25-Hydroxycholesterol Protects Host against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model.
Zika virus (ZIKV) has become a public health threat due to its global transmission and link to severe congenital disorders. The host immune responses to ZIKV infection have not been fully elucidated, and effective therapeutics are not currently available. Herein, we demonstrated that cholesterol-25-hydroxylase (CH25H) was induced in response to ZIKV infection and that its enzymatic product, 25-hydroxycholesterol (25HC), was a critical mediator of host protection against ZIKV. Synthetic 25HC addition inhibited ZIKV infection in vitro by blocking viral entry, and treatment with 25HC reduced viremia and conferred protection against ZIKV in mice and rhesus macaques. 25HC suppressed ZIKV infection and reduced tissue damage in human cortical organoids and the embryonic brain of the ZIKV-induced mouse microcephaly model. Our findings highlight the protective role of CH25H during ZIKV infection and the potential use of 25HC as a natural antiviral agent to combat ZIKV infection and prevent ZIKV-associated outcomes, such as microcephaly.
Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China; Suzhou Institute of Systems Medicine, Suzhou, 215123 Jiangsu, China; Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 100071 Beijing, China.
Chunfeng
C
Li
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 100071 Beijing, China.
Yong-Qiang
YQ
Deng
State Key Laboratory of Molecular Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences; Parkinson's Disease Center, Beijing Institute for Brain Disorders, 100101 Beijing, China.
Shuo
S
Wang
Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China; Suzhou Institute of Systems Medicine, Suzhou, 215123 Jiangsu, China; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
Feng
F
Ma
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
Roghiyh
R
Aliyari
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 100071 Beijing, China.
Xing-Yao
XY
Huang
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 100071 Beijing, China; Guangxi Medical University, 530021 Nanning, China.
Na-Na
NN
Zhang
Department of Neurobiology and Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA.
Momoko
M
Watanabe
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 100071 Beijing, China.
Hao-Long
HL
Dong
CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, 100101 Beijing, China.
Ping
P
Liu
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 100071 Beijing, China.
Xiao-Feng
XF
Li
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 100071 Beijing, China.
Qing
Q
Ye
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 100071 Beijing, China; Beijing Traditional Medicine Chinese Hospital, Capital Medical University, 100069 Beijing, China.
Min
M
Tian
State Key Laboratory of Molecular Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences; Parkinson's Disease Center, Beijing Institute for Brain Disorders, 100101 Beijing, China.
Shuai
S
Hong
State Key Laboratory of Molecular Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences; Parkinson's Disease Center, Beijing Institute for Brain Disorders, 100101 Beijing, China.
Junwan
J
Fan
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 100071 Beijing, China.
Hui
H
Zhao
CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, 100101 Beijing, China.
Lili
L
Li
Department of Neurobiology and Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA.
Neda
N
Vishlaghi
Department of Neurobiology and Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA.
Jessie E
JE
Buth
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
Connie
C
Au
CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, 100101 Beijing, China.
Ying
Y
Liu
CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, 100101 Beijing, China.
Ning
N
Lu
CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, 100101 Beijing, China.
Peishuang
P
Du
Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China; Suzhou Institute of Systems Medicine, Suzhou, 215123 Jiangsu, China.
F Xiao-Feng
FX
Qin
CAS Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Science, 430071 Wuhan, China.
Bo
B
Zhang
Department of Molecular and Medical Pharmacology and California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Danyang
D
Gong
Department of Molecular and Medical Pharmacology and California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Xinghong
X
Dai
Department of Molecular and Medical Pharmacology and California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Ren
R
Sun
Department of Neurobiology and Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA. Electronic address: bnovitch@ucla.edu.
Bennett G
BG
Novitch
State Key Laboratory of Molecular Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences; Parkinson's Disease Center, Beijing Institute for Brain Disorders, 100101 Beijing, China. Electronic address: zhxu@genetics.ac.cn.
Zhiheng
Z
Xu
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 100071 Beijing, China; Guangxi Medical University, 530021 Nanning, China. Electronic address: qincf@bmi.ac.cn.
Cheng-Feng
CF
Qin
Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China; Suzhou Institute of Systems Medicine, Suzhou, 215123 Jiangsu, China; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA. Electronic address: gcheng@mednet.ucla.edu.
Genhong
G
Cheng
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D008253:Macaca mulatta; D051379:Mice; D008831:Microcephaly / Q000821:virology*; D018613:Microscopy, Confocal; D053586:Virus Internalization / Q000187:drug effects; D000071244:Zika Virus / Q000187:drug effects / Q000502:physiology; D000071243:Zika Virus Infection / Q000150:complications*
D000998:Antiviral Agents; D006888:Hydroxycholesterols; C007997:25-hydroxycholesterol
25HC; CH25H; ZIKV; antiviral immunity; microcephaly