Acute SARS-CoV-2 infection in pregnancy is associated with placental ACE-2 shedding

  1. Elizabeth S. Taglauer
  2. Elisha M. Wachman
  3. Lillian Juttukonda
  4. Timothy Klouda
  5. Jiwon Kim
  6. Qiong Wang
  7. Asuka Ishiyama
  8. David J. Hackam
  9. Ke Yuan
  10. Hongpeng Jia

Reviewed by

Read the full article

Listed in

Log in to save this article

Abstract

Human placental tissues have variable rates of SARS-CoV-2 invasion resulting in consistently low rates of fetal transmission suggesting a unique physiologic blockade against SARS-CoV-2. Angiotensin-converting enzyme (ACE)-2, the main receptor for SARS-CoV-2, is expressed as cell surface and soluble forms regulated by a metalloprotease cleavage enzyme, ADAM17. ACE-2 is expressed in the human placenta, but the regulation of placental ACE-2 expression in relation to timing of maternal SARS-CoV-2 infection in pregnancy is not well understood. In this study, we evaluated ACE-2 expression, ADAM17 activity and serum ACE-2 abundance in a cohort of matched villous placental and maternal serum samples from Control pregnancies (SARS-CoV-2 negative, n=8) and pregnancies affected by symptomatic maternal SARS-CoV-2 infections in the 2 nd trimester (“2 nd Tri COVID”, n=8) and 3rd trimester (“3 rd Tri COVID”, n=8). In 3 rd Tri COVID as compared to control and 2 nd Tri-COVID villous placental tissues ACE-2 mRNA expression was remarkably elevated, however, ACE-2 protein expression was significantly decreased with a parallel increase in ADAM17 activity. Soluble ACE-2 was also significantly increased in the maternal serum from 3 rd Tri COVID infections as compared to control and 2 nd Tri-COVID pregnancies. These data suggest that in acute maternal SARS-CoV-2 infections, decreased placental ACE-2 protein may be the result of ACE-2 shedding. Overall, this work highlights the importance of ACE-2 for ongoing studies on SARS-CoV-2 responses at the maternal-fetal interface.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2021.11.19.469335: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: Study enrollment: The current study was approved by the Boston University Medical School Institutional Review Board and written informed consent was obtained from all
    Consent: Study enrollment: The current study was approved by the Boston University Medical School Institutional Review Board and written informed consent was obtained from all
    Field Sample Permit: Sample collection and processing: Maternal blood samples were collected in EDTA collection tubes by trained staff within 24 hours pre or post-delivery.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Primary antibodies of interest, including sheep anti-CD31 (1:100; AF806, R&D systems), rabbit anti-SARS-N protein (1:500; 200-401-A50 Rockland) and goat anti-ACE2 (1:50; AF933, R&D Systems) were then incubated at 4°C overnight.
    anti-CD31
    suggested: None
    anti-SARS-N protein
    suggested: (IMGENEX Cat# IMG-5085, RRID:AB_317353)
    anti-ACE2
    suggested: None
    After blocking with donkey serum at room temperature for 1h, secondary conjugate antibodies, donkey anti-sheep Alexa Fluor 488 (1:250; 713-545-003, Jackson Immunoresearch)
    anti-sheep
    suggested: (Jackson ImmunoResearch Labs Cat# 713-545-003, RRID:AB_2340744)
    Software and Algorithms
    SentencesResources
    All statistical analyses were conducted using Prism 7 software (GraphPad, San Diego, CA).
    Prism
    suggested: (PRISM, RRID:SCR_005375)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    This study has several limitations. First, the cohort is a small sample size and the gestational evaluation only spanned infections in the 2nd and 3rd (but not 1st) trimesters of pregnancy. Additionally, as stated above, soluble ACE-2 in maternal serum cannot be directly identified as placental in origin and could be derived from multiple sources. Ongoing mechanistic studies, including relevant animal models, are needed to more completely evaluate ACE-2 expression relative to maternal COVID-19 infection in all trimesters of pregnancy, to clarify the placental origin of maternal serum ACE-2 and to functionally correlate ADAM 17 activity with ACE-2 placental regulation. In conclusion, our work highlights a previously unrecognized dynamic expression of ACE-2 in the human placenta which can impacted by the timing of maternal SARS-CoV-2 infection in pregnancy relative to delivery. Taken together our data provide support for the growing body of evidence on the importance of ACE-2 regulation in the placental response against SARS-CoV-2. The human placenta has many functional and structural parallels with the human lung 46, and thus continues to be an important primary human tissue for identification of key targets to combat COVID-19 pathogenesis.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 18. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.11.19.469335v1 on bioRxiv