Placental infection by SARS-CoV-2: exploring alternative entry pathways

The placenta possesses several structural and immunological barriers against viral infections, the SARS-CoV-2 detection in placental tissues has raised concerns regarding possible alternative viral entry mechanisms beyond the canonical ACE2/TMPRSS2-mediated pathway. In this context, the present study evaluated the immunohistochemical expression patterns of ADAM17, Cathepsin L, Clathrin, ACE-2, Furin, NRP-1, and TMPRSS2-molecules involved in SARS-CoV-2 placental entry pathways - as well as the detection of viral RNA by RT-qPCR in paraffin-embedded samples. The study included 75 paraffin-embedded placental samples (decidua and villi) collected after spontaneous placental delivery at birth from patients who tested positive for COVID-19 (COVID-19 Group), and 19 paraffin-embedded control placental samples collected prior to the COVID-19 pandemic (NON-COVID-19 Group). A statistically significant reduction in NRP-1 expression was observed in the COVID-19 group decidua (<i>p</i> < 0.001), including in RT-qPCR - positive samples (<i>p</i> = 0.001), regardless of comorbidities or underlying conditions. A statistically significant reduction in Clathrin expression was also found in the decidual samples of the COVID-19 group and in RT-qPCR - positive samples (<i>p</i> = 0.05and 0.013, respectively), while Cathepsin L expression was significantly increased in the placental villi of the COVID-19 group (<i>p</i> < 0.001) and in RT-qPCR - positive samples (<i>p</i> = 0.005). These findings may contribute to a better understanding of the mechanisms underlying SARS-CoV-2 interaction with the placenta, possibly through auxiliary and/or endocytic entry pathways, and may support future investigations into the impact of these alterations in the context of maternal SARS-CoV-2 infection.