SARS-CoV-2 treatment effects induced by ACE2-expressing microparticles are explained by the oxidized cholesterolincreased endosomal pH of alveolar macrophages  

作　　者：Zhenfeng Wang Jiadi Lv Pin Yu Yajin Qu Yabo Zhou Li Zhou Qiangqiang Zhu Shunshun Li Jiangping Song Wei Deng Ran Gao Yuying Liu Jiangning Liu Wei-Min Tong Chuan Qin Bo Huang 

机构地区：[1]Department of Immunology&National Key Laboratory of Medical Molecular Biology,Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences(CAMS)&Peking Union Medical College,Beijing 100005,China [2]NHC Key Laboratory of Human Disease Comparative Medicine,Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases,Institute of Laboratory Animal Science,CAMS and Comparative Medicine Center,Peking Union Medical College,Beijing,China [3]State Key Laboratory of Cardiovascular Disease,Fuwai Hospital,National Center for Cardiovascular Diseases,CAMS and Peking Union Medical College,Beijing,China [4]Department of Pathology,Institute of Basic Medical Sciences,CAMS and Peking Union Medical College,Beijing,China [5]Department of Biochemistry&Molecular Biology,Tongji Medical College,Huazhong University of Science&Technology,Wuhan 430030,China

出　　处：《Cellular & Molecular Immunology》2022年第2期210-221,共12页中国免疫学杂志（英文版）

基　　金：supported by the National Natural Science Foundation of China(81788101,91942314);CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-021).

摘　　要：Exploring the cross-talk between the immune system and advanced biomaterials to treat SARS-CoV-2 infection is a promising strategy.Here,we show that ACE2-overexpressing A549 cell-derived microparticles(AO-MPs)are a potential therapeutic agent against SARS-CoV-2 infection.Intranasally administered AO-MPs dexterously navigate the anatomical and biological features of the lungs to enter the alveoli and are taken up by alveolar macrophages(AMs).Then,AO-MPs increase the endosomal pH but decrease the lysosomal pH in AMs,thus escorting bound SARS-CoV-2 from phago-endosomes to lysosomes for degradation.This pH regulation is attributable to oxidized cholesterol,which is enriched in AO-MPs and translocated to endosomal membranes,thus interfering with proton pumps and impairing endosomal acidification.In addition to promoting viral degradation,AO-MPs also inhibit the proinflammatory phenotype of AMs,leading to increased treatment efficacy in a SARS-CoV-2-infected mouse model without side effects.These findings highlight the potential use of AO-MPs to treat SARS-CoV-2-infected patients and showcase the feasibility of MP therapies for combatting emerging respiratory viruses in the future.

关 键 词：SARS-CoV-2 MICROPARTICLES Alveolar macrophages ENDOSOMES LYSOSOMES 

分 类 号：R563.1[医药卫生—呼吸系统]