Date of Award
Doctor of Philosophy (PhD)
The maternal-fetal interface during pregnancy is an underexplored environment rich in immunological factors that must propel developmental processes while simultaneously providing protection from invading pathogens such as viruses. Almost half of all cells in the maternal decidua in pregnancy are leukocytes, which are required for successful pregnancy, and the placenta has increasingly become recognized as an immunological organ. Viral infections during pregnancy are associated with significant mortality and morbidity, both for the pregnant female and the developing fetus. Notably, impacts on fetal development have typically been attributed to direct viral damage to cells and tissues during the course of infection, without a deep consideration of the potential collateral damage incurred upon the activation of antiviral immune responses. In this dissertation, I characterize the contribution of the immune system and antiviral responses to pathologies of pregnancy and fetal development, using both mouse models of maternal immune activation and human studies of viral infection and immunization during the coronavirus disease 2019 (COVID-19) pandemic. First, I establish and characterize a novel model of maternal immune activation (MIA) in early pregnancy that leads to a high rate of neural tube defects (NTDs) and craniofacial abnormalities in the affected offspring. Using systemic administration of the double-stranded RNA mimic poly(I:C) to pregnant mice, I demonstrate that the activation of antiviral immune responses alone is capable of driving fetal birth defects. These phenotypes mirror human NTDs, among the most common birth defects seen worldwide. I identify key immunological pathways and factors driving pathogenesis, which is TLR3- and STAT1-dependent. Strikingly, mice deficient in γδ T cells are protected from the development of MIA-induced NTDs. Together with collaborators, I use immunofluorescence imaging and a spatial gene expression approach to show that γδ T cells are associated with laminin loss at the ectoplacental cone of the primitive placenta. I demonstrate that these changes at the maternal-fetal interface are associated with decreased proliferation of neural progenitors in the developing fetus, resulting in the failure of neural tube closure. We thus uncover a previously unrecognized role for γδ T cells at the maternal-fetal interface and novel mechanism underlying NTD pathogenesis. Next, I interrogate the impact of antiviral responses on outcomes in human pregnancy. The emergence of SARS-CoV-2 and the ongoing COVID-19 pandemic has highlighted the importance of studying the unique consequences of viral infections during pregnancy, as pregnant individuals are at much greater risk for severe COVID-19 disease than nonpregnant individuals. Working with a multidisciplinary team, I help to identify one of the first reports worldwide showing that SARS-CoV-2 is capable of infecting the placenta. I discover that SARS-CoV-2 is capable of infecting the placenta at the syncytiotrophoblast layer, the multinucleated layer of trophoblast derived from stem cell cytotrophoblasts, and that infection, while rare, is restricted to this region of the maternal-fetal interface. In pregnancies affected by asymptomatic SARS-CoV-2, the vast majority of placentas are not infected due to a robust antiviral response at the maternal-fetal interface. However, I find that this powerful antiviral defense includes a distinct inflammatory profile at the placenta that is directly associated with preeclampsia and other inflammatory disorders of pregnancy, suggesting that antiviral immunity mounted to effectively shield the fetus from viral infection may come at the price of dysregulation of the maternal-fetal interface. This observation lends insight as to why pathogens typically are not able to invade the placenta during pregnancy and how even asymptomatic or mild infections limited to the respiratory tract can lead to severe maternal outcomes at a distant organ site. Finally, I directly address some of the most prevalent vaccine misinformation encountered by the public today, including false theories that the COVID-19 mRNA vaccines cause infertility and harm developing fetuses in utero when administered in pregnancy. With a mouse model of vaccination during early pregnancy, I show that administration of the mRNA-1273 vaccine has no impact on fetal size at term and does not lead to birth defects. In contrast, poly(I:C) administration, which unlike the mRNA vaccines activates TLR3 pathways, significantly reduces crown-rump length and weight at term. I further demonstrate that mRNA-1273 vaccination even in the earliest stages of pregnancy, prior to formation of the definitive placenta, leads to high levels of protective antibodies in fetuses at term. In a large study of human volunteers, we challenge a common infertility myth by providing direct evidence that COVID-19 vaccination with either mRNA-1273 or BNT162b2 does not lead to an increase in circulating anti-syncytin-1 antibodies. Together, these contributions dispel a number of the most common vaccine rumors fueling vaccine hesitancy worldwide.
Lu-Culligan, Alice, "Investigating the Impact of Maternal Antiviral Responses on Pregnancy and Fetal Development" (2022). Yale Graduate School of Arts and Sciences Dissertations. 628.