Placental expression of ACE2 and TMPRSS2 in maternal SARS-CoV-2 infection: are placental defenses mediated by fetal sex?

  1. Lydia L Shook
  2. Evan A Bordt
  3. Marie-Charlotte Meinsohn
  4. David Pepin
  5. Rose M De Guzman
  6. Sara Brigida
  7. Laura J Yockey
  8. Kaitlyn E James
  9. Mackenzie W Sullivan
  10. Lisa M Bebell
  11. Drucilla J Roberts
  12. Anjali J Kaimal
  13. Jonathan Z Li
  14. Danny Schust
  15. Kathryn J Gray
  16. Andrea G Edlow
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Abstract

Background

Sex differences in vulnerability to and severity of SARS-CoV-2 infection have been described in non-pregnant populations. ACE2 and TMPRSS2, host molecules required for viral entry, are regulated by sex steroids and expressed in the placenta. We sought to investigate whether placentalACE2andTMPRSS2expression vary by fetal sex and in the presence of maternal SARS-CoV-2 infection.

Methods

Placental ACE2 and TMPRSS2 were quantified in 68 pregnant individuals (38 SARS-CoV-2 positive, 30 SARS-CoV-2 negative) delivering at Mass General Brigham from April to June 2020. Maternal SARS-CoV-2 status was determined by nasopharyngeal RT-PCR. Placental SARS-CoV-2 viral load was quantified. RTqPCR was performed to quantify expression ofACE2andTMPRSS2relative to the reference geneYWHAZ. Western blots were performed on placental homogenates to quantify protein levels. The impact of fetal sex and SARS-CoV-2 exposure on ACE2 and TMPRSS2 expression was analyzed by 2-way ANOVA.

Results

SARS-CoV-2 virus was undetectable in all placentas. Maternal SARS-CoV-2 infection impacted TMPRSS2 placental gene and protein expression in a sexually dimorphic fashion (2-way ANOVA interaction p-value: 0.002). We observed no impact of fetal sex or maternal SARS-CoV-2 status on placental ACE2 gene or protein expression. PlacentalTMPRSS2expression was significantly correlated withACE2expression in males (Spearman’s ρ=0.54, p=0.02) but not females (ρ=0.23, p=0.34) exposed to maternal SARS-CoV-2.

Conclusions

Sex differences in placental TMPRSS2 but not ACE2 were observed in the setting of maternal SARS-CoV-2 infection. These findings may have implications for offspring vulnerability to placental infection and vertical transmission.These findings may have implications for offspring vulnerability to placental infection and vertical transmission.

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