Harnessing 2D and 3D human endometrial cell culture models to investigate SARS-CoV-2 infection in early pregnancy.

Vertical transmission of SARS-CoV-2 during human pregnancy remains highly controversial as most studies have focused on the third trimester or the peripartum period. Given the lack of early trimester data, determining the prevalence of vertical transmission during early pregnancy and assessing the potential risks for fetal morbidity and mortality pose a challenge. Therefore, we analysed the impact of SARS-CoV-2 infection on an endometrial 3D spheroid model system. The 3D spheroids are capable of decidualization and express angiotensin-converting enzyme 2 (ACE2) as well as transmembrane protease serine 2 (TMPRSS2), rendering them susceptible to SARS-CoV-2 infection. Employing this 3D cell model, we identified that SARS-CoV-2 can infect both non-decidualized and decidualized endometrial spheroids. Infection significantly increased the chemokine Monocyte chemoattractant protein-1 (MCP-1) compared to non-infected spheroids. Decidualized spheroids exhibited upregulated Interleukin (IL)-8 levels. Furthermore, RNA sequencing revealed dysregulation of several genes involved in tissue-specific immune response, Fc receptor signalling, angiotensin-activated signalling and actin function. Gene expression changes varied between SARS-CoV-2 infected non-decidualized and decidualized spheroids and genes associated with the innate immune system (CD38, LCN2 and NR4A3) were dysregulated as a potential mechanism for immune evasion of SARS-CoV-2. Altogether, our study demonstrates that endometrial spheroids are a useful model to examine the clinical implications of SARS-CoV-2 vertical transmission, warranting further investigations.