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

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. ### Competing Interest Statement K.J.G. has consulted for Illumina, BillionToOne, and Aetion outside the submitted work. A.F. reported serving as a cofounder and owning stock in Alba Therapeutics and serving on scientific advisory boards for NextCure and Viome outside the submitted work. G.A. reported serving as a founder of Systems Seromyx. J.Z.L. reported serving as a consultant for Abbvie and Jan Biotech. D.P. reported owning stock in Gilead Sciences, BioNano Genomics, Biogen, Bluebird Bio, ImmunoGen, Pfizer, and Bristol-Myers Squibb. D.J.R. reported receiving author royalties from UpToDate and Cambridge University Press outside the submitted work. Any opinion, findings, and conclusions or recommendation expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. All others report no conflicts of interest.