Wayne State Research Reveals Fetuses Exposed to Zika Virus Have Long-Term Immune Challenges

Newswise — DETROIT — A Wayne State University study published in the Oct. 3, 2025, issue of Nature Communications revealed that Zika virus exposure during pregnancy causes long-term, sex-specific changes to a baby’s immune system, particularly affecting the frontline immune cells that fight 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.”

Ding and her research team discovered that male offspring are more affected by Zika infection during pregnancy; when exposed to the Zika virus in the womb, they exhibited slower growth compared to control males. In addition, they showed an overly exaggerated and delayed inflammatory response when later challenged with a simulated bacterial infection. This finding suggests male offspring are at a higher risk for chronic inflammation and tissue damage later in life if they were exposed to the Zika virus before birth.

The research team also identified a sex-specific effect linked to how the placenta responded to the virus. Male placentas showed a stronger activation of immune-related signaling pathways (like IFN-β and IL-1β), whereas the female placenta showed more metabolic adaptations. In their mouse model, the virus did not reach the fetus. Instead, it was the placenta’s immune response that had the major effect on the developing offspring.

The function of neutrophils — the most critical “first responder” cells of the innate immune system — is compromised in Zika virus-exposed offspring of both sexes. The neutrophils showed a reduced reactive oxygen species production, which indicates being less effective at generating the necessary toxic chemicals required to kill the virus pathogens. The team also discovered a defective Neutrophil Extraceullar Trap (NET) formation that created an impaired ability to form the NET web-like structures used to capture and invade germs — a process called NETosis.

The team also pinpointed a protein called A20 (Tnfaip3) as a crucial sex-dimorphic regulator of neutrophil activation and survival. The upregulation of A20 specifically in male neutrophils after Zika virus exposure likely contributes to their dampened inflammatory response in vitro and helps promote neutrophil survival.

“Our research showed that prenatal exposure to Zika virus can increase a child’s susceptibility to infections and inflammatory diseases later in life compared to children who were not exposed to the virus,” said Ding.  “Our research shows that even children exposed to Zika virus before birth who appear healthy may have altered immune defenses that require long-term monitoring. While we focused on Zika, these findings may also apply to other viral infections, such as COVID-19, highlighting the importance of monitoring and supporting the immune system of virus-exposed children. In addition, our results underscore the ongoing need to prevent viral transmission, particularly in high-risk areas and among pregnant women.”

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 Gil Mor.

Funding for the study was provided by NIH grants R01AI145829-05 (GM), P42ES030991 (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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