The CH24H metabolite, 24HC, blocks viral entry by disrupting intracellular cholesterol homeostasis
Yueming Yuan,
An Fang,
Zongmei Wang,
Zhihui Wang,
Baokun Sui,
Yunkai Zhu,
Yuan Zhang,
Caiqian Wang,
Rong Zhang,
Ming Zhou,
Huanchun Chen,
Zhen F. Fu,
Ling Zhao
Affiliations
Yueming Yuan
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China; Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
An Fang
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China; Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
Zongmei Wang
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China; Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
Zhihui Wang
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China; Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
Baokun Sui
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China; Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
Yunkai Zhu
School of Basic Medical Sciences, Fudan University, Shanghai, 200433, China
Yuan Zhang
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China; Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
Caiqian Wang
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China; Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
Rong Zhang
School of Basic Medical Sciences, Fudan University, Shanghai, 200433, China
Ming Zhou
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China; Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
Huanchun Chen
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China; Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
Zhen F. Fu
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China; Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China
Ling Zhao
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China; Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China; Corresponding author. State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China.
Cholesterol-24-hydroxylase (CH24H or Cyp46a1) is a reticulum-associated membrane protein that plays an irreplaceable role in cholesterol metabolism in the brain and has been well-studied in several neuro-associated diseases in recent years. In the present study, we found that CH24H expression can be induced by several neuroinvasive viruses, including vesicular stomatitis virus (VSV), rabies virus (RABV), Semliki Forest virus (SFV) and murine hepatitis virus (MHV). The CH24H metabolite, 24-hydroxycholesterol (24HC), also shows competence in inhibiting the replication of multiple viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 24HC can increase the cholesterol concentration in multivesicular body (MVB)/late endosome (LE) by disrupting the interaction between OSBP and VAPA, resulting in viral particles being trapped in MVB/LE, ultimately compromising VSV and RABV entry into host cells. These findings provide the first evidence that brain cholesterol oxidation products may play a critical role in viral infection.
