Dissecting Zika Virus pathogenesis through maternal-fetal immune interactions and sex-based susceptibility 2260838

Abstract Introduction Despite extensive research on ZIKV vertical transmission and its threat to pregnant women and their babies, the mechanisms by which maternal inflammation may contribute to developmental impairments in the offspring remain unclear. This is crucial given growing evidence that maternal immune activation can have long-term effects on the progeny. Considering this, we aimed to demonstrate that ZIKV-induced maternal inflammation is important for its pathogenesis in the offspring. Methods Wild-type (WT) females, resistant to ZIKV, were mated with hSTAT2 knock-in (KI) males, generating offspring expressing hSTAT2 in fetal-derived tissues but not in the mother, creating ZIKV-susceptible fetuses within a resistant maternal environment. Conversely, hSTAT2 KI females (susceptible to ZIKV) were mated with WT males, generating both hSTAT2 KI and WT within a susceptible maternal environment. Pregnant females were infected at embryonic day 10.5. Results In hSTAT2 KI placentas, viral load was comparable between susceptible and resistant dams. However, placentas from susceptible dams showed higher inflammatory markers and increased CD11c+MHC-II+ and CD8+ T cells. A pronounced sex difference in female offspring revealed higher viral load, greater pro-inflammatory cytokine expression, and elevated NK1.1+ and CD8+ T lymphocytes in the placenta. This increased female susceptibility may be linked to higher AXL and lower type III interferon receptor expression in the placenta. After birth, offspring from susceptible dams showed increased vocalization, with females most affected. By four weeks, female offspring exhibited a higher frequency of effector CD8+, CD4+ T cells, and NK cells in the spleen, indicating a sex-specific immune impact of prenatal ZIKV exposure. Conclusion Maternal inflammation and sex-based susceptibility are relevant factors in ZIKV pathogenesis, emphasizing the need for long-term monitoring of prenatally exposed children beyond Congenital Zika Syndrome. Funding Source n/a Topic Categories Viral Immunology (VIR)