A study published in the American Journal of Obstetrics & Gynecology by researchers at Baylor College of Medicine, UTHealth Houston and collaborating institutions reveals that maternal COVID-19 infection triggers distinct stress responses in the placenta, including upregulation of preeclampsia-associated genes. The stress responses promote cell proliferation in the placenta that reinforces the barrier between the fetus and maternal blood circulation. Comparing placental stress responses in COVID-19 and preeclampsia revealed similarities that may help explain the overlapping presentation of these clinical syndromes.
"It's well known that maternal COVID-19 increases the risk of adverse pregnancy outcomes, including preeclampsia, stillbirth and preterm delivery," said first author Rachel Keuls, graduate student in Dr. Ronald Parchem lab at Baylor. Parchem, co-corresponding author of the work, is an associate professor of molecular and cellular biology and member of the Stem Cells and Regenerative Medicine Center and Dan L Duncan Comprehensive Cancer Center at Baylor.
The virus triggers a cytokine storm in the mother - an excessive, uncontrolled release of mediators of strong inflammatory immune responses. The cytokines circulating in the maternal blood reach the syncytiotrophoblasts, specialized epithelial cells that form the outermost layer of the placenta, a barrier that separates maternal and fetal circulation and whose functions include protecting the fetus from disease-causing microbes and toxic compounds. Syncytiotrophoblasts respond to the maternal cytokine storm with a stress response of their own that is not well understood.
"In the current study, we investigated the syncytiotrophoblast stress response within the human placenta from mothers with COVID-19 at birth," Keuls said. "It's important to note that direct placental infection with the COVID-19 virus is rare. The placental stress responses are triggered by the maternal inflammatory response to the virus."
Syncytiotrophoblasts are unique because they are fused, multinucleated cells instead of typical cells with one nucleus, posing a challenge to profiling gene expression in syncytiotrophoblasts with high resolution using current methods. To understand how syncytiotrophoblasts responded to maternal COVID-19, the researchers used single-nucleus transcriptional profiling, a technique to identify changes in gene expression that circumvents the challenges associated with capturing syncytiotrophoblasts with methods previously used for profiling the placenta.
"This technique revealed multiple clusters of syncytiotrophoblasts. Each cluster expresses a different set of genes, meaning that the clusters have distinct stress responses to the COVID-19-triggered maternal inflammatory response," said co-corresponding author Dr. Jacqueline G. Parchem, assistant professor in the Department of Obstetrics, Gynecology and Reproductive Sciences at McGovern Medical School at UTHealth Houston. She also is an adjunct faculty member in the Department of Molecular and Cellular Biology at Baylor.
The right place, at the right time
"This project has been very close to the team personally," Parchem said. "I was pregnant during the early days of the pandemic and concerned about the unknown consequences getting infected would have on the baby. I was extremely invested in understanding the biology. We did not know then whether the virus infected the placenta directly, and a vaccine was not available, yet. But we were in a unique position to find answers about how this newly emerging and rapidly spreading virus affected pregnancies. As a physician, I was able to collect placenta samples for our study. It would be impossible to collect severe, primary infection cases from unvaccinated patients today."
"I conducted the analyses of the placentas working through the very early days of the pandemic," Keuls said. "As a developmental biologist, I applied my expertise to study the placentas at high cellular resolution to explore uncharted territory, something we knew nothing about - what the direct effects of COVID-19 were on the placenta. I worked in the deserted lab, walked empty hallways. Most of the lights were off in the buildings as access was limited due to the pandemic. These were difficult times, but the findings are very rewarding."
Other contributors to this work include Scott A. Ochsner, Mary B. O'Neill, Diana R. O'Day, Akihiko Miyauchi, Kadeshia M. Campbell, Natalie Lanners, Jeffrey A. Goldstein, Connor Yee, Neil J. McKenna and Ronald J. Parchem. The authors are affiliated with one of the following institutions: Baylor College of Medicine, UTHealth Houston, University of Washington and Northwestern University Feinberg School of Medicine.
This work was supported by funding from the Center for Clinical and Translational Sciences COVID-19 Pilot Grant and the Department of Obstetrics and Gynecology at UTHealth Houston, Eunice Kennedy Shriver NICHD 1F31HD110243-01A1 and NIEHS T32ES027801-04 grants, the Burroughs Wellcome Fund CAMS #1023003 and the Doris Duke Foundation #2023-0244.
