Consistent localization of SARS-CoV-2 spike glycoprotein and ACE2 over TMPRSS2 predominance in placental villi of 15 COVID-19 positive maternal-fetal dyads

Abstract

Introduction While the COVID-19 pandemic continues to have a significant global health impact, rates of maternal to infant vertical transmission remain low (<5%). Parenchymal changes of placentas from COVID-19 infected mothers have been reported by several groups, but the localization and relative abundance of SARS-CoV-2 viral proteins and cellular entry machinery has not been fully characterized within larger placental tissue cohorts. Methods An extended placental tissue cohort including samples from 15 COVID-19 positive maternal-fetal dyads (with n = 5 cases with evidence of fetal transmission) in comparison with 10 contemporary COVID-19 negative controls. Using comparative immunofluorescence, we examined the localization and relative tissue abundance of SARS-CoV2 spike glycoprotein (CoV2 SP) along with the co-localization of two SARS-CoV2 viral entry proteins angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). Results/conclusions CoV2 SP was present within the villous placenta in COVID-19 positive pregnancies with and without evidence of fetal transmission. We further identified the predominance of ACE2 expression in comparison with TMPRSS2. Importantly, both CoV2 SP and ACE2 expression consistently localized primarily within the outer syncytiotrophoblast layer placental villi, a key physiologic interface between mother and fetus. Overall this study provides an important basis for the ongoing evaluation of SARS-CoV-2 physiology in pregnancy and highlights the importance of the placenta as a key source of primary human tissue for ongoing diagnostic and therapeutic research efforts to reduce the global burden of COVID-19.

The Effects of COVID-19 on Placenta and Pregnancy: What Do We Know So Far?

“…A higher frequency of maternal vascular malperfusion (MVM) of the placental bed was reported in placentas of pregnant women infected with SARS-CoV-2 by 13 studies [ 16 , 22 , 23 , 25 , 27 , 28 , 31 , 32 , 38 , 40 , 42 , 43 , 44 ]. It is a recognized pattern of placental injury related to abnormal uterine perfusion, leading to a myriad of pathological changes such as accelerated villous maturation, increased perivillous and intervillous fibrin deposition, decidual vasculopathy, Tenney–Parker change, villous infarction, and intervillous thrombosis [ 75 ].…”

“…Maternal hypoxia secondary to severe COVID-19 lung infection may initiate uterine underperfusion and subsequent hypoxic-ischemic injury to the placenta. Taglauer et al (2020) reported that 14 of the 15 (93%) third trimester placentas revealed at least a feature of MVM, with infarcts and increased fibrin deposition being the most frequently observed, compared to healthy controls where MVM was observed only in 30% (3/10) of cases [ 42 ]. This was similar with that reported by Zhang et al (2020) and Hecht et al (2020) [ 25 , 44 ], although their findings did not meet statistical significance.…”

“…Similar to other RNA viral infections, e.g., Zika virus [ 81 ], cytomegalovirus [ 82 ], and dengue virus [ 83 ] in pregnancy, SARS-CoV-2 placental infection was associated with chronic inflammatory pathologies which include lymphohistiocytic villitis [ 27 , 31 , 40 , 42 ], chronic histiocytic intervillositis [ 22 , 28 , 32 , 35 , 38 ], and chronic deciduitis [ 31 ]. Unexpectedly, maternal inflammatory responses as characterized histologically by acute subchorionitis/chorionitis (stage 1) and chorioamnionitis (stage 2) were the most reported features in SARS-CoV-2 positive placentas (11/33, 33%), documented in 11 studies.…”

“…In comparison, only one (1.7%) out of 60 SARS-CoV-2-negative placentas in COVID-19-infected mothers showed evidence of acute chorioamnionitis [ 30 ]. Fetal inflammatory response (chorionic vasculitis or fetal vasculitis) was occasionally described in SARS-CoV-2 positive placentas [ 25 , 31 , 42 ], but showed no statistical difference with the control group. Collectively, whether or not the presence and the extent of inflammatory response correspond with the detection of SARS-CoV-2 in placentas awaits further investigations.…”

“…Reference lists of the included papers were also checked to identify additional relevant studies. We reviewed all articles (both peer-reviewed and preprints) with reports on placental pathology in pregnant women tested positive for SARS-CoV-2 that were published between 1 January 2020 to 10 October 2020 ( n = 29) [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. Articles written in languages other than English and Mandarin were excluded.…”