Limited vertical transmission but profound immune dysregulation at the maternal-fetal interface after SARS-CoV-2 infection
The endemic of SARS-CoV-2 underscores the imperative to elucidate its effects on pregnancy, particularly regarding the potential for vertical transmission and its influence on the early maternal-fetal interface, which remain insufficiently defined. To address this, we performed an extensive cohort study involving 761 pregnant women who voluntarily terminated the pregnancy during the first trimester. Analyses conducted using qRT-PCR, fluorescence in situ hybridization, and indirect immunofluorescence assay revealed minimal indications of SARS-CoV-2 infection within chorionic and decidual tissues. Although both tissues exhibited substantial expression of the viral entry receptors ACE2 and TMPRSS2, single-cell RNA sequencing analysis identified no cell populations with significant co-expression of these receptors. The restricted co-expression of viral entry receptors provides a mechanistic explanation for the rare occurrence of direct viral infection in placental tissues. The maternal systemic inflammatory response was notably attenuated relative to the classical cytokine storm, with only IL-31, IL-5, and GRO-a exhibiting elevated levels during acute infection. Furthermore, elevated IgG titers were inversely correlated with tumor necrosis TNF-ß concentrations, suggesting a protective immunomodulatory function of IgG antibodies. Conversely, both bulk and single-cell transcriptomic analyses revealed pronounced, cell type-specific antiviral and immune responses within the placental microenvironment. A pervasive interferon-stimulated gene signature was identified, accompanied by emergence of M2-like macrophages with diminished antigen presentation capacity in convalescence. Importantly, maternal SARS-CoV-2 infection disrupted intercellular communication networks, notably impairing WNT and TGF-ß signaling pathways to trophoblasts, thereby altering their differentiation trajectories. In summary, within this large first-trimester cohort, evidence for vertical transmission of SARS-CoV-2 was minimal. Nonetheless, infection substantially perturbs the placental immune milieu and trophoblast dynamics, which may adversely affect pregnancy outcomes.