Infectious organisms are a major cause of poor pregnancy outcome, including prematurity, growth retardation, stillbirth, congenital deformity and neonatal morbidity and mortality. Even if the maternal circulation is cleared of infection, persistent viral infection of the placenta is a major outcome of maternal infection, with severe consequences for the infant. Further, the placenta can be a source of persistent maternal systemic infection. Despite the dire consequences of persistent placental infection, we do not fully understand the mechanisms enough to generate targeted interventions in infected mothers. We have developed a mouse model of maternal infection with Lymphocytic Choriomeningitis virus LCMV and observed that although the maternal circulation is cleared within 8 days of infection, the placenta remains persistently infected and so does the uterus many days post-partum. We have evidence suggesting that this is related to CD8 T cell function, as manipulation of the cytokine milieu increases both presence and function of these cells and is associated with decreased viral load. Understanding mechanisms for metabolic change in immune cells is becoming a major area of interest. Due to their exponential expansion in response to antigen stimulation, the effect of metabolism in T cells is recognized as critical. In addition to proliferation, changes in metabolism can also affect effector function (e.g. cytokine secretion, cytotoxicity). We, like others, have found that this is particularly true for CD8 T cells and through our collaborator, Dr. Rincon and her examination of this, she has discovered a unique protein, Methylation-Controlled J protein (MCJ) that regulates mitochondrial metabolism in CD8 T cells. Importantly, deficiency in this molecule leads to enhanced metabolism and function, as well as overall improvement in immunologic memory in the setting of influenza infection. In this R21 application, we propose to i) test the hypothesis that there is downregulation of placental CD8 T cell effector function through upregulation in MCJ and ii) test the hypothesis that deficiency in MCJ leads to decreased placental virus after maternal infection with LCMV. These studies are in keeping with renewed interest in maternal immunity in NIAID, as they will advance our understanding of microbe-vector-host interactions and their influence on pregnancy outcomes.
The mother's immune system must be able to protect the baby during pregnancy. However, the mother's immune system must not harm the baby either. Understanding how this fundamental balance is maintained is of critical importance, especially if the mother is infected with a virus that infects the placenta. This application builds proposes to explore a novel molecule, MCJ, that regulates the metabolism of T cells. We will use a model system of mice infected with lymphocytic choriomeningitis virus during pregnancy to determine if the activity of MCJ mediates placental infection with viruses. The information gained may help us find treatments for mothers infected with Zika, cytomegalovirus, or other viruses that cause birth defects by trans-placental infection during pregnancy.
