Neutrophil infiltration leads to fetal growth restriction by impairing the placental vasculature in DENV-infected pregnant miceResearch in context
Yingying Zhang,
Ziyang Sheng,
Qiaozhu Chen,
Anni Zhou,
Jiaying Cao,
Feiyang Xue,
Yanzhen Ye,
Na Wu,
Na Gao,
Dongying Fan,
Libo Liu,
Yuetong Li,
Peigang Wang,
Li Liang,
Deshan Zhou,
Fuchun Zhang,
Fang Li,
Jing An
Affiliations
Yingying Zhang
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
Ziyang Sheng
Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China; Corresponding author.
Qiaozhu Chen
Department of Ob&Gyn, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
Anni Zhou
Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Department of Gastroenterology, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
Jiaying Cao
Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
Feiyang Xue
Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
Yanzhen Ye
Department of Obstetrics and Gynecology, People's Hospital of Nanhai District, Foshan City, 528200, Guangdong, China
Na Wu
Laboratory Animal Center, Capital Medical University, Beijing, 100069, China
Na Gao
Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
Dongying Fan
Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
Libo Liu
Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
Yuetong Li
Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
Peigang Wang
Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
Li Liang
Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
Deshan Zhou
Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Fuchun Zhang
Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
Fang Li
Department of Ob&Gyn, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China; Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China; Corresponding author. Department of Ob&Gyn, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
Jing An
Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China; Corresponding author.
Summary: 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.).
