Throughout pregnancy, normal placentation is central to prenatal development and the health of both mother and baby. Placental abnormalities are strongly associated with several common pregnancy complications, such as preeclampsia and preterm birth, responsible for ~35% of neonatal and 10% pregnancy-related deaths in women worldwide. Despite some progress in combating these diseases, our understanding of the placental abnormalities contributing to these complications is still lacking, since many of the basic molecular and cellular processes underlying normal placentation are not yet fully understood. Recently, there has been a growing interest in the biological role of endogenous retrovirus (ERV) derived proteins during early development and placentation. ERVs are endogenous viral elements found in the mammalian genome that closely resemble and are derived from ancient exogenous retroviruses. While most ERVs within the genome are highly mutated and lack the ability to express viral genes, some have been shown to contain conserved open reading frames (ORFs) and encode viral-like proteins. The most notable examples of these in humans are Syncytin-1 and Syncytin-2 in the placenta, proteins encoded by the envelope (env) gene of ERVs belonging to the ERV-W and ERV-FRD family, respectively. Syncytins possess fusogenic activity, which is critical during placentation for the normal formation and maintenance of the outer trophoblast layer at the maternal-fetal interface. Recently, a primate- specific ERV envelope protein, ERV-K-env, has also been shown to be expressed within trophoblast subpopulations during normal human placentation. This protein is derived from the ERV-K group, the youngest and most recently expanded ERV; unlike the Syncytins, ERV-K contains dozens of proviral insertions in the human genome with predicted intact ORFs. Recent studies using the ERV-K-env consensus sequence identified fusion (FD) and immunosuppression (ISD) domains closely resembling those found in exogenous retroviruses, and the inherent ability to elicit fusion and immunosuppression in other cell types. Even though ERV-K activity during early human development has been the focus of numerous studies, the native expression and function of ERV-K-env in primate placentation have largely been overlooked.
The aims of the proposed studies are to assess the fusogenic role of ERV-K-env within primate trophoblasts in vitro and to characterize and elucidate changes in ERV-K-env expression within healthy and pathological placental tissues in vivo.
In Aim 1, we will test the hypothesis that ERV-K-env plays a fusogenic role within isolated primate placental trophoblast cells.
For Aim 2, we will test the hypothesis that ERV-K-env expression observed within the healthy placenta is significantly altered during preterm birth, specifically in a manner that is consistent with reduced ISD and/or FD function. The ultimate goals of this project are to elucidate the function of ERV-K-env in normal primate placentation, whether it has a role in common pregnancy complications, and set the stage for future therapeutic investigations targeting ERV-K-env expression in the placenta.
Preterm birth and preeclampsia are common pregnancy complications associated with defects in placental development and are responsible for ~10% of neonatal and pregnancy-related deaths in women worldwide. The proposed work aims to uncover the role of a recently discovered endogenous viral protein expressed within the healthy primate placenta, ERV-K-env, which we hypothesize plays an important role in normal placental trophoblast cell fusion and maternal immunosuppression; and that its aberrant expression underlies the loss of cellular fusion and increased inflammation associated with preterm birth and preeclampsia. Collectively, these studies would provide the first experimental evidence of an ERV-K derived protein playing an important physiological function during normal primate development, and set the stage for future functional and therapeutic investigations related ERV-K-env expression in the placenta.
