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

Li, Chunfeng; Deng, Yong-Qiang; Wang, Shuo; Ma, Feng; Aliyari, Roghiyh; Huang, Xing‐Yao; Zhang, Nana; Watanabe, Momoko; Dong, Hao-Long; Liu, Ping; Li, Xiaofeng; Ye, Qing; Tian, Min; Hong, Shuai; Fan, Junwan; Zhao, Hui; Li, Lili; Vishlaghi, Neda; Buth, Jessie E.; Au, Connie; Liu, Ying; Lü, Ning; Du, Pu; Qin, F. Xiao-Feng; Zhang, Bo; Gong, Danyang; Dai, Xinghong; Sun, Ren; Novitch, Bennett G.; Xu, Zhiheng; Qin, Cheng‐Feng; Cheng, Genhong

doi:10.1016/j.immuni.2017.02.012

Cited by 292 publications

(311 citation statements)

References 49 publications

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“…CH25H converts cholesterol to 25-hydroxycholesterol (25HC), a soluble factor that blocks viral entry by inhibiting membrane fusion (Liu et al, 2013). The therapeutic potential for 25HC has been further demonstrated through our recent studies showing that administration to adult non-human primates and mice can reduce viremia and block ZIKV-induced fetal microcephaly when administered during pregnancy (Li et al, 2017). As 25HC is a natural defense protein against several viruses, we tested whether this mechanism could be augmented to alleviate ZIKV-induced cytopathy.…”

Section: Resultsmentioning

confidence: 99%

Self-Organized Cerebral Organoids with Human-Specific Features Predict Effective Drugs to Combat Zika Virus Infection

et al. 2017

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Summary The human cerebral cortex possesses distinct structural and functional features that are not found in the lower species traditionally used to model brain development and disease. Accordingly, considerable attention has been placed on the development of methods to direct pluripotent stem cells to form human brain-like structures termed organoids. However, many organoid differentiation protocols are inefficient and display marked variability in their ability to recapitulate the three-dimensional architecture and course of neurogenesis in the developing human brain. Here, we report optimized organoid culture methods that efficiently and reliably produce cortical and basal ganglia structures similar to those in the human fetal brain in vivo. Neurons within the organoids are functional and exhibit network-like activities. We further demonstrate the utility of this organoid system for modeling the teratogenic effects of Zika virus on the developing brain and identifying more susceptibility receptors and therapeutic compounds that can mitigate its destructive actions.

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Section: Resultsmentioning

confidence: 99%

Self-Organized Cerebral Organoids with Human-Specific Features Predict Effective Drugs to Combat Zika Virus Infection

et al. 2017

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“…Replicon assay. The ZIKV replicon containing the Renilla luciferase reporter gene was used for mutagenesis analysis (49). The mutants were generated using similar strategies for mutagenesis based on pACNR-GZ01-Intron-IC.…”

Section: Fig 5 Legend (Continued)mentioning

confidence: 99%

“…Here, we first explored the roles of SLA and CS elements with the replicon system of ZIKV (49), in which the structural genes were replaced by the Renilla luciferase reporter gene. Replicon RNAs were transfected into BHK-21 cells, and Renilla luciferase reporter activities were monitored at 6, 24, 48, and 72 h posttransfection (p.t.…”

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confidence: 99%

Characterization of cis -Acting RNA Elements of Zika Virus by Using a Self-Splicing Ribozyme-Dependent Infectious Clone

Liu

Huang

et al. 2017

J Virol

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Zika virus (ZIKV) has caused significant outbreaks and epidemics in the Americas recently, raising global concern due to its ability to cause microcephaly and other neurological complications. A stable and efficient infectious clone of ZIKV is urgently needed. However, the instability and toxicity of flavivirus cDNA clones in Escherichia coli hosts has hindered the development of ZIKV infectious clones. Here, using a novel self-splicing ribozyme-based strategy, we generated a stable infectious cDNA clone of a contemporary ZIKV strain imported from Venezuela to China in 2016. The constructed clone contained a modified version of the group II self-splicing intron P.li.LSUI2 near the junction between the E and NS1 genes, which were removed from the RNA transcripts by an easy-to-establish in vitro splicing reaction. Transfection of the spliced RNAs into BHK-21 cells led to the production of infectious progeny virus that resembled the parental virus. Finally, potential cis-acting RNA elements in ZIKV genomic RNA were identified based on this novel reverse genetics system, and the critical role of 5=-SLA promoter and 5=-3= cyclization sequences were characterized by a combination of different assays. Our results provide another stable and reliable reverse genetics system for ZIKV that will help study ZIKV infection and pathogenesis, and the novel self-splicing intron-based strategy could be further expanded for the construction of infectious clones from other emerging and reemerging flaviviruses.IMPORTANCE The ongoing Zika virus (ZIKV) outbreaks have drawn global concern due to the unexpected causal link to fetus microcephaly and other severe neurological complications. The infectious cDNA clones of ZIKV are critical for the research community to study the virus, understand the disease, and inform vaccine design and antiviral screening. A panel of existing technologies have been utilized to develop ZIKV infectious clones. Here, we successfully generated a stable infectious clone of a 2016 ZIKV strain using a novel self-splicing ribozyme-based technology that abolished the potential toxicity of ZIKV cDNA clones to the E. coli host. Moreover, two crucial cis-acting replication elements (5=-SLA and 5=-CS) of ZIKV were first identified using this novel reverse genetics system. This novel self-splicing ribozyme-based reverse genetics platform will be widely utilized in future ZIKV studies and provide insight for the development of infectious clones of other emerging viruses.

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“…Interestingly, other hypolipidemic agents targeting sterol-responsive element binding protein (SREBP) activity, such as nordihydroguaiaretic acid and its derivative, tetra-O-methyl nordihydroguaiaretic acid (M 4 N), an anticancer drug in clinical trials, PF-429242, and fatostatin, also reduced ZIKV infection in cultured Vero cells (T. Merino-Ramos, N. Jiménez de Oya, J.-C. Saiz, and M. A. Martín-Acebes, submitted for publication). Along this line, anti-ZIKV activity has also been reported for 25-hydroxycholesterol, which also regulates SREBP activity and is involved in the innate immune response to toll-like receptor ligands and interferon (52). Importantly, 25-hydroxycholesterol inhibited ZIKV infection in vitro (IC 50 , 0.2 M) by blocking viral entry, reduced viremia and conferred protection against ZIKV in mice and rhesus macaques, and reduced tissue damage in human cortical organoids and the embryonic brains of infected mice (52).…”

Section: Host-targeting Antiviralsmentioning

confidence: 91%

“…Along this line, anti-ZIKV activity has also been reported for 25-hydroxycholesterol, which also regulates SREBP activity and is involved in the innate immune response to toll-like receptor ligands and interferon (52). Importantly, 25-hydroxycholesterol inhibited ZIKV infection in vitro (IC 50 , 0.2 M) by blocking viral entry, reduced viremia and conferred protection against ZIKV in mice and rhesus macaques, and reduced tissue damage in human cortical organoids and the embryonic brains of infected mice (52). Finally, an additional study has identified three antimalarial compounds that inhibited ZIKV in Vero cells, namely, quinacrine (EC 50 , 2.3 M), mefloquine (EC 50 , 3.9 M), and GSK369796 (EC 50 , 2.8 M) (53).…”

Section: Host-targeting Antiviralsmentioning

confidence: 91%

The Race To Find Antivirals for Zika Virus

Saiz

Martín-Acebes

2017

Antimicrob Agents Chemother

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Zika virus (ZIKV), a flavivirus transmitted by mosquitoes, was an almost neglected pathogen until its introduction in the Americas in 2015 and its subsequent explosive spread throughout the continent, where it has infected millions of people. The virus has caused social and sanitary alarm, mainly due to its association with severe neurological disorders (Guillain-Barré syndrome and microcephaly in fetuses and newborns). Nowadays, no specific antiviral therapy against ZIKV is available. However, during the past months, a great effort has been made to search for antiviral candidates using different approaches and methodologies, ranging from testing specific compounds with known antiviral activity to the screening of libraries with hundreds of bioactive molecules. The identified antiviral candidates include drugs targeting viral components as well as cellular ones. Here, an updated review of what has been done in this line is presented.

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

Cited by 292 publications

References 49 publications

Self-Organized Cerebral Organoids with Human-Specific Features Predict Effective Drugs to Combat Zika Virus Infection

Self-Organized Cerebral Organoids with Human-Specific Features Predict Effective Drugs to Combat Zika Virus Infection

Characterization of cis -Acting RNA Elements of Zika Virus by Using a Self-Splicing Ribozyme-Dependent Infectious Clone

The Race To Find Antivirals for Zika Virus

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