This project will study the mammalian mucosal barrier to transmission of viral infection, using an established mouse model. The lactate dehydrogenase-elevating virus (LDV) causes a persistent infection in mice, and may be transmitted to uninfected mice during exposure to either free or cell-associated virus at a variety of body sites. Normal mice have a relative mucosal barrier which governs the minimum infectious dose (MID) of LDV, which is lower for rectal inoculation than for oral, ocular, or vaginal inoculation. LDV is an ideal virus for the proposed work, since within four days of inoculation with the virus, infection is easily determined by a blood enzyme measurement. Mucosal barriers to LDV at gastrointestinal (GI) and genital sites will be investigated during exposure of mice to both free and macrophage-associated virus, in order to construct a model for contrasting free and cell-associated MID's. This model will be significant because there is currently a need to better understand mechanisms which can potentially regulate the MID with respect to both types of viral transmission. The proposed work will determine whether viral protection at mucosal sites can be established following passive immunization of uninfected animals with monocional anti-LDV antibodies, or active immunization with normal allogeneic cell-surface antigens. Uninfected mice will receive intravenous injections of anti-LDV antibodies, or will be immunized with allogeneic macrophages prior to live virus exposure in the form of free virus of LDV-infected macrophages, and effects on the rate of infection will be determined. Virus localization studies will be carried out on mice exposed to LDV at GI or genital sites. Using fluorescence antibody analysis, the cells at these sites in which LDV initiates a primary infection will be localized. These results will lead to a better understanding of how the mucosal barrier to infection is initially broken down. The long-term objective of this work is to gain a better understanding of mucosal mechanisms of viral defense, and to develop strategies to enhance these mechanisms. This work has important implications for certain medically important viruses, such as human immunodeficiency virus, which may be transmitted at mucosal sites, and for which better preventive strategies are currently needed.
