Maternal SARS-CoV-2 infection elicits sexually dimorphic placental immune responses.

Evan A Bordt,Caroline Atyeo,Lydia L Shook,Stephanie Fischinger,Lisa M Bebell,Jonathan Z Li,Kaitlyn James,Krista M Pullen,Kathryn J Gray,Lael M Yonker,Rosiane Lima,Rose M De Guzman,Drucilla J Roberts,Alessio Fasano,David Pépin,Jun R Huh,Laura J Yockey,Staci D Bilbo,Galit Alter,Danny J Schust,Sara Brigida,Andrea G Edlow,Marie-Charlotte Meinsohn,Anjali J Kaimal ,Maëva Chauvin ,Douglas A Lauffenburger

doi:10.1126/scitranslmed.abi7428

Abstract

There is a persistent bias toward higher prevalence and increased severity of coronavirus disease 2019 (COVID-19) in males. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of COVID-19 disease in adults and play a key role in the placental antiviral response. Moreover, the interferon response has been shown to alter Fc receptor expression and therefore may affect placental antibody transfer. Here, we examined the intersection of maternal-fetal antibody transfer, viral-induced placental interferon responses, and fetal sex in pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Placental Fc receptor abundance, interferon-stimulated gene (ISG) expression, and SARS-CoV-2 antibody transfer were interrogated in 68 human pregnancies. Sexually dimorphic expression of placental Fc receptors, ISGs and proteins, and interleukin-10 was observed after maternal SARS-CoV-2 infection, with up-regulation of these features in placental tissue of pregnant individuals with male fetuses. Reduced maternal SARS-CoV-2–specific antibody titers and impaired placental antibody transfer were also observed in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.

Highlights

Mortality and morbidity risk during the perinatal period and infancy is higher in males than females [1,2,3,4]
Women with SARS-CoV-2 infection during pregnancy were more likely to be Hispanic compared to negative controls, concordant with our prior report of ethnic disparities in COVID-19 vulnerability in our hospital catchment area [58]
Given the key role interferon stimulated gene (ISG) are known to play in the placental antiviral response [46, 47, 73] and placental barrier function [74], and previous reports of sex differences in expression of interferon-stimulated proteins in the plasma of patients with COVID-19 [42], we examined whether maternal SARS-CoV-2 infection was associated with sex-specific alterations in placental Type I, II and III interferon pathways (Fig. S8A)

Summary

Introduction

Mortality and morbidity risk during the perinatal period and infancy is higher in males than females [1,2,3,4]. Emerging data point to a retrograde impact of infant sex on maternal immunity [13, 14], with specific differences in innate immune signaling across fetal sex, which may contribute to a differential dialogue between female and male fetuses and their mothers. This differential dialogue may critically impact immunity across the dyad, pointing to one potential explanation for sex differences in perinatal vulnerability to infectious disease: differential transplacental antibody transfer from the mother may provide female and

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