Abstract

Recent studies have shown that dengue virus (DENV) infection during pregnancy is linked to adverse pregnancy outcomes, presenting an emerging clinical challenge with poorly understood pathogenic mechanisms. Uterine vascular remodeling, a critical determinant of successful pregnancy, is predominantly regulated by uterine natural killer (uNK) cells. In this study, we explored the effect of uNK cells on uterine injury in a DENV-induced adverse pregnancy mouse model. Transcriptomic analysis revealed significant dysregulation of uterine vascular remodeling and immune response-related gene expression after DENV-2 infection. Histopathological analysis revealed vascular remodeling disorders characterized by the preservation of vascular smooth muscle and a high level of tight junction protein in the vascular wall, accompanied by abnormal dilation of the lumen. These structural abnormalities coincided with a marked increase in uNK cell infiltration in the uterus. Moreover, the depletion of NK cells with anti-Asialo-GM1 mitigated uterine vascular damage and improved pregnancy outcomes. Single-cell RNA sequencing revealed a subpopulation of uNK cells (uNK2) that is characterized by upregulated expression of cytotoxicity-related genes. We further revealed that monocytes/macrophages (Mon_Macro) serve as intermediates in uNK2-mediated neutrophil (NE) recruitment. The SPP1–CD44 signaling axis is the dominant pathway governing uNK2-Mon_Macro crosstalk, and activated Mon_Macro2 can secrete chemokines such as CXCL2 to recruit NE. These findings provide valuable insights into the pathogenesis of DENV-induced uterine injury and facilitate the development of targeted therapeutic interventions for DENV-associated gestational disorders.