Deciphering Placental Antiviral Defense Mechanisms

About This Grant

Summary The maternal-fetal interface in eutherian mammals is a uniquely complex immunological environment, tasked with the dual challenge of maintaining immune tolerance to the semi-allogenic fetus while mounting robust defenses against pathogens. Central to this protection are trophoblasts, the placental barrier cells, which constitutively secrete type III interferons (IFNLs) to restrict viral infections within the placenta and adjacent maternal tissues. Recent discoveries have highlighted that two lineage-specific placental miRNA clusters— primate-specific C19MC and rodent-specific C2MC—have independently evolved to be enriched with short interspersed nuclear elements (SINEs), such as Alu or B1 repeats. These SINE-rich regions produce double- stranded RNA (dsRNA) that triggers a viral mimicry response, activating IFNL signaling and conferring potent antiviral protection independent of classical miRNA pathways. Despite the conservation of this mechanism across species, critical gaps remain: specifically, how C19MC-derived Alu dsRNA is sensed by human trophoblasts and how this process shapes antiviral immunity at the maternal-fetal interface. To address these questions, the Totary-Jain and Coyne laboratories have joined forces to elucidate the mechanisms by which human trophoblasts constitutively produce IFNLs and defend against viral threats. Their central hypothesis posits that SINE dsRNAs derived from C19MC (in humans) and C2MC (in rodents) are recognized by distinct cellular sensors in trophoblasts, leading to the sustained release of type III IFNs. The project is organized around two specific aims. Aim 1 will define the mechanisms by which C19MC-derived Alu dsRNA is sensed and drives cell type-specific IFNL release from human trophoblasts, using advanced organoid models and genetic tools to pinpoint the relevant sensors and signaling pathways. Aim 2 will investigate the role of C19MC in placental antiviral defense and barrier integrity in vivo, leveraging innovative mouse models. Collectively, these studies aim to uncover how human C19MC orchestrates IFNL-mediated antiviral defenses, preserves placental barrier integrity, and prevents congenital viral infections, ultimately paving the way for novel strategies to bolster placental immunity.