Infection of pregnant women by Listeria monocytogenes results in abortion or delivery of severely infected neonates which either die shortly after delivery or survive with severe lifelong intellectual and physical impairment. Analysis of murine Listeriosis as a model for intrauterine infections has importance because altogether these infections pose a major human maternal and infant health problem affecting approximately 5 live births/1000. These infections are complex events involving the pathogen, the feto-placental unit, the maternal immune response, and the fetal-maternal relationship which, because of the fetus' paternal antigens, may be regarded as an allograft-host situation. Recently, a number of regulatory mechanisms have been shown to inhibit active maternal immune responses locally in the placenta and uterine decidua. These may be important in preventing rejection of the fetus and include alpha-fetoprotein, inhibitory macromolecules secreted by trophoblast cells of the placenta, suppressor lymphocytes in the uterine decidua, and high local concentrations of progesterone. The overall goal of this proposal is to understand how these regulatory mechanisms and Listeria infection of the feto-placental unit influence each other. Two specific questions will be addressed: 1) Is the increased susceptibility of the feto-placental unit the immunological price of local regulatory mechanisms which ordinarily prevent rejection of the fetal allograft? This proposal will determine the effects of these local inhibitors on specific well-defined macrophage and T-lymphocyte interactions which are known to be important in the host defense against Listeria. 2) After the infection is established, does intra-uterine Listeriosis inactivate these local regulators, thus causing rejection of the fetal allograft? This proposal will use monoclonal antibodies against cell surface markers as well as functional assays to determine if maternal lymphocytes with anti-fetal activity enter fetal tissue during infection. The effect of Listeriosis on specific immunoinhibitory mechanisms in the placenta will also be studied.
