Immunopathogenesis and pathological features of NADC34-like PRRSV infection in pregnant sows during late gestation.

The recently emerged NADC34-like PRRSV-2 strain (Lineage 1A) has been increasingly linked to severe reproductive failures in sow herds, yet its immunopathogenic mechanisms remain poorly understood, especially in pregnant sow models. In this study, we compared the pathogenic and immunological characteristics of a NADC34-like isolate (JBNU-22-N01) with a prevalent NADC30-like strain (PJ73, Lineage 1C) in pregnant sows during late gestation. JBNU-22-N01 infection resulted in earlier peak viremia, more severe maternal pathology, and greater fetal growth restriction compared with PJ73, despite comparable overall fetal viral loads. Notably, JBNU-22-N01-infected fetuses were overrepresented in high viral burden clusters, suggesting enhanced transplacental viral transmission. Transcriptomic and cytokine profiling at the maternal-fetal interface revealed strain-specific downregulation of epithelial junction genes (e.g., CLDN1, CDH1) and immune effector genes in JBNU-22-N01 infection, accompanied by elevated local IFN-α but attenuated immune activation. In contrast, PJ73 elicited more robust antiviral transcriptional responses. Additionally, JBNU-22-N01 infection induced a higher serum kynurenine/tryptophan ratio, indicative of systemic activation of the immunosuppressive kynurenine pathway, which may have contributed to local immune dampening at the maternal-fetal interface. Cytokine analyses across maternal and fetal compartments demonstrated compartmentalized regulation, with maternal cytokine expression shaped by viral strain and fetal cytokine responses more strongly correlated with absolute viral burden. Together, these findings suggest that NADC34-like PRRSV impairs maternal barrier and immune defenses via local and systemic modulation, facilitating fetal infection and compromise. This study expands our understanding of immunopathogenic mechanisms driving PRRSV-induced reproductive failure during late gestation and provides insights for future vaccine development strategies.