Spatiotemporal transcriptomics at the maternal-fetal interface in COVID placenta

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COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as the greatest threat to global health and significantly impact pregnant women worldwide. COVID-19 infection during pregnancy is associated with substantial risk of increases in maternal morbidity and mortality and neonatal complications, compared with their non-infected pregnant counterparts. However, vertical transmission of the virus is uncommon, which suggest that innate immune system must function at the maternal-fetal interface to shield the developing fetus from infection. Despite fast-tracked intensive research on many aspects of SARS- CoV-2, the impact of the viral infection in the placenta and the placental defense mechanism(s) are poorly explored. Placenta is the structural and immunological barrier of pathogen transmission. To explore the innate antiviral defense mechanism(s), in our preliminary study we specifically determined expression of interferon pathway-related molecules in placental tissues. Strikingly, we found distinct patterns of stimulator of interferon genes (STING), interferon regulator factor 3 (IRF3), and Type I IFN (such as IFNb) expression at the maternal- fetal interface of the placentas from women infected with COVID-19. STING is a sensor for viral infection. STING-IRF3 pathway signaling regulates Type I IFN production, and Type I IFNs are potent antiviral cytokines. We also noticed that Toll-like receptor 7 (TLR7) is upregulated in both syncytiotrophoblasts ( STs) and extravillous trophoblasts (EVTs) in placentas from patients with COVID-19 compared to those are not. TLR7, located on the X chromosome, is a sensor for single strand RNA (ssRNA) viruses. These findings are intriguing and indicate that an innate antiviral immune system is activated at the maternal-fetal interface in patients with COVID-19 during pregnancy. The objective of the study is to identify spatiotemporal transcriptomic signatures and networks of the innate antiviral immune system at the maternal-fetal interface. We will test the hypothesis an effective and robust innate antiviral immune system is activated at the maternal-fetal interface to prevent viral transmission and shield the fetus from infection, which will be tested in two specific aims. Aim 1 will identify spatiotemporal innate immunity gene profiles and networks in villous tissue that respond to maternal SARS-CoV-2 infection. Aim 2 will identify spatiotemporal innate immunity gene profiles and networks in fetal membrane and decidual tissue that respond to maternal SARS-CoV-2 infection. A state-of-the-art novel technique of 10x Genomics Visium Gene Expression assay in placental formalin-fixed paraffin embedded (FFPE) tissues combined with RNA-seq will be employed . Placentas from women with active COVID infection, recovered from COVID infection, and received COVID vaccination, etc. will be studied. This novel ideal approach will allow us to map the whole transcriptome with morphological context in placental FFPE tissue and discover the cellular and molecular profiles and networks in different cell types and gene activity at the maternal-fetal interface without disruption of the tissue integrity. Results of the study will provide novel insights into how SARS-CoV-2 infection impacts the innate immune system at the mater-fetal interface, and how the innate immune system at the maternal-fetal interface responds to COVID vaccination during pregnancy, which may help to identify new strategies to prevent COVID-19 infection and reduce maternal and fetal complications in women with COVID-19 infection in the future.