SARS-CoV-2 is a betacoronavirus that has a unique pathology and causes a wide range of symptoms in its host. The impact of infection is multisystemic, with an aggressive inflammatory and hyperactive immune response. There are increasing reports of adverse pregnancy outcomes upon SARS-CoV-2 infection, despite lack of placental infection. Pregnancy outcomes are heavily dependent on normal placenta function. Therefore, I aimed to elucidate the molecular changes at the maternal-fetal interface in patients infected with SARS-CoV-2. We conducted single nuclei and bulk multi-omic analysis to delineate cell type-specific transcriptomic and epigenetic alterations arising from infection. I found a robust inflammatory activation and an imbalance of angiogenesis related pathways in specific cell ty...[ Read more ]

SARS-CoV-2 is a betacoronavirus that has a unique pathology and causes a wide range of symptoms in its host. The impact of infection is multisystemic, with an aggressive inflammatory and hyperactive immune response. There are increasing reports of adverse pregnancy outcomes upon SARS-CoV-2 infection, despite lack of placental infection. Pregnancy outcomes are heavily dependent on normal placenta function. Therefore, I aimed to elucidate the molecular changes at the maternal-fetal interface in patients infected with SARS-CoV-2. We conducted single nuclei and bulk multi-omic analysis to delineate cell type-specific transcriptomic and epigenetic alterations arising from infection. I found a robust inflammatory activation and an imbalance of angiogenesis related pathways in specific cell types. Additionally, I discovered a dysregulation of retrotransposons in patients. My results reveal that LTR8B elements function as enhancers for nearby pregnancy specific glycoprotein (PSG) genes. The elements and target genes are concordantly downregulated upon infection. This demonstrates the importance of studying non-coding regions of the genome, including cis-regulatory elements, in the context of SARS-COV-2 pathogenesis in host cells. Furthermore, most of the SARS-CoV-2 genome encodes for non-structural proteins (NSPs), which are imperative in viral replication, pathogenesis, and host immunomodulation.

NSPs are multifunctional and are key to understanding viral-host interactions. Therefore, I analysed transcriptomic data of host cells expressing NSP1 and NSP5 to identify their impacts. The results indicate a distinct dysregulation of genes and retrotransposons upon NSP1 and NSP1 expression, suggesting that they play a role in modifying the host transcriptome. This is corroborated with analysis of live infections in host cells, showing similar dysregulation of genes and retrotransposons. Taken together, this work elucidates the molecular changes in the epigenome and transcriptome of various cell types infected with SARS-CoV-2 and its components. These findings provide a better molecular understanding of SARS-CoV-2 which hopefully lead to avenues for therapy.