Immune regulation of arenavirus infections in the placenta

Project Summary. The rodent-borne arenaviruses can cause severe hemorrhagic fevers; several of these potential pandemic pathogens have been noted to cause high rates of maternal mortality, congenital infection, and/or fetal demise when pregnant people are infected. The objective of this project is to determine how arenavirus infection causes adverse pregnancy outcomes. Clinical observations that Lassa virus (LASV) replicates to high titer in the placenta prompted us to conduct a preliminary study using in vitro models of the human placenta and experimental guinea pig infections with an arenavirus that is not pathogenic in humans, Pichinde virus (PICV), to ascertain the role of infection at the maternal fetal interface in severe disease. We found that PICV replicates to high titers in undifferentiated and differentiated first trimester human trophoblasts and explants derived from term placenta. Furthermore, infection during pregnancy led to fetal demise, high viral loads in the placenta and decidua, and low rates of congenital infection in guinea pigs. We hypothesize that the placenta and decidua serve as a reservoir for arenavirus replication and that the antiviral immune response to infection at the maternal-fetal interface leads to placental dysfunction. This project will use a combination of methods and models that include diverse New World (PICV and Junin virus [JUNV]) and Old World (LASV and lymphocytic choriomeningitis virus [LCMV]) viruses to reveal how arenaviruses circumvent host defense to infect the placenta and cause severe disease. The placenta is generally an effective barrier against the bloodborne transmission of pathogens and primary trophoblasts are broadly restrictive to viral infection. Using a genetically tractable model of the first trimester placenta, human trophoblast stem cells, and term placental explants, we will investigate the viral factors that allow arenaviruses to circumvent innate and intrinsic immunity and establish productive infections in trophoblasts (Aim 1). We will next use guinea pigs to assess how the immune response to arenavirus infection during pregnancy either causes placental dysfunction or may be harnessed to protect the mother and fetus (Aim 2). A detailed study of PICV pathogenesis at the maternal-fetal interface will be complemented with experiments using JUNV and LASV to determine whether these highly pathogenic viruses have a similar tropism for and effects on the placenta and decidua. The completion of this project will address a critical knowledge gap by revealing the mechanisms by which arenaviruses damage the placenta and cause pregnancy complications, informing the future development of much-needed therapies to minimize harm to pregnant people and their offspring.