Boosting stem cell immunity to viruses

doi:10.1126/science.abj5673

GSTDTAP > 气候变化

DOI	10.1126/science.abj5673
	Boosting stem cell immunity to viruses
	Shabihah Shahrudin; Shou-Wei Ding
	2021-07-09
发表期刊	Science
出版年	2021
英文摘要	Mammalian stem cells exhibit deficiencies in innate immunity regulated by interferons (IFNs), so they rely on constitutive expression of some IFN-stimulated genes (ISGs) ([ 1 ][1]) and Argonaute 2 (AGO2)–dependent RNA interference (RNAi) ([ 2 ][2], [ 3 ][3]) for antiviral protection. Mammalian antiviral RNAi is initiated by Dicer, which processes viral double-stranded RNA (dsRNA) replicative intermediates into small interfering RNAs (siRNAs) that act as specificity determinants for viral RNA cleavage by RNA-induced silencing complex \[(RISC) which contains AGO2\] ([ 2 ][2]–[ 10 ][4]). However, it remains unclear how stem cells activate antiviral RNAi because deletion of Dicer paradoxically enhances virus resistance in mouse embryonic stem cells ([ 11 ][5]). On page 231 of this issue, Poirier et al. ([ 12 ][6]) show that mouse and human stem cells have a specialized Dicer isoform for virus-derived siRNA (vsiRNA) production to initiate potent antiviral RNAi. This further indicates that siRNA therapeutic strategies may be viable for RNA viruses such as Zika virus (ZIKV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Similar to Caenorhabditis elegans nematodes ([ 13 ][7]), mammals encode a single Dicer ribonuclease (RNase) that is responsible for the biogenesis of both microRNAs from their stem-loop precursor transcripts and siRNAs from long dsRNA. Dicers have an amino-terminal helicase domain and tandem RNase III domains as well as additional domains between them, such as the RNA-binding PAZ domain (see the figure). Helicase domains of Dicers and mammalian retinoic acid–inducible gene 1 (RIG-I)–like receptors that trigger IFN-regulated immune responses are highly homologous and contain a distinct helicase-insertion subdomain (Hel2i). The study by Poirier et al. began with discovering an alternatively spliced mouse and human Dicer messenger RNA (mRNA) from embryonic, neuronal, and tissue stem cells. These transcripts contain an in-frame deletion of exons 7 and 8 so that Hel2i is absent. Poirier et al. demonstrate that RNAi initiated by this Dicer isoform, designated antiviral Dicer (aviD), protects mouse stem cells from infections with the RNA viruses ZIKV and SARS-CoV-2. The authors found that the loss of Hel2i enhances aviD processing of long dsRNA into siRNAs without impairing its ability to generate microRNAs. Notably, ZIKV and another RNA virus, Sindbis virus, replicated to lower amounts in human cells forced to express aviD. Moreover, the antiviral activity of aviD was abolished by depletion of AGO2 or ectopic expression of the viral suppressor of RNAi (VSR) encoded by Nodamura virus ([ 1 ][1], [ 2 ][2], [ 14 ][8]), providing further evidence that aviD confers virus resistance by RNAi. ![Figure][9] Intrinsic and innate antiviral immunity in mammalian cells Inducible IFN-regulated immune responses and antiviral RNAi act additively to establish an antiviral state in differentiated cells. By contrast, stem cells are refractory to IFN signaling, so they predominantly respond to virus infection through RNAi activation using an antiviral Dicer. This isoform of Dicer processes viral dsRNA replicative intermediates into vsiRNAs that act as specificity determinants for viral RNA cleavage by AGO2 in the RISC. This prevents RNA virus replication in stem cells. GRAPHIC: V. ALTOUNIAN/ SCIENCE ZIKV may cause devastating microcephaly in infants born from infected mothers because the virus infects human neural progenitor cells (hNPCs) during brain development. Infection of hNPCs by ZIKV induces AGO2-dependent RNAi, and enhancing antiviral RNAi can provide protection in hNPC-derived brain organoids, which recapitulate much of the composition, diversity, and organization of cell types found in the developing human fetal brain ([ 3 ][3]). Thus, Poirier et al. generated brain organoids from wild-type mouse embryonic stem cells, which express both Dicer and aviD, and mutant organoids expressing only Dicer or aviD. They detected no significant differences in growth among these brain organoids. However, the absence of aviD compromised stem cell resistance to ZIKV infection in brain organoids, resulting in increased numbers of virally infected stem cells and production of infectious virus particles and more potently inhibited stem cell division and organoid growth. Sequencing of small RNAs in ZIKV-infected wild-type and mutant mouse stem cell–derived organoids revealed production of predominantly 22-nucleotide vsiRNAs, consistent with previous observations in ZIKV-infected hNPCs ([ 3 ][3]). After normalization by the yield of ZIKV particles, however, brain organoids that do not express aviD accumulated much less vsiRNAs than those that do, with or without Dicer coexpression. This demonstrated significantly enhanced activity of aviD to process the viral dsRNA replicative intermediates into vsiRNAs compared with full-length Dicer. Thus, aviD protects brain organoids from ZIKV infection by triggering antiviral RNAi. Poirier et al. also provided evidence of vsiRNA production targeting SARS-CoV-2 in infected brain organoids derived from mouse embryonic stem cells engineered to express the human viral entry receptor angiotensin-converting enzyme 2 (ACE2). As for ZIKV infection, aviD depletion was more effective in promoting SARS-CoV-2 infection of stem cells in brain organoids than Dicer depletion. Consistently, SARS-CoV-2 replicated to higher titers in human cells deficient in aviD expression. By contrast, both aviD - and Dicer -deficient cells supported replication of two DNA viruses at similar levels, possibly because only RNA viruses produce sufficiently abundant dsRNA replicative intermediates to trigger antiviral RNAi. Future studies will be necessary to determine whether specific deletion of only aviD or Dicer produces in vivo phenotypic differences in development or antiviral RNAi. Poirier et al. propose that aviD may have evolved to protect stem cells from RNA viruses in part to compensate for stem cell deficiencies in IFN production and signaling, which may be critical to maintain pluripotency ([ 1 ][1]). Consistently, Poirier et al. found that expression of aviD , but not Dicer , is lost upon the differentiation of cultured neural stem cells into astrocytes, and a previous study observed decreased vsiRNA abundance upon the differentiation of mouse embryonic stem cells ([ 2 ][2]). Virus infection of differentiated cells induces production of type I and III IFNs, which induce the transcription of hundreds of ISGs to establish an antiviral state. Blocking type I IFN signaling in RNAi-defective mouse fibroblasts can further increase the accumulation of several RNA viruses, suggesting an RNAi-independent and additive contribution of IFN signaling to the innate antiviral defense in differentiated cells ([ 5 ][10]–[ 9 ][11]). Identification of SARS-CoV-2 as both an inducer and target of antiviral RNAi during authentic infections ([ 12 ][6]) supports ongoing efforts to develop siRNA drugs for the human disease, and a recent study has demonstrated efficacy of an siRNA therapeutic against SARS-CoV-2 in an animal model ([ 15 ][12]). However, it is important to note that mammalian RNA viruses from distinct families produce nonhomologous proteins that are RNAi suppressors, such as influenza viral nonstructural protein 1 and SARS-CoV-2 nucleocapsid protein ([ 2 ][2]–[ 10 ][4], [ 14 ][8]). Moreover, mammalian vsiRNAs made in host cells to target SARS-CoV-2 and other RNA viruses are all predominantly 22 nucleotides long, in contrast to the synthetic therapeutic siRNAs that are exclusively 21 nucleotides long. Thus, designing and testing siRNA cocktails containing 22-nucleotide species plus additional targeting specificity to VSR mRNA may lead to further improvements in antiviral siRNA therapeutics. 1. [↵][13]1. X. 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领域	气候变化 ; 资源环境
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引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/334236
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Shabihah Shahrudin,Shou-Wei Ding. Boosting stem cell immunity to viruses[J]. Science,2021.
APA	Shabihah Shahrudin,&Shou-Wei Ding.(2021).Boosting stem cell immunity to viruses.Science.
MLA	Shabihah Shahrudin,et al."Boosting stem cell immunity to viruses".Science (2021).