Fri. Jan 21st, 2022

To date, the 2019 coronavirus disease pandemic (COVID-19) has claimed more than 5.17 million lives worldwide. This pandemic has been caused by the sudden and rapid outbreak of a new coronavirus, namely severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).

Despite advanced COVID-19 detection tools and vaccine availability, COVID-19 was not included. This is primarily due to the development of the SARS-CoV-2 virus.

A deeper understanding of the pathogenesis and viral mechanisms of viral infection is needed to develop effective therapies.

Study: Acute SARS-CoV-2 infection during pregnancy is associated with ACE-2 loss in the placenta. Image credit: 10 FACE / Shutterstock

The role of ACE2 in COVID-19 infection

Previous studies have revealed that angiotensin-converting enzyme 2 (ACE2) is the primary receptor on the surface of the host cell, whereby SARS-CoV-2 invades the host cell. The variability and inducibility of ACE2 determine viral tropism, infectivity, disease progression, or severity.

ACE2 is an important member of the renin-angiotensin (RAS) system and a monocarboxylic peptidase and type I transmembrane protein. In addition, ACE2 contains a large ectodomain, where both viruses (SARS-CoV-1 and -2) bind and maintain enzymatically active domains separately.

Researchers indicated that the ectodomain of ACE2 is secreted, which is induced via various stimuli (eg bacteria and viruses) and remains active. As a promising COVID-19 therapeutic agent, researchers have suggested that the soluble ACE2 could be used as a bait receptor to capture the SARS-CoV-2 virus.

At present, this study is undergoing clinical trials for validation. Another group of researchers discussed this strategy because soluble ACE2 could initiate viral entry via an alternative route.

Previous studies have revealed that ACE2 secretion depends on the activity of a disintegrin and metalloprotease domain 17 (ADAM17) or tumor necrosis factor-alpha-converting enzyme (TACE).

ADAM17 genes encode functional proteases and are involved in ectodomain secretion by a variety of growth factors, cytokines, and adhesion molecules, including TNF-α and ACE-2.

Previous studies have revealed that the enzymatic activity of ADAM17 could be controlled via post-transcriptional metalloprotease (TIMPs) tissue inhibitors. The expression of Adam 17 is influenced by a number of stimuli.

ACE2 and placenta

Generally, ACE-2 is found in the outer trophoblast epithelial cell layers of the villous placenta, i.e. at the functional main interface between the mother and the fetus.

During early pregnancy, placental expression levels of ACE-2 are a prominent phenomenon that gradually decreases throughout pregnancy.

Some studies have shown that ACE-2 expression occurs only in the trophoblast epithelial cells and not among other stromal cells and fetal endothelium.

ADAM17 has been shown to be present in trophoblast trophoblast cells in wild placenta, and its expression has been linked to the production of TNF in inflammatory pregnancy conditions.

Most available studies have focused on evaluating ACE-2 expression in pregnant women infected with SARS-CoV-2 in the third trimester.

Researchers revealed that many women had experienced COVID-19 disease throughout their pregnancies with a consistently low SARS-CoV-2 fetal transmission.

To date, not much evidence has been documented related to ACE-2 expression in different stages of pregnancy in women infected with COVID-19.

A new study, published on bioRxiv* preprint server, assuming that ACE-2 expression and ADAM17 activity in the placenta are affected by the time of maternal SARS-CoV-2 infection.

The present study determined ACE-2 expression / ADAM17 activity in placental villus tissue and ACE-2 levels in maternal serum using samples related to the 2nd and 3rd trimesters of pregnant women infected with SARS-CoV -2.

These results were compared with a control group of healthy pregnant women in a similar time frame. This study design helped to understand the pathway for responses to SARS-CoV-2 infection at the maternal-fetal interface.

The authors documented new evidence of placental ACE-2 expression in SARS-CoV2 infections during pregnancy. They reported that the changes in expression of the ACE-2 protein are associated with placental ACE2 secretion mediated by ADAM17 as a result of maternal SARS-CoV-2 infection.

The 3rd trimester COVID-specific increase in ACE2 mRNA was observed, which may be due to upregulation of ACE-2 transcripts triggered via the active secretion process in this disease state.

This study also revealed that no significant differences in maternal serum estradiol were found between our patient groups.

This result indicated that other hormonal signaling affected the expression of placenta ACE-2 in these pregnancies. In the future, more research is needed in the evaluation of other factors affecting ACE-2 post-translational regulation and ADAM17 activity, in particular to shed more light on the mechanisms that govern this process.

Researchers indicated the absence of ACE-2 on the fetal endothelium in COVID-19 placental tissue compared with the lung epithelial cells. This suggests the possibility of ACE-2 as a gatekeeper preventing perinatal transmission of SARS-CoV-2.

Villøs placenta ACE-2-ekspression i akutte vs fjerntliggende SARS-CoV-2-infektioner under graviditet.  A. Studiedesign.  Kontrolgruppe: Graviditeter, der ikke havde nogen rapport om SARS-CoV-2-infektion eller COVID-19-symptomer under deres graviditet og var SARS-CoV-2-negative via universel screening på tidspunktet for indlæggelse til fødslen og fødslen.  COVID-gruppe: kvinder med dokumenterede COVID-19-symptomer og en SARS-CoV-2-positiv test i løbet af deres 2. trimester (2. tri-covid) eller 3. trimester (3. tri-covid) af graviditeten.  Skematisk viser tidspunktet for maternel SARS-CoV-2-infektion i forhold til prøvetagning ved levering.  B. Repræsentative billeder fra immunhistokemisk undersøgelse af ACE-2 i villøst placentavæv fra hver patientgruppe (n=8 pr. gruppe).  Rød: ACE-2, Grøn: CD31, Blå: DAPI nuklear farve.  Indsat billede: 2. eneste antistof negativ kontrol.  Skala barer: 25mm.  VP: Villøs placenta;  BV: føtalt blodkar.  C. ACE-2-ekspression i villøst placentavævshomogenater som analyseret ved human ACE-2 ELISA.  D qRT-PCR-analyse af ACE-2 mRNA-ekspression i villøst placentavæv.  Fejlbjælker: +/- standardfejl for middelværdien.  * p < 0,05, ** p < 0,01 *** p < 0,001
Villous placenta ACE-2 expression in acute vs distant SARS-CoV-2 infections during pregnancy. A. Study design. Control group: Pregnancies that had no report of SARS-CoV-2 infection or COVID-19 symptoms during their pregnancy and were SARS-CoV-2 negative via universal screening at the time of admission and delivery. COVID group: women with documented COVID-19 symptoms and a SARS-CoV-2 positive test during their 2nd trimester (2nd tri-covid) or 3rd trimester (3rd tri-covid) of pregnancy. Schematic shows the time of maternal SARS-CoV-2 infection in relation to sampling at delivery. B. Representative images from immunohistochemical study of ACE-2 in wild-type placental tissue from each patient group (n = 8 per group). Red: ACE-2, Green: CD31, Blue: DAPI nuclear color. Inserted image: 2. only antibody negative control. Scale bars: 25mm. VP: Villøs placenta; BV: fetal blood vessel. C. ACE-2 expression in wild-type placental tissue homogenates as analyzed by human ACE-2 ELISA. D qRT-PCR analysis of ACE-2 mRNA expression in wild-type placental tissue. Error bars: +/- standard error for the mean value. * p <0.05, ** p <0.01 *** p <0.001

Conclusion

Some of the limitations of this study include the small sample size and the pregnancy evaluation, which only covers infections in the 2nd and 3rd trimesters of pregnancy.

The authors claimed that this study is the first to document the levels of ACE-2 in the serum of pregnant women affected by COVID-19. They reported that ACE-2 levels are increased in pregnant women compared to non-pregnant women.

In the future, several mechanistic studies, including animal models, will be required to thoroughly evaluate ACE-2 expression associated with maternal COVID-19 infection in all trimesters of pregnancy.

*Important message

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered essential, guide clinical practice / health-related behavior or be treated as established information.

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