中性粒细胞浸润通过损害登革热病毒感染的妊娠小鼠胎盘血管导致胎儿生长受限。

Neutrophil infiltration leads to fetal growth restriction by impairing the placental vasculature in DENV-infected pregnant mice.

机构信息

Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China; Department of Blood Transfusion, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.

出版信息

EBioMedicine. 2023 Sep;95:104739. doi: 10.1016/j.ebiom.2023.104739. Epub 2023 Aug 4.

DOI:10.1016/j.ebiom.2023.104739

PMID:37544202

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10432184/

Abstract

BACKGROUND

Dengue virus (DENV) infection during pregnancy increases the risk of adverse fetal outcomes, which has become a new clinical challenge. However, the underlying mechanism remains unknown.

METHODS

The effect of DENV-2 infection on fetuses was investigated using pregnant interferon α/β receptor-deficient (Ifnar1) mice. The histopathological changes in the placentas were analyzed by morphological techniques. A mouse inflammation array was used to detect the cytokine and chemokine profiles in the serum and placenta. The infiltration characteristics of inflammatory cells in the placentas were evaluated by single-cell RNA sequencing.

FINDINGS

Fetal growth restriction observed in DENV-2 infection was mainly caused by the destruction of the placental vasculature rather than direct damage from the virus in our mouse model. After infection, neutrophil infiltration into the placenta disrupts the expression profile of matrix metalloproteinases, which leads to placental dysvascularization and insufficiency. Notably, similar histopathological changes were observed in the placentas from DENV-infected puerperae.

INTERPRETATION

Neutrophils play key roles in placental histopathological damage during DENV infection, which indicates that interfering with aberrant neutrophil infiltration into the placenta may be an important therapeutic target for adverse pregnancy outcomes in DENV infection.

FUNDING

The National Key Research and Development Plans of China (2021YFC2300200-02 to J.A., 2019YFC0121905 to Q.Z.C.), the National Natural Science Foundation of China (NSFC) (U1902210 and 81972979 to J. A., 81902048 to Z. Y. S., and 82172266 to P.G.W.), and the Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan, China (IDHT20190510 to J. A.).

摘要

背景

登革病毒（DENV）感染孕妇会增加不良胎儿结局的风险，这已成为新的临床挑战。然而，其潜在机制尚不清楚。

方法

利用妊娠干扰素 α/β 受体缺陷（Ifnar1）小鼠研究 DENV-2 感染对胎儿的影响。采用形态学技术分析胎盘的组织病理学变化。利用小鼠炎症基因芯片检测血清和胎盘细胞因子和趋化因子谱。利用单细胞 RNA 测序评估胎盘炎症细胞的浸润特征。

结果

在我们的小鼠模型中，DENV-2 感染导致的胎儿生长受限主要是由胎盘血管破坏引起的，而不是病毒的直接损伤。感染后，中性粒细胞浸润胎盘破坏了基质金属蛋白酶的表达谱，导致胎盘血管发育不良和功能不全。值得注意的是，在 DENV 感染的产妇胎盘中也观察到了类似的组织病理学变化。

结论

中性粒细胞在 DENV 感染时胎盘组织病理学损伤中起关键作用，这表明干扰异常中性粒细胞浸润胎盘可能是 DENV 感染不良妊娠结局的重要治疗靶点。

资助

国家重点研发计划（2021YFC2300200-02 给 J.A.，2019YFC0121905 给 Q.Z.C.），国家自然科学基金（NSFC）（U1902210 和 81972979 给 J.A.，81902048 给 Z.Y.S.，82172266 给 P.G.W.），以及中国“十四五”期间北京高校高水平教师队伍建设支持计划（IDHT20190510 给 J.A.）。