Placental SARS-CoV-2 distribution correlates with level of tissue oxygenation in COVID-19-associated necrotizing histiocytic intervillositis/perivillous fibrin deposition.

INTRODUCTION: Recent evidence supports the - rare - occurrence of vertical transplacental SARS-CoV-2 transmission. We previously determined that placental expression of angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, and associated viral cell entry regulators is upregulated by hypoxia. In the present study, we utilized a clinically relevant model of SARS-CoV-2-associated chronic histiocytic intervillositis/massive perivillous fibrin deposition (CHIV/MPFVD) to test the hypothesis that placental hypoxia may facilitate placental SARS-CoV-2 infection. METHODS: We performed a comparative immunohistochemical and/or RNAscope in-situ hybridization analysis of carbonic anhydrase IX (CAIX, hypoxia marker), ACE2 and SARS-CoV-2 expression in free-floating versus fibrin-encased chorionic villi in a 20-weeks' gestation placenta with SARS-CoV-2-associated CHIV/MPVFD. RESULTS: The levels of CAIX and ACE2 immunoreactivity were significantly higher in trophoblastic cells of fibrin-encased villi than in those of free-floating villi, consistent with hypoxia-induced ACE2 upregulation. SARS-CoV-2 showed a similar preferential localization to trophoblastic cells of fibrin-encased villi. DISCUSSION: The localization of SARS-CoV-2 to hypoxic, fibrin-encased villi in this placenta with CHIV/MPVFD suggests placental infection and, therefore, transplacental SARS-CoV-2 transmission may be promoted by hypoxic conditions, mediated by ACE2 and similar hypoxia-sensitive viral cell entry mechanisms. Understanding of a causative link between placental hypoxia and SARS-CoV-2 transmittability may potentially lead to the development of alternative strategies for prevention of intrauterine COVID-19 transmission.

Increased placental expression of angiotensin-converting enzyme 2, the receptor of SARS-CoV-2, associated with hypoxia in twin anemia-polycythemia sequence (TAPS).

INTRODUCTION: Recent reports suggest SARS-CoV-2, the virus causing COVID-19, may be transmittable from pregnant mother to placenta and fetus, albeit rarely. The efficacy of vertical transmission of SARS-CoV-2 critically depends on the availability of its receptor, ACE2, in the placenta. In the present study, we tested the hypothesis that placental ACE2 expression is oxygenation-dependent by studying the expression of ACE2 and associated cell entry regulators in the monochorionic twin anemia-polycythemia (TAPS) placenta, a model of discordant placental oxygenation. METHODS: We performed a retrospective comparative immunohistochemical, immunofluorescence and Western blot analysis of ACE2, TMPRSS2 and Cathepsin B expression in anemic and polycythemic territories of TAPS placentas (N = 14). RESULTS: ACE2 protein levels were significantly higher in the anemic twin territories than in the corresponding polycythemic territories, associated with upregulation of the key ACE2-related cell entry regulators, TMPRSS2 and Cathepsin B, immunolocalized to villous trophoblastic and stromal cells. Cellular colocalization of ACE2 and TMPRSS2, suggestive of functionality of this cell entry axis, was demonstrated by double immunofluorescence studies. DISCUSSION: Placental hypoxia is associated with upregulation of ACE2 expression, concomitant with increased expression of its key cell entry proteases. ACE2-regulated placental functions, both infection- and non-infection related, may be highly oxygenation-dependent.