Zika virus infection induces RNAi-mediated antiviral immunity in human neural progenitors and brain organoids

Xu, Yan‐Peng; Qiu, Yang; Zhang, Boya; Chen, Guilai; Chen, Qi; Wang, Miao; Mo, Fan; Xu, Junchao; Wu, Jin; Zhang, Rongrong; Cheng, Meng-Li; Zhang, Nana; Lyu, Bao; Zhu, Wenliang; Wu, Menghua; Ye, Qing; Zhang, Da; Man, Jianghong; Li, Xiaofeng; Cui, Jie; Xu, Zhiheng; Hu, Baoyang; Zhou, Xi; Qin, Cheng‐Feng

doi:10.1038/s41422-019-0152-9

Cited by 131 publications

(153 citation statements)

References 69 publications

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“…For example, novel anti-ZIKV activities of enoxacin, amodiaquine and niclosamide were discovered recently using human neural progenitor cells, human pluripotent stem cell-derived cortical neural progenitor cells, and human induced neural stem cells, respectively (Cairns et al, 2018;Xu et al, 2019;Zhou et al, 2017).…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Discovery and development of safe-in-man broad-spectrum antiviral agents

Andersen

Ianevski

Lysvand

et al. 2020

International Journal of Infectious Diseases

198

108

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# Contributed equally J o u r n a l P r e -p r o o f Highlights  We reviewed discovery and development process of broad-spectrum antiviral agents.  We summarized the information on 119 safe-in-man agents in freely accessible database.  Further studies will increase the number of broad-spectrum antivirals, expand spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections. Abstract: Viral diseases are one of the leading causes of morbidity and mortality in the world. Virus-specific vaccines and antiviral drugs are the most powerful tools to combat viral diseases. However, broad-spectrum antiviral agents (BSAAs, i.e. compounds targeting viruses belonging to two or more viral families) could provide additional protection of general population from emerging and reemerging viral diseases reinforcing the arsenal of available antiviral options. Here, we reviewed discovery and development of BSAAs and summarized the information on 119 safe-in-man agents in freely accessible database (https://drugvirus.info/). Future and ongoing pre-clinical and clinical studies will increase the number of BSAAs, expand spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections as well as co-infections. J o u r n a l P r e -p r o o f 2015). Antiviral drugs and vaccines are used to fight viral infections in human (De Clercq and Li, 2016; Marston et al., 2014). Previously, there has been a focus on "one drug, one virus" dogma, which relied on targeting virus-specific factors. A counterpoint to this is "one drug, multiple viruses" paradigm, which came with the discovery of broad-spectrum antiviral agents (BSAAs), small-molecules that inhibit a wide range of human viruses (Bekerman and Einav, 2015; de Clercq and Montgomery, 1983; Debing et al., 2015; Ianevski et al., 2019; Rada and Dragun, 1977; Sidwell et al., 1972). This paradigm was based on the observation that different viruses utilize similar pathways and host factors to replicate inside a cell (Bosl et al., 2019). Although the concept of BSAAs has been around for almost 50 years, the field received a new impetus with recent outbreaks of Ebola, Zika, Dengue, influenza and other viral infections, the discovery of novel host-directed agents as well as development of drug repositioning methodology. Drug repurposing, also called repositioning, redirecting, reprofiling, is a strategy for generating additional value from an existing drug by targeting disease other than that for which it was originally intended (Nishimura and Hara, 2018; Pushpakom et al., 2019). This has significant advantages over new drug discovery since chemical synthesis steps, manufacturing processes, reliable safety, and pharmacokinetic properties in pre-clinical (animal model) and early clinical developmental phases (phase 0, I and IIa) are already available (Figure 1). Therefore, repositioning of launched or even failed drugs to viral diseases provides unique translational opportunities, includi...

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Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Discovery and development of safe-in-man broad-spectrum antiviral agents

Andersen

Ianevski

Lysvand

et al. 2020

International Journal of Infectious Diseases

198

108

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“…While this review was in production, a study reported that Zika virus (ZIKV) infection resulted in the production of canonical viRNAs in human neural progenitor cells (hNPCs), the major target cells of ZIKV, but not in neurons differentiated from hNPCs (Xu et al, ). This study supports the notion that RNAi can play an antiviral role in certain progenitor cells, including those involved in brain development.…”

Section: Note Added In Proofmentioning

confidence: 99%

Slicing and dicing viruses: antiviral RNA interference in mammals

et al. 2019

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To protect against the harmful consequences of viral infections, organisms are equipped with sophisticated antiviral mechanisms, including cell‐intrinsic means to restrict viral replication and propagation. Plant and invertebrate cells utilise mostly RNA interference ( RNA i), an RNA ‐based mechanism, for cell‐intrinsic immunity to viruses while vertebrates rely on the protein‐based interferon ( IFN )‐driven innate immune system for the same purpose. The RNA i machinery is conserved in vertebrate cells, yet whether antiviral RNA i is still active in mammals and functionally relevant to mammalian antiviral defence is intensely debated. Here, we discuss cellular and viral factors that impact on antiviral RNA i and the contexts in which this system might be at play in mammalian resistance to viral infection.

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“…For mammals, vRI-dsRNAs and other viral nucleic acids usually induce innate antiviral immunity such as the type I interferon (IFN-I) system (1). Recently, accumulating evidence have provided strong support for the existence of antiviral RNAi in mammals (6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

The Capsid Protein of Semliki Forest Virus Antagonizes RNA Interference in Mammalian Cells

Zhou

Shu

et al. 2020

J Virol

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RNA interference (RNAi) is a conserved antiviral immune defense in eukaryotes, and numerous viruses have been found to encode viral suppressors of RNAi (VSRs) to counteract antiviral RNAi. Alphaviruses are a large group of positive-stranded RNA viruses that maintain their transmission and life cycles in both mosquitoes and mammals. However, there is little knowledge about how alphaviruses antagonize RNAi in both host organisms. In this study, we identified that Semliki Forest virus (SFV) capsid protein can efficiently suppress RNAi in both insect and mammalian cells by sequestrating double-stranded RNA and small interfering RNA. More importantly, when the VSR activity of SFV capsid was inactivated by reverse genetics, the resulting VSR-deficient SFV mutant showed severe replication defects in mammalian cells, which could be rescued by blocking the RNAi pathway. Besides, capsid protein of Sindbis virus also inhibited RNAi in cells. Together, our findings show that SFV uses capsid protein as VSR to antagonize RNAi in infected mammalian cells, and this mechanism is probably used by other alphaviruses, which shed new light on the knowledge of SFV and alphavirus. IMPORTANCE Alphaviruses are a genus of positive-stranded RNA viruses and include numerous important human pathogens, such as Chikungunya virus, Ross River virus, Western equine encephalitis virus, etc., which create the emerging and reemerging public health threat worldwide. RNA interference (RNAi) is one of the most important antiviral mechanisms in plants and insects. Accumulating evidence has provided strong support for the existence of antiviral RNAi in mammals. In response to antiviral RNAi, viruses have evolved to encode viral suppressors of RNAi (VSRs) to antagonize the RNAi pathway. It is unclear whether alphaviruses encode VSRs that can suppress antiviral RNAi during their infection in mammals. In this study, we first uncovered that capsid protein encoded by Semliki Forest virus (SFV), a prototypic alphavirus, had a potent VSR activity that can antagonize antiviral RNAi in the context of SFV infection in mammalian cells, and this mechanism is probably used by other alphaviruses.

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Zika virus infection induces RNAi-mediated antiviral immunity in human neural progenitors and brain organoids

Cited by 131 publications

References 69 publications

Discovery and development of safe-in-man broad-spectrum antiviral agents

Discovery and development of safe-in-man broad-spectrum antiviral agents

Slicing and dicing viruses: antiviral RNA interference in mammals

The Capsid Protein of Semliki Forest Virus Antagonizes RNA Interference in Mammalian Cells

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