune regulation; the knowledge gained will be useful in development of effective novel vaccine strategies for mucosal pathogens, such as human immunodeficiency virus-1, Chlamydia, influenza etc., that infect at or invade across mucosal surfaces. ? ? ?
