A new study from Wayne State University, published in Nature Communications, reveals that even when Zika virus does not infect the fetus directly, exposure during pregnancy can cause lasting, sex dependent changes in the immune system of the offspring.
Using a mouse model, the research team led by Dr. Jiahui Ding found that male offspring exposed to Zika before birth showed slower growth and a delayed but exaggerated inflammatory response to bacterial challenges. This suggests that males exposed to Zika in the womb may be more prone to chronic inflammation and tissue damage later in life.
The study also identified clear differences between male and female placental immune responses. Male placentas showed stronger activation of immune pathways such as interferon beta (IFN β) and interleukin 1 beta (IL 1β), whereas female placentas exhibited greater metabolic adaptation. The virus did not cross into the fetus; rather, the immune reaction in the placenta itself shaped immune development in the offspring.
The researchers focused on neutrophils, which are the body’s first responder immune cells. They found that neutrophils from both male and female offspring exposed to Zika were less effective. These cells produced fewer reactive oxygen species and formed weaker neutrophil extracellular traps (NETs), both of which are crucial for trapping and destroying pathogens.
A major finding was the involvement of A20 (Tnfaip3), a regulatory protein that controls inflammation. Male neutrophils had higher levels of A20, which appeared to suppress inflammatory activity and prolong cell survival, leading to immune imbalance and sex specific differences in outcomes.
Overall, the study shows that prenatal Zika exposure can increase vulnerability to infections and inflammatory diseases later in life, even in infants who seem healthy at birth. The findings highlight the importance of long term monitoring of children who were exposed to viral infections before birth.
Supporting earlier findings by Zanluqui and colleagues, the study reinforces that Zika infection can impair neutrophil function by reducing reactive oxygen species production and phagocytic activity, and by weakening NET formation. These mechanisms may underlie viral persistence and fetal susceptibility.
Although the research focused on Zika, the results may also apply to other viral infections such as COVID 19, underscoring the importance of preventing viral transmission during pregnancy. This study provides valuable insight into how prenatal viral exposure can leave a lasting imprint on the immune system and influence health across the lifespan.
References
- Ding, J., Hu, A., Nguyen, A.T. et al. Prenatal exposure to Zika virus shapes offspring neutrophil function in a sex-specific manner. Nat Commun 16, 8839 (2025).
- Zanluqui NG, Oliveira LG, Polonio CM, França TT, Souza GD, Muraro SP, et al. Zika Virus Infection of Murine and Human Neutrophils and their Function as Trojan Horses to the Placenta [Internet]. bioRxiv; 2021 [cited 2025 Oct 6]. p. 2021.09.14.460378.