Significance: Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality. The genetics and molecular characteristics of PTB remain unclear. FKBP51 is an important mediator of the stress response and is implicated in the etiology of stress-related disorders. By combining studies in humans and Fkbp5 ^−/− mice, we show that maternal stress up-regulates FKBP51 levels and enhances binding of FKBP51 to progesterone receptors. FKBP51 binding to progesterone receptors reduces progesterone receptor activity by causing functional progesterone withdrawal that induces PTB. In contrast, Fkbp5 ^−/− mice are resistant to maternal stress–induced PTB and exhibit prolonged gestation. These findings provide molecular insights into stress-related PTB, indicating the importance of the potential use of inhibitor(s) against FKBP51 to treat PTB in future studies.

Vertical transmission of the Zika virus (ZIKV) causes severe fetal defects, but the exact pathogenic mechanism is unclear. We identified up to a 10,480-fold higher expression of viral attachment factors AXL, GAS6, and PROS1 and a 3880-fold increase in ZIKV infectiousness/propagation in human term decidual stromal cells versus trophoblasts. Moreover, levels of viral attachment factors and ZIKV are significantly increased, whereas expression of innate immune response genes are significantly decreased, in human first trimester versus term decidual cells. ZIKV-infected decidual cell supernatants increased cytotrophoblasts infection up to 252-fold compared with directly infected cytotrophoblasts. Tizoxanide treatment efficiently inhibited Zika infection in both maternal and fetal cells. We conclude that ZIKV permissiveness, as well as innate immune responsiveness of human decidual cells, are gestational age dependent, and decidual cells augment ZIKV infection of primary human cytotrophoblast cultures, which are otherwise ZIKV resistant. Human decidual cells may act as reservoirs for trimester-dependent placental transmission of ZIKV, accounting for the higher Zika infection susceptibility and more severe fetal sequelae observed in early versus late pregnancy. Moreover, tizoxanide is a promising agent in preventing perinatal Zika transmission as well as other RNA viruses such as coronavirus. Key Points ZIKV permissiveness of decidual cells is gestational age dependent. ZIKV-infected DC supernatants enhance ZIKV infection of trophoblasts. Tizoxanide inhibits ZIKV infection of both decidual and trophoblast cells.

Context: Unchanging plasma progesterone (P4) levels suggest that human labor is initiated by reduced P4 receptor (PR) expression, which elicits functional P4 withdrawal. The glucocorticoid receptor (GR) is also implicated in this process. Objective: Our objective was to compare PR and GR staining in human decidual cells (DCs) and interstitial trophoblasts (ITs) of gestational age-matched pre- and postcontraction specimens and to evaluate steroid effects on PR and GR expression in human DC cultures. Interventions and Main Outcome Measures: Decidua basalis and parietalis sections were immunostained for PR or GR and then for the cytoplasmic DC and IT markers vimentin and cytokeratin. Western blotting measured PR and GR levels in nuclear extracts of cultured leukocyte-free term DCs after incubation with estradiol-17β (E2) with or without medroxyprogesterone acetate (MPA). Results: PR histological scores (HSCOREs) were significantly higher in DC nuclei from pre- vs. post-uterine-contraction decidua basalis and parietalis sections with PR immunostaining absent from ITs. In contrast, immunoreactive GR was localized in IT and DC nuclei. GR HSCORES were significantly higher in ITs than DCs but similar in pre- vs. post-uterine-contraction specimens. In term DC monolayers, PR-A and PR-B were enhanced by E2 and inhibited by MPA, whereas E2 plus MPA produced intermediate PR expression. The GR was constitutively expressed. Conclusions: In post- vs. pre-uterine-contraction specimens, significantly lower HSCOREs in DC nuclei, but not IT, and unchanging GR levels in DCs and ITs suggest that functional P4 withdrawal may occur in DCs and is unlikely to involve the GR. Nuclear extracts from DC monolayer cultures express steroid-regulated PR-A and PR-B and constitutive GR.