Alterations of placental HERV expression as a result of gestational COVID-19 disease.

INTRODUCTION: Activation of human endogenous retroviral elements (HERV) is a well-documented phenomenon in inflammatory pathologies including COVID-19, with HERVW ENV frequently mentioned as a toxic protein. Given that COVID-19 during pregnancy has been associated with placental damage and a higher risk of adverse pregnancy outcomes (APOs), we investigated whether gestational COVID-19 alters placental HERV expression, and if such alterations correlate with placental damage or dysfunction. METHODOLOGY AND RESULTS: We quantitively analyzed mRNA expression of HERV in placental samples using qPCR assays rigorously tested for efficiency and specificity or transcriptomic analysis. Combined qPCR and transcriptomic analyses of placentas from maternal COVID-19 cases revealed an overall trend toward reduced expression of several HERV elements, including HERVW ENV-related transcripts, with a more pronounced downregulation in SARS-CoV-2-positive placentas. HERVW ENV protein was detected by immunofluorescence in the syncytiotrophoblast (STB), co-staining with HCGβ, using conditions minimizing cross-reactivity with ERVWE1. HERVW ENV protein levels were diminished in COVID-19 patients, especially in those cases in which SARS-CoV-2 was present in the placenta. CONCLUSIONS AND DISCUSSION: While HERV expression is reportedly induced in blood lymphocytes and other tissues as a response to SARS-CoV-2 infection, we detect unaltered or lower RNA levels of selected retroviral elements in the placenta of COVID-19 patients. HERVW ENV protein was present in non-COVID-19 placenta, and downregulated by maternal COVID-19 disease. The absence of HERVW ENV protein induction was confirmed by the careful study of cases with placental SARS-CoV-2 infection, as HERVW ENV was mostly absent from these samples, probably as an indirect result of placental damage. We identified two independent triggers for the downregulation of both HERVW ENV RNA and protein in placenta: maternal COVID-19 and local effects of SARS-CoV-2. Therefore, this HERV downregulation may represent part of the molecular response to placental SARS-CoV-2 infection, contributing to placental dysfunction and APOs.