Investigating the role of maternal-fetal crosstalk on neonatal immunity in COVID-19 infection or vaccination in pregnancy

摘要 抗SARS-CoV-2的免疫球蛋白（IgG）通过以下途径从母体被动转移至胎儿： 经胎盘转移，可以保护新生儿免受感染或引起疾病。最近的研究 显示母亲SARS-CoV-2感染导致脐带血中婴儿免疫反应失调 包括改变的T细胞相关细胞因子和免疫细胞亚群的扰动。目前还没有证据表明， 这种免疫引发是SARS-CoV-2抗原特异性的，或者如果它是继发于非特异性母体或胎盘 炎症此外，最近的证据表明，接种疫苗后免疫力下降，进一步的工作是 需要了解SARS-CoV-2表位的保护性免疫原性反应，以优化未来的 怀孕期间的疫苗接种战略，使母亲和婴儿都受益。我们假设母亲的SARS- CoV-2感染通过1）免疫复合物的转移积极引发子宫内的胎儿免疫反应 具有免疫刺激活性，和2）保护性和自身反应性抗体两者被动转移到免疫系统中。 胎儿此外，我们假设不同的胎盘组织反应与母体- 胎儿串话在此应用中，我们利用来自两个COVID-19前瞻性队列的有价值样本 妊娠期感染和疫苗接种，以解决以下具体目标：1）研究胎儿T细胞 SARS-CoV-2抗原通过一种新的免疫复合物转移到胎儿体内的免疫刺激潜力 基于质谱的方法; 2）绘制SARS-CoV后产生的Ab的抗体库谱图- 2感染与接种疫苗，以确定保护性与自身反应性免疫的母胎转移的宽度 使用PhIP-Seq技术的应答;和3）鉴定对以下的差异转录组学和蛋白质组学应答： SARS-CoV-2在母胎界面的感染介导免疫复合物转移的差异 通过在病人活检上应用激光显微切割。这些结果直接关系到 了解病毒感染后母胎免疫串扰的新机制。我们的数据将有助于 保护母亲和婴儿免受COVID-19感染的疫苗接种策略， 我们对围产期感染中母胎免疫相互作用的理解。

ABSTRACT Passive transfer of immunoglobulins (IgG) against SARS-CoV-2 occurs from the mother to fetus by transplacental transfer and may protect the neonate against infection or cause disease. Recent studies have shown maternal SARS-CoV-2 infection leads to the dysregulation of infant immune responses in cord blood including altered T cell related cytokines and perturbations of immune cell subsets. It has not been yet shown if this immune priming is SARS-CoV-2 antigen-specific or if it is secondary to non-specific maternal or placental inflammation. Additionally, recent evidence has shown waning immunity after vaccination and further work is needed to understand protective immunogenic responses to SARS-CoV-2 epitopes to optimize future vaccination strategies in pregnancy, to benefit both mother and infant. We hypothesize that maternal SARS- CoV-2 infection actively primes fetal immune responses in utero through 1) the transfer of immune complexes with immunostimulatory activity, and 2) the passive transfer of both protective and autoreactive antibodies to the fetus. Further, we hypothesize that differential placental tissue responses correlate with differences in maternal- fetal crosstalk. In this application, we leverage valuable samples from two prospective cohorts of COVID-19 infection and vaccination in pregnancy to address the following specific aims: 1) Investigate the fetal T cell immunostimulatory potential of SARS-CoV-2 Ags transferred to the fetus in immune complexes through a novel mass spectrometry-based approach; 2) Map the antibody repertoire profiles of Abs generated after SARS-CoV- 2 infection vs vaccination to determine the breadth of maternal-fetal transfer of protective vs autoreactive immune responses using PhIP-Seq technology; and 3) Identify differential transcriptomic and proteomic responses to SARS-CoV-2 infection at the maternal-fetal interface that mediate differences in immune complex transfer through the application of laser microdissection on patient biopsies. These results have immediate relevance to understanding novel mechanisms of maternal-fetal immune crosstalk after viral infection. Our data will aid vaccination strategies to protect both the mother and baby against COVID-19 and may significantly advance in our understanding of maternal-fetal immune interplay in perinatal infections.