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1.
J Infect Dis ; 224(Suppl 6): S647-S659, 2021 12 08.
Article in English | MEDLINE | ID: covidwho-1559634

ABSTRACT

BACKGROUND: Expression of angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2), host molecules required for viral entry, may underlie sex differences in vulnerability to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We investigated whether placental ACE2 and TMPRSS2 expression vary by fetal sex in the presence of maternal SARS-CoV-2 infection. METHODS: Placental ACE2 and TMPRSS2 expression was quantified by quantitative reverse transcription polymerase chain reaction (RT-PCR) and by Western blot in 68 pregnant women (38 SARS-CoV-2 positive, 30 SARS-CoV-2 negative) delivering at Mass General Brigham from April to June 2020. The impact of fetal sex and maternal SARS-CoV-2 exposure on ACE2 and TMPRSS2 was analyzed by 2-way analysis of variance (ANOVA). RESULTS: Maternal SARS-CoV-2 infection impacted placental TMPRSS2 expression in a sexually dimorphic fashion (2-way ANOVA interaction, P = .002). We observed no impact of fetal sex or maternal SARS-CoV-2 status on ACE2. TMPRSS2 expression was significantly correlated with ACE2 expression in males (Spearman ρ = 0.54, P = .02) but not females (ρ = 0.23, P = .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, which may have implications for offspring vulnerability to placental infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/diagnosis , Fetal Blood/immunology , Placenta/metabolism , SARS-CoV-2/immunology , Serine Endopeptidases/metabolism , Sex Factors , Adult , COVID-19/blood , Female , Fetal Blood/virology , Fetus/virology , Gene Expression , Humans , Infectious Disease Transmission, Vertical , Male , Pregnancy , Pregnancy Complications, Infectious/virology
2.
American Journal of Obstetrics and Gynecology ; 224(2):S568-S569, 2021.
Article in English | PMC | ID: covidwho-1384871

ABSTRACT

Objective: Sex differences in the immune response to SARS-CoV-2 infection have been described. ACE2 and TMPRSS2, host cell receptors required for viral entry, are regulated by sex steroids and expressed by trophoblasts. Although vertical transmission of SARS-CoV-2 is rare, how the placenta defends against SARS-CoV-2, and whether there is a sex bias in the risk of vertical transmission, is not well understood. We sought to investigate whether placental ACE2 and TMPRSS2 expression vary by fetal sex in the presence of maternal SARS-CoV-2 infection. Study Design: This is a cohort study of 66 pregnant women (37 SARS-CoV-2 exposed, 29 SARS-CoV-2 unexposed) enrolled on admission to Massachusetts General Hospital from April-June 2020, coincident with universal screening for SARS-CoV-2 infection. SARS-CoV-2 exposure status was determined by nasopharyngeal RT-PCR. Groups were balanced for fetal sex and maternal disease severity. RNA was isolated from placental homogenates and RTqPCR was performed to quantify expression of ACE2 and TMPRSS2 relative to the reference gene YWHAZ, using the 2-(DELTADELTACt) method. The impact of fetal sex and SARS-CoV-2 exposure on ACE2 and TMPRSS2 expression was analyzed by 2-way ANOVA. Previously determined placental viral loads showed no evidence of SARS-CoV-2 infection in any placentas. Result(s): While there were no fetal sex or SARS-CoV-2 exposure-mediated differences in ACE2 expression (1A), we observed 1.73-fold increased TMPRSS2 expression in SARS-CoV-2 exposed placentas of female offspring compared to female controls (P=0.04, 1B), and 1.84 -fold reduced TMPRSS2 expression in SARS-CoV-2 exposed placentas of male offspring compared to male controls (P=0.0003, 1B). TMPRSS2 expression was significantly higher in placentas of male compared to female offspring in controls (P<0.0001). Conclusion(s): Sexually dimorphic patterns of TMPRSS2 placental gene expression were observed in the setting of maternal SARS-CoV-2 infection, driven by sex differences in TMPRSS2 expression in controls. Implications of these findings for offspring vulnerability to vertical transmission warrants further investigation. [Formula presented]Copyright © 2020

3.
Cell ; 184(3): 628-642.e10, 2021 02 04.
Article in English | MEDLINE | ID: covidwho-1385216

ABSTRACT

SARS-CoV-2 infection causes more severe disease in pregnant women compared to age-matched non-pregnant women. Whether maternal infection causes changes in the transfer of immunity to infants remains unclear. Maternal infections have previously been associated with compromised placental antibody transfer, but the mechanism underlying this compromised transfer is not established. Here, we used systems serology to characterize the Fc profile of influenza-, pertussis-, and SARS-CoV-2-specific antibodies transferred across the placenta. Influenza- and pertussis-specific antibodies were actively transferred. However, SARS-CoV-2-specific antibody transfer was significantly reduced compared to influenza- and pertussis-specific antibodies, and cord titers and functional activity were lower than in maternal plasma. This effect was only observed in third-trimester infection. SARS-CoV-2-specific transfer was linked to altered SARS-CoV-2-antibody glycosylation profiles and was partially rescued by infection-induced increases in IgG and increased FCGR3A placental expression. These results point to unexpected compensatory mechanisms to boost immunity in neonates, providing insights for maternal vaccine design.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Immunoglobulin G/immunology , Maternal-Fetal Exchange/immunology , Placenta/immunology , Pregnancy Complications, Infectious/immunology , SARS-CoV-2/immunology , Adult , Female , Humans , Infant, Newborn , Pregnancy , Pregnancy Trimester, Third/immunology , Receptors, IgG/immunology , THP-1 Cells
4.
American Journal of Obstetrics and Gynecology ; 224(2, Supplement):S709, 2021.
Article in English | ScienceDirect | ID: covidwho-1056243
5.
American Journal of Obstetrics and Gynecology ; 224(2, Supplement):S568-S569, 2021.
Article in English | ScienceDirect | ID: covidwho-1056213
6.
JAMA Netw Open ; 3(12): e2030455, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-985883

ABSTRACT

Importance: Biological data are lacking with respect to risk of vertical transmission and mechanisms of fetoplacental protection in maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Objective: To quantify SARS-CoV-2 viral load in maternal and neonatal biofluids, transplacental passage of anti-SARS-CoV-2 antibody, and incidence of fetoplacental infection. Design, Setting, and Participants: This cohort study was conducted among pregnant women presenting for care at 3 tertiary care centers in Boston, Massachusetts. Women with reverse transcription-polymerase chain reaction (RT-PCR) results positive for SARS-CoV-2 were recruited from April 2 to June 13, 2020, and follow-up occurred through July 10, 2020. Contemporaneous participants without SARS-CoV-2 infection were enrolled as a convenience sample from pregnant women with RT-PCR results negative for SARS-CoV-2. Exposures: SARS-CoV-2 infection in pregnancy, defined by nasopharyngeal swab RT-PCR. Main Outcomes and Measures: The main outcomes were SARS-CoV-2 viral load in maternal plasma or respiratory fluids and umbilical cord plasma, quantification of anti-SARS-CoV-2 antibodies in maternal and cord plasma, and presence of SARS-CoV-2 RNA in the placenta. Results: Among 127 pregnant women enrolled, 64 with RT-PCR results positive for SARS-CoV-2 (mean [SD] age, 31.6 [5.6] years) and 63 with RT-PCR results negative for SARS-CoV-2 (mean [SD] age, 33.9 [5.4] years) provided samples for analysis. Of women with SARS-CoV-2 infection, 23 (36%) were asymptomatic, 22 (34%) had mild disease, 7 (11%) had moderate disease, 10 (16%) had severe disease, and 2 (3%) had critical disease. In viral load analyses among 107 women, there was no detectable viremia in maternal or cord blood and no evidence of vertical transmission. Among 77 neonates tested in whom SARS-CoV-2 antibodies were quantified in cord blood, 1 had detectable immunoglobuilin M to nucleocapsid. Among 88 placentas tested, SARS-CoV-2 RNA was not detected in any. In antibody analyses among 37 women with SARS-CoV-2 infection, anti-receptor binding domain immunoglobin G was detected in 24 women (65%) and anti-nucleocapsid was detected in 26 women (70%). Mother-to-neonate transfer of anti-SARS-CoV-2 antibodies was significantly lower than transfer of anti-influenza hemagglutinin A antibodies (mean [SD] cord-to-maternal ratio: anti-receptor binding domain immunoglobin G, 0.72 [0.57]; anti-nucleocapsid, 0.74 [0.44]; anti-influenza, 1.44 [0.80]; P < .001). Nonoverlapping placental expression of SARS-CoV-2 receptors angiotensin-converting enzyme 2 and transmembrane serine protease 2 was noted. Conclusions and Relevance: In this cohort study, there was no evidence of placental infection or definitive vertical transmission of SARS-CoV-2. Transplacental transfer of anti-SARS-CoV-2 antibodies was inefficient. Lack of viremia and reduced coexpression and colocalization of placental angiotensin-converting enzyme 2 and transmembrane serine protease 2 may serve as protective mechanisms against vertical transmission.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Fetal Blood/immunology , Immunity, Maternally-Acquired/immunology , Infectious Disease Transmission, Vertical/statistics & numerical data , Placenta/metabolism , Pregnancy Complications, Infectious/immunology , SARS-CoV-2/immunology , Adult , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/blood , COVID-19/transmission , COVID-19 Serological Testing , Case-Control Studies , Cohort Studies , Coronavirus Nucleocapsid Proteins/immunology , Female , Fetal Blood/virology , Humans , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Infant, Newborn , Influenza A virus/immunology , Male , Phosphoproteins/immunology , Placenta/pathology , Placenta/virology , Pregnancy , Pregnancy Complications, Infectious/blood , Prospective Studies , RNA, Viral/metabolism , Receptors, Coronavirus/metabolism , Serine Endopeptidases/metabolism , Severity of Illness Index , Spike Glycoprotein, Coronavirus/immunology , Viral Load
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