Sexually dimorphic placental responses to maternal SARS-CoV-2 infection

  1. Evan A Bordt
  2. Lydia L Shook
  3. Caroline Atyeo
  4. Krista M Pullen
  5. Rose M De Guzman
  6. Marie-Charlotte Meinsohn
  7. Maeva Chauvin
  8. Stephanie Fischinger
  9. Laura J. Yockey
  10. Kaitlyn James
  11. Rosiane Lima
  12. Lael M Yonker
  13. Alessio Fasano
  14. Sara Brigida
  15. Lisa M Bebell
  16. Drucilla J Roberts
  17. David Pépin
  18. Jun R Huh
  19. Staci D Bilbo
  20. Jonathan Z Li
  21. Anjali Kaimal
  22. Danny Schust
  23. Kathryn J Gray
  24. Douglas Lauffenburger
  25. Galit Alter
  26. Andrea G Edlow

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

There is a persistent male bias in the prevalence and severity of COVID-19 disease. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of disease in adults, and play a key role in the placental anti-viral response. Moreover, the interferon response has been shown to alter Fc-receptor expression, and therefore may impact placental antibody transfer. Here we examined the intersection of viral-induced placental interferon responses, maternal-fetal antibody transfer, and fetal sex. Placental interferon stimulated genes (ISGs), Fc-receptor expression, and SARS-CoV-2 antibody transfer were interrogated in 68 pregnancies. Sexually dimorphic placental expression of ISGs, interleukin-10, and Fc receptors was observed following maternal SARS-CoV-2 infection, with upregulation in males. Reduced maternal SARS-CoV-2-specific antibody titers and impaired placental antibody transfer were noted in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2021.03.29.437516: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementConsent: All participants provided written informed consent (virtual).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableStudy design and participant recruitment: Pregnant women at two tertiary care centers in Boston, Massachusetts were approached for enrollment in a COVID-19 pregnancy biorepository study starting April 2, 2020 (Massachusetts General Hospital and Brigham and Women’s Hospital; Mass General Brigham IRB approval #2020P000804).

    Table 2: Resources

    Antibodies
    SentencesResources
    Phycoerythrin (PE)-coupled mouse anti-human detection antibodies (Southern Biotech) were used to detect antigen-specific antibody binding.
    anti-human detection antibodies (Southern Biotech)
    suggested: None
    antigen-specific
    suggested: None
    The next morning, membranes were washed 6x 10 min in TBS-T (20x stock from ThermoFisher was diluted 1:20 in H2O), followed by incubation with secondary antibodies at 1:15,000 dilution and hFAB Rhodamine Anti-Tubulin (Bio-Rad) at 1:4000 dilution for 1 hr in Intercept T20 (TBS) Antibody Diluent (Li-Cor Biosciences).
    Rhodamine Anti-Tubulin
    suggested: (Bio-Rad Cat# 12004165, RRID:AB_2884950)
    Samples were then incubated in primary antibodies diluted in 5% bovine serum albumin (BSA) for 1.5h at room temperature (Placental Alkaline Phosphatase (PLAP – ab212383) - 1:1000, Neonatal Fc Receptor (FcRn – ab193148) – 1:100, CD16 (CD16 – Leica NCL-L-CD16) – 1:100), CD32 (R&D AF1330) – 10ug/ml, CD64 (Origene TA506331)-1:100.
    PLAP
    suggested: None
    FcRn – ab193148
    suggested: None
    CD16
    suggested: None
    CD32
    suggested: (US Biological Cat# C2384-02G, RRID:AB_2278355)
    CD64
    suggested: (OriGene Cat# TA506331, RRID:AB_2623714)
    The slides were washed in PBS Tween 0.1% and incubated in fluorescently conjugated secondary antibodies (1:400 in 5% BSA – Goat anti-Mouse IgG2a (A-21133), Goat anti-mouse IgG2b (A-21141), Goat anti-rabbit (ab150080), anti-mouse Igg1-(AF647 biolegend), donkey anti goat (AA1056)).
    anti-rabbit
    suggested: (Abcam Cat# ab150080, RRID:AB_2650602)
    Software and Algorithms
    SentencesResources
    CellProlifer software was similarly used to quantify immunohistochemistry for ACE2 and CD163.
    CellProlifer
    suggested: None
    O-PLSDA models were built using the R ‘ropls’ Bioconductor package (orthI =1; PredI=1).
    Bioconductor
    suggested: (Bioconductor, RRID:SCR_006442)
    Statistical analyses were performed using GraphPad Prism 9 and R (version 4.0.0).
    GraphPad Prism
    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:
    A limitation of our study is the infection of participants primarily in the third trimester, because these samples were collected during the initial wave of the SARS-CoV-2 pandemic in Boston. Whether maternal SARS-CoV-2 infection in the first and second trimester alters ISG and Fc receptor expression, and how such altered expression might durably impact placental immune function, is a question that remains to be answered in future studies. In addition, although we found no significant association between disease severity and placental gene expression or antibody transfer, such examinations were limited by the relatively small number of women with severe or critical illness. Finally, while our regression models did not find time from infection to delivery to be a significant contributor to the antibody transfer ratios, we cannot entirely rule out any contribution of timing of maternal infection to the reduced antibody transfer noted in males. However, our robust sexually dimorphic gene and protein expression results, with significant upregulation of both placental ISGs and Fc receptors in males, demonstrate placental factors are a stronger driver of antibody transfer than any time-from-infection effect. In conclusion, our comprehensive evaluation of the impact of fetal sex on placental gene expression and transplacental antibody transfer in maternal SARS-CoV-2 infection provides insight into sexually dimorphic or sex-specific placental innate and adaptive immune responses to m...

    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: We did not find any issues relating to colormaps.

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

    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 10.1101/2021.03.29.437516v1 on bioRxiv