A University of South Florida Health preclinical study indicates that FKBP51-progesterone receptor binding plays a critical role in stress-induced preterm birth

Babies born before 37 weeks, particularly those born before 34 weeks, have more health problems and may face long-term complications like heart and lung diseases and neurodevelopmental delays.

Tampa, FL (March 8, 2021) — Preterm birth is a leading cause of infant deaths and illness in the U.S. — yet its underlying molecular causes remain largely unclear. About 40 to 50% of preterm births, defined as births before 37 weeks of pregnancy, are estimated to be “idiopathic,” meaning they arise from unexplained or spontaneous labor. And, maternal stress linked to depression and post-traumatic stress disorders as well as fetal stress have been strongly implicated in preterm births with no known cause.

Now, for the first time, a University of South Florida Health (USF Health) preclinical study has uncovered a mechanism to help explain how psychological and/or physiological stress in pregnant women triggers idiopathic preterm birth. A research team at the USF Health Morsani College of Medicine Department of Obstetrics and Gynecology shows how cortisol — the “fight-or-flight” hormone critical for regulating the body’s response to stress — acts through stress-responsive protein FKBP51 binding to progesterone receptors to inhibit receptor function in the uterus. This reduced progesterone receptor activity stimulates labor.

The findings were published online first March 8 in Proceedings of the National Academy of Sciences (PNAS).

“This new study fills in some longstanding mechanistic gaps in our understanding of how normal labor begins and how stress causes preterm birth,” said the paper’s senior author Charles J. Lockwood, MD, senior vice president of USF Health, dean of the USF Health Morsani College of Medicine, and a professor of obstetrics and gynecology specializing in maternal-fetal medicine.

Dr. Lockwood was a co-principal investigator for the study along with the paper’s lead author Ozlem Guzeloglu-Kayisli, PhD, a USF Health associate professor of obstetrics and gynecology. Nihan Semerci, MSc, a senior biological scientist, shares the lead authorship with Dr. Guzeloglu-Kayisli.

The preclinical study providing molecular insights into maternal stress and preterm birth of unknown cause was led by USF Health’s Charles J. Lockwood, MD, (above) and Ozlem Guzeloglu-Kayisli, PhD. | Photos by Freddie Coleman and Allison Long, USF Health Communications

Progesterone reduces contractions of the uterus and sustained levels are essential to prevent a baby from being born too early. Reduced uterine progesterone receptor expression and signaling stimulates labor. In the brain, elevated FKBP51 expression has been strongly associated with increased risk for stress-related disorders.

Previous work by the USF Health team showed that normal human labor starting at term (between 37 and 42 weeks of pregnancy) was associated with reduced expression of progesterone receptors and increased expression of FKBP51, specifically in maternal decidual cells (specialized cells lining the uterus).

For the current study focused on maternal stress-induced idiopathic preterm birth, the researchers combined experiments in human maternal decidual cells and a mouse model in which FKBP5, the gene that makes FKBP51, had been removed, or “knocked out.” Altogether, their results revealed a novel functional progesterone withdrawal mechanism, mediated by maternal stress-induced uterine FKBP51 overexpression and enhanced FKPB51-progesterone receptor binding, that decreased progestational effects and triggered preterm birth. The researchers found that Fkbp5 knockout mice (with depletion of the gene encoding for FKBP51) exhibit prolonged gestation and are completely resistant to maternal stress-induced preterm birth.

Among the USF Health team’s key findings:

– FKPB51 levels were greater and FKPB51 binding to progesterone receptors was significantly increased in the decidual cells of women with idiopathic preterm birth, compared to decidual cells of gestational age-matched controls.

– The study reports for the first time that Fkbp5-deficient (knockout) mice are completely resistant to maternal stress-induced preterm birth and exhibit prolonged pregnancies accompanied by slower decline in systemic progesterone levels. This indicates that FKBP51 plays a crucial role in the length of pregnancy and initiation of labor and delivery.

– In contrast, mice with the FKPB5 gene intact and normal levels of FKPB51 protein (wild type mice) delivered earlier when exposed to maternal stress than either non-stressed wild type mice or FKPB5 knockout mice under nonstressed or stressed conditions.

“Collectively, these results suggest that FKBP51 plays a pivotal role both in term labor and stress-associated preterm parturition (birth) and that inhibition of FKBP51 may prove to be a novel therapy to prevent idiopathic preterm birth,” the study authors conclude.

Dr. Guzeloglu-Kayisli (center) in the Ob-Gyn research team’s laboratory, USF Health Morsani College of Medicine, with MCOM maternal-fetal medicine fellow Anthony Kendle, MD (left) and biological scientist Xiaofang Guo (right), who are isolating tissue samples | Photo by Allison Long, USF Health Communications.

Currently, injectable progesterone is the only drug approved to help prevent preterm birth in high-risk women who have had a previous preterm birth. However, its effectiveness was not confirmed by a recent large clinical trial, sparking debate in the health care community.  The authors finding that progesterone receptor activity was reduced in idiopathic preterm birth may explain the apparent lack of effectiveness of supplemental progesterone.

Babies born before 37 weeks, particularly those born before 34 weeks, have more health problems and may face long-term health complications, including childhood lung or heart disease and neurodevelopmental delays, Dr. Guzeloglu-Kayisli said. The likelihood of poor outcomes decreases as gestational age (length of the pregnancy) increases.

“Prevention of idiopathic preterm birth by extending gestation even two or three weeks can benefit the newborn, because it provides critical time needed for the fetus’s lungs and brain to mature,” Dr. Guzeloglu-Kayisli said. “Our research indicates the importance of investigating the potential use of FKBP51 inhibitors as a targeted therapy to reduce the risk of stress-related preterm birth.”

The USF Health study was supported in part by The March of Dimes Prematurity Research Center Ohio Collaborative grant.

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Findings correlate with clinical observations of more fetal abnormalities and other Zika-related health problems in late versus early pregnancy

Tampa, FL (Feb. 2, 2021) — A preclinical study by a University of South Florida Health (USF Health) Morsani College of Medicine research team has discovered a new mechanism for how Zika virus passes from mothers to their children during pregnancy – a process known as vertical transmission.

The researchers showed, for the first time, that specialized cells lining the uterus (maternal decidual cells) act as reservoirs for trimester-dependent transmission of the virus through the placenta – accounting for both the fetus’s greater susceptibility to first-trimester Zika infection and for the more serious congenital defects observed in early versus late pregnancy. They also report that the agent tizoxanide inhibits ZIKA virus in maternal decidual cells grown in the lab, offering promise for preventing perinatal transmission that can cause devastating malformations and brain damage in developing fetuses and infants.

The findings appeared Dec. 1, 2020 in the Journal of Immunology.

The study was led by co-principal investigators Ozlem Guzeloglu-Kayisli, PhD, a USF Health associate professor of obstetrics and gynecology, and Charles J. Lockwood, MD, USF Health senior vice president, dean of the Morsani College of Medicine, and a professor of obstetrics and gynecology specializing in maternal-fetal medicine.

“If we can better understand Zika virus vertical transmission and successfully block infection in maternal (decidual) cells early in the pregnancy, the virus will not pass through the placenta to reach the fetus and it is less likely to cause severe abnormalities,” said Dr. Guzeloglu-Kayisli, the paper’s lead author.

Ozlem Guzeloglu-Kayisli, PhD, USF Health associate professor of obstetrics and gynecology, was the paper’s lead author.| Photo by Allison Long, USF Health Communications and Marketing

Charles J. Lockwood, MD, dean of the USF Health Morsani College of Medicine and a professor of obstetrics and gynecology specializing in maternal-fetal medicine, was a co-principal investigator for the Zika study along with Dr. Guzeloglu-Kayisli. | Photo by Freddie Coleman, USF Health Communications and Marketing

The widespread global alarm caused by the spread of mosquito-borne Zika virus throughout the Americas in 2015-2016 dissipated after the virus all but disappeared in 2017. Yet, resurgence remains possible in areas where the Aedes aegypti mosquito is prevalent, and there is no treatment or vaccine available for Zika virus infection.

While most Zika-infected adults show no symptoms, the virus can cause minor flu-like symptoms, and in rare cases has been associated with Guillain-Barre syndrome. However, Zika poses the most concern for pregnant women, because up to one in 10 newborns of affected mothers suffer Zika-associated birth defects, including smaller than normal head size (microcephaly) that can lead to developmental disabilities and other health problems. Zika has also been linked to pregnancy complications, including preterm birth, preeclampsia and miscarriage. Moreover, timing appears important. Mothers infected in the first trimester are much more likely to have babies with severe Zika birth defects than mothers infected in the third semester.

The placenta, the organ supplying maternal oxygen and nutrients to the growing fetus, has ways to prevent most pathogens, including viruses, from crossing its protective maternal-fetal barrier. A subtype of fetally-derived placental cells known as syncytiotrophoblasts, in direct contact with maternal blood, are assumed to be the site where the Zika virus enters the placenta, leading to potential fetal infection. However, Dr. Ozlem Guzeloglu-Kayisli said, these particular trophoblasts resist Zika virus attachment and replication.

Above and close-up below: A model for mother-to-fetus transmission of Zika virus (green particles) through maternal decidual cell-mediated infection of villi attaching the placenta to the endometrium (uterine lining). | Images courtesy of USF Health first appeared in the Journal of Immunology: doi: 10.4049/jimmunol.2000713

To learn more about how Zika gets through the placental wall, the USF Health team began by investigating the cellular and molecular mediators of Zika virus replication. Among their key findings, the researchers:

–  Showed that specialized uterine cells from both pregnant and nonpregnant women were highly infectable by Zika virus. These immunologically active decidual cells, which line the uterus in preparation for and during pregnancy, form the maternal part of the placenta closest to the fetus.

–  Identified a more than 10,000-fold higher expression of the Zika virus attachment-entry receptor in the maternal decidual cells than in the fetal trophoblasts. Once inside the maternal cells, the Zika virus (an RNA virus) hijacks the cellular machinery to make proteins needed to copy its genetic material and churn out new viral particles. The proliferation of viral particles released from the maternal cells are then transmitted through branch-like vascular projections (villi) on the placenta’s surface layer where they can infect fetal trophoblast cells otherwise resistant to Zika virus.

–  Found that the efficiency of viral replication was significantly greater in first-trimester decidual cells than in those from term pregnancies.

–  Concluded that maternal (decidual) cells likely serve as the source for initial Zika virus infection and enhance subsequent transmission through the placenta to the fetus. “Moreover, trimester-dependent responses of decidual cells to Zika virus help to explain why pregnant women are susceptible to Zika infection and why the subsequent effects are more detrimental in the first trimester than in late pregnancy,” the study authors wrote.

–  Demonstrated that tizoxanide, the active metabolite of FDA-approved antiparasitic drug nitazoxanide, effectively impeded Zika virus infection in both maternal decidual cells and fetal trophoblast cells. The drug has been shown preclinically to inhibit a broad range of flu-like viruses and is being tested clinically against coronavirus. The finding warrants further testing of tizoxanide to block perinatal transmission of Zika virus and thereby protect the fetus from harmful outcomes, the researchers conclude.

The team’s work was supported in part by a Zika Research Initiative grant from the Florida Department of Health.