Give credit to your dad’s gene for keeping you safe during those long months in your mother’s womb.

Because without this genetic warrior, you might have succumbed to any number of viral infections that otherwise could be fatal to a fetus. A new paper published this week in the journal Cell Host & Microbe explains the mechanisms behind this anti-viral protection.

Hana Totary-Jain, PhD, associate professor of Molecular Pharmacology and Physiology and Heart Institute at the USF Health Morsani College of Medicine

“What’s unique about this gene is how it produces a form of defense for the baby in the womb,’’ said Hana Totary-Jain, PhD., associate professor of Molecular Pharmacology and Physiology and Heart Institute at the USF Health Morsani College of Medicine and senior author of the paper.

Their research focused on viruses that affect a pregnant mother and consequently her fetus, which are highly vulnerable to infection because their immune systems are immature. Some viruses, including Zika, rubella, and other serious infections, are rarely transmitted from mother to fetus in utero and can cause devastating consequences.

But the biological processes that protect a fetus from most viral infections are less clear. In the new paper, titled “SINE RNA of the imprinted miRNA clusters mediates constitutive type III interferon expression and antiviral protection in hemochorial placentas,’’ Dr. Totary-Jain and her team describe how a certain gene in the placenta is always armed for the battle.

“The placenta, in human and in mouse, is the first organ the fetus develops, and it is constantly exposed to maternal blood. This increases the chances of transmitting viral infections from the mother to the fetus. Therefore, the placenta has evolved robust defense mechanisms to prevent this transmission. We discovered a gene in the placenta that is expressed only from the paternal allele and produces a viral mimicry response. It tricks the placenta into thinking it’s infected and induces a constant state of antiviral defense”, Dr. Totary-Jain explained.

“So when we turned on this gene in other cells, we could protect the cells from several viruses. This is evolution’s way of protecting the baby. Without it, chances are you wouldn’t have made it into childbirth.’’

Ishani Wickramage, a PhD candidate in Dr. Totary-Jain’s laboratory and a lead author of the study added: “This research fills the gap in our knowledge about how many viruses that may infect a pregnant mother, including SARS-CoV-2, only rarely affect the fetus.’’

“Learning more about how the placenta shields the fetus from viruses also has important implications beyond childbirth,” said Dr. Charles Lockwood, MD, MHCM, one of the paper’s authors, who also is dean of the Morsani College of Medicine and executive vice president of USF Health.

“This is a novel placental mechanism that protects the developing fetus from transplacental transmission of most viruses,” Dr. Lockwood said. “This is the kind of knowledge that could lead to the development of new anti-viral medications to fight viruses that can be deadly for fetuses and newborn babies.”

This work was supported by a grant from the National Institutes of Health. Dr. Totary-Jain and a team of researchers at USF spent five years investigating this intriguing phenomenon in collaboration with Dr. Thomas Tuschl’s lab at Rockefeller University, who performed the sRNAseq and bioinformatic analysis, including researcher Klaas Max and Kemel Akat; and Drs. Kimiko Inoue and Atsuo Ogura from RIKEN and University of Tsukuba, Japan, who provided the mouse model that was used to show that the mouse placenta also developed the same mechanism to protect the fetus from viral infections.

Other USF Health members of the research team are: Jeffrey VanWye; John H. Lockhart; Ismet Hortu; Ezinne F. Mong; John Canfield; Hiran M. Lamabadu Warnakulasuriya Patabendige; Ozlem Guzeloglu-Kayisli; and Umit A. Kayisli.

— Story by Kurt Loft for USF Health News

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.