Prenatal Zika virus exposure causes long-term, sex-specific immune changes in offspring, study finds

DETROIT — A team of researchers at the C.S. Mott Center for Human Growth and Development at Wayne State University has uncovered how exposure to the Zika virus during pregnancy can cause lasting, sex-specific changes to a child’s immune system, even when no birth defects are apparent. The findings published Oct. 3, 2025, in Nature Communications, revealed that Zika infection during pregnancy disrupts the development of immune cells that serve as the body’s first line of defense against infection.

The study, “Prenatal exposure to Zika virus shapes offspring neutrophil function in a sex-specific manner,” was led by Dr. Jiahui Ding, assistant professor of obstetrics and gynecology in Wayne State’s School of Medicine.

“We discovered that when a pregnant mother is infected with Zika virus, the resulting inflammatory response in the placenta permanently changes how the offspring’s immune system develops,” said Ding. “This occurs even if the infection is mild or asymptomatic in the mother and does not lead to obvious congenital birth defects in the offspring.”

The research team found that male offspring were particularly vulnerable to the effects of prenatal Zika exposure. Male mice exhibited slower growth and an exaggerated, delayed inflammatory response when later challenged with infection, suggesting a greater risk for chronic inflammation and tissue damage later in life.

The researchers found that the virus does not reach the fetus in this model. Instead, the placenta’s immune response – not direct viral infection – was responsible for programming long-term immune changes in the offspring. Male placentas showed stronger activation of immune-related signaling pathways such as IFN-β and IL-1β, while female placentas demonstrated more metabolic adaptations.

At the cellular level, the team observed that neutrophils, the immune system’s “first responder” cells, were less effective in offspring exposed to Zika in utero. These neutrophils had reduced production of reactive oxygen species and defective NETosis – the process by which neutrophils release web-like structures (NETs) to capture pathogens. The researchers also identified A20 (Tnfaip3) as a key sex-dimorphic regulator of neutrophil activation, whose upregulation in males dampened inflammatory responses and promoted cell survival.

“Our research showed that prenatal exposure to Zika virus can increase a child’s susceptibility to infections and inflammatory diseases later in life, even when they appear healthy at birth,” said Ding. “While we focused on Zika, these findings may also apply to other viral infections, including COVID-19, emphasizing the need for long-term monitoring of virus-exposed children and prevention of infections during pregnancy.”

Dr. Gil Mor, scientific director of the C.S. Mott Center for Human Growth and Development, emphasized the broader significance of these findings.

“This study exemplifies the Mott Center’s mission to understand how events during pregnancy influence lifelong health and disease,” said Mor. “By uncovering how a transient viral exposure can reprogram the fetal immune system in a sex-specific manner, we gain critical insight into the origins of immune-related diseases, from chronic inflammation to autoimmunity. These findings help us connect prenatal environmental exposures with health outcomes later in life.”

This work not only deepens understanding of fetal immune programming, but also underscores the importance of maternal health and viral prevention strategies to safeguard future generations.

Other Wayne State University researchers involved in the study include Anna Hu, Annie Thy Nguyen, Grace M. Swanson, Aditi Singh, Nicholas Adzibolosu, Diana Manchorova, Elizabeth Findeis, Anthony Maxwell, Yuan He, Marta Rodriguez Garcia and Mor.

Funding for the study was provided by NIH grant NIAID 5R01AI145829 (GM), 5P42ES030991 (GM Project 4), R01HD111146 (GM) and R00ES028734 (MP).

To read the full paper, visit https://www.nature.com/articles/s41467-025-63941-x.

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Wayne State University is one of the nation’s pre-eminent public research universities in an urban setting. Through its multidisciplinary approach to research and education, and its ongoing collaboration with government, industry and other institutions, the university seeks to enhance economic growth and improve the quality of life in the city of Detroit, state of Michigan and throughout the world. For more information about research at Wayne State University, visit research.wayne.edu.