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Immunity. 2017 Mar 21;46(3):446-456. doi: 10.1016/j.immuni.2017.02.012. Epub 2017 Mar 14.

25-Hydroxycholesterol Protects Host against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model.

Author information

1
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.
2
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 100071 Beijing, China.
3
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.
4
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.
5
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
6
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.
7
Department of Neurobiology and Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA.
8
CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, 100101 Beijing, China.
9
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.
10
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.
11
CAS Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Science, 430071 Wuhan, China.
12
Department of Molecular and Medical Pharmacology and California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
13
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.
14
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.
15
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.
16
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.

Abstract

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.

KEYWORDS:

25HC; CH25H; ZIKV; antiviral immunity; microcephaly

PMID:
28314593
PMCID:
PMC5957489
DOI:
10.1016/j.immuni.2017.02.012
[Indexed for MEDLINE]
Free PMC Article

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