COVID-19 is caused by the SARS-CoV-2 virus and is associated with critical illness requiring hospitalization, maternal mortality, stillbirth, and preterm birth. SARS-CoV-2 has been shown to induce placental pathology. However, substantial gaps exist in our understanding of the pathophysiology of COVID-19 disease in pregnancy and the long-term impact of SARS-CoV-2 on the placenta and fetus. To what extent a SARS-CoV-2 infection of the placenta alters the placental antiviral innate immune response is not well understood. A dysregulated innate immune response in the setting of maternal COVID-19 disease may increase the risk of inflammatory tissue injury or placental compromise and may contribute to deleterious pregnancy outcomes. We sought to determine the impact of a maternal SARS-CoV-2 infection on placental immune response by evaluating gene expression of a panel of 6 antiviral innate immune mediators that act as biomarkers of the antiviral and interferon cytokine response. Our hypothesis was that a SARS-CoV-2 infection during pregnancy would result in an up-regulated placental antiviral innate immune response. We performed a case–control study on placental tissues (chorionic villous tissues and chorioamniotic membrane) collected from pregnant patients with (N=140) and without (N=24) COVID-19 disease. We performed real-time quantitative polymerase chain reaction and immunohistochemistry, and the placental histopathology was evaluated. Clinical data were abstracted. Fisher exact test, Pearson correlations, and linear regression models were used to examine proportions and continuous data between patients with active (<10 days since diagnosis) vs recovered COVID-19 (>10 days since diagnosis) at the time of delivery. Secondary regression models adjusted for labor status as a covariate and evaluated potential correlation between placental innate immune gene expression and other variables. SARS-CoV-2 viral RNA was detected in placental tissues from 5 women with COVID-19 and from no controls (0/24, 0%). Only 1 of 5 cases with detectable SARS-CoV-2 viral RNA in placental tissues was confirmed to express SARS-CoV-2 nucleocapsid and spike proteins in syncytiotrophoblast cells. We detected a considerably lower gene expression of 5 critical innate immune mediators (, , , , ) in the chorionic villi and chorioamniotic membranes from women with active or recovered COVID-19 than controls, which remained significant after adjustment for labor status. There were minimal correlations between placental gene expression and other studied variables including gestational age at diagnosis, time interval between COVID-19 diagnosis and delivery, prepregnancy body mass index, COVID-19 disease severity, or placental pathology. A maternal SARS-CoV-2 infection was associated with an impaired placental innate immune response in chorionic villous tissues and chorioamniotic membranes that was not correlated with gestational age at COVID-19 diagnosis, time interval from COVID-19 diagnosis to delivery, maternal obesity, disease severity, or placental pathology.

中文翻译：

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母体 SARS-CoV-2 感染后胎盘中抗病毒先天免疫基因表达减少


COVID-19 是由 SARS-CoV-2 病毒引起的，与需要住院治疗的危重疾病、孕产妇死亡、死产和早产有关。 SARS-CoV-2 已被证明可诱发胎盘病理。然而，我们对妊娠期 COVID-19 疾病的病理生理学以及 SARS-CoV-2 对胎盘和胎儿的长期影响的理解存在很大差距。胎盘的 SARS-CoV-2 感染在多大程度上改变了胎盘抗病毒先天免疫反应尚不清楚。母亲患有 COVID-19 疾病时，先天免疫反应失调可能会增加炎症组织损伤或胎盘受损的风险，并可能导致有害的妊娠结局。我们试图通过评估一组 6 种抗病毒先天免疫介质的基因表达来确定母体 SARS-CoV-2 感染对胎盘免疫反应的影响，这些介质充当抗病毒和干扰素细胞因子反应的生物标志物。我们的假设是，怀孕期间感染 SARS-CoV-2 会导致胎盘抗病毒先天免疫反应上调。我们对从患有 (N=140) 和不患有 (N=24) COVID-19 疾病的孕妇中收集的胎盘组织（绒毛膜绒毛组织和绒毛膜羊膜）进行了病例对照研究。我们进行了实时定量聚合酶链反应和免疫组织化学，并对胎盘组织病理学进行了评估。提取临床数据。使用 Fisher 精确检验、Pearson 相关性和线性回归模型来检查分娩时处于活动状态（诊断后<10 id=379>10 天）的患者之间的比例和连续数据。 二次回归模型将分娩状态作为协变量进行调整，并评估胎盘先天免疫基因表达与其他变量之间的潜在相关性。在 5 名患有 COVID-19 的女性和无对照女性的胎盘组织中检测到 SARS-CoV-2 病毒 RNA（0/24，0%）。在胎盘组织中可检测到 SARS-CoV-2 病毒 RNA 的 5 例病例中，只有 1 例被证实在合体滋养层细胞中表达 SARS-CoV-2 核衣壳和刺突蛋白。我们检测到，与对照组相比，患有活动性或恢复性 COVID-19 的女性的绒毛膜绒毛和绒毛膜羊膜中 5 种关键先天免疫介质 (, , , , ) 的基因表达显着降低，并且在调整分娩状态后仍然显着。胎盘基因表达与其他研究变量之间的相关性极小，包括诊断时的孕龄、COVID-19 诊断和分娩之间的时间间隔、孕前体重指数、COVID-19 疾病严重程度或胎盘病理学。产妇 SARS-CoV-2 感染与绒毛膜绒毛组织和绒毛羊膜中的胎盘先天免疫反应受损有关，与 COVID-19 诊断时的孕龄、从 COVID-19 诊断到分娩的时间间隔、产妇肥胖、疾病严重程度或胎盘病理。