UCR

Plant Pathology Graduate Program



Shou-Wei Ding


Shou-Wei Ding
Office: 951-827-2341
Fax:
3202A Genomics
Office Hours: , not specified - not specified
Email: dingsw@ucr.edu

Shou-Wei Ding

Professor: Molecular Virology and Immunology

PhD -- Australian National University (Canberra, Australia)

Participating Graduate programs: (i) Cell, Molecular & Developmental Biology; (ii) Genetics, Genomics & Bioinformatics; (iii) Microbiology; (iv) Plant Pathology


Biography & Research Interests

The research programs in my lab focus on the host immune responses to RNA viruses and viral counter-defense strategies. Viruses with an RNA genome exhibit distinct genetic and immunological properties from DNA viruses. Many important human diseases (e.g. Ebola, influenza, SARS, Dengue, West Nile and polio) are caused by RNA viruses and > 70% of plant viruses are RNA viruses. RNA viruses that infect plants and animals are remarkably similar in genome structure and replication strategies. We have been taking a comparative approach to investigate the immune responses of plants, insects, nematodes and mammals to RNA viruses. Studies from my lab and others have shown that RNA viruses are targeted in plants, invertebrates and mammals by a conserved form of antiviral immunity mediated by RNA interference (RNAi). In antiviral RNAi, virus-specific dsRNA replicative intermediates are recognized and processed into small interfering RNAs (siRNAs) to guide specific virus clearance by RNAi. As a result, successful virus infection requires suppression of the antiviral immunity by a distinct class of viral proteins known as viral suppressors of RNAi (VSRs).

Awards

Fellow, American Association for the Advancement of Science, 2006

Fellow, American Academy of Microbiology, 2012

Publications

The main topics of research in my lab are:

1. A mouse model for antiviral RNAi. We have recently developed a mouse model to characterize the RNAi response of mammals to RNA viruses (Li et al., 2013). Nodamura virus (NoV) contains a positive-strand RNA genome, is mosquito transmissible and lethally infects suckling mice. NoV and other Nodaviruses such as Flock house virus (FHV), an insect pathogen, encode a VSR protein B2 that binds dsRNA and suppresses its processing into siRNA by the Dicer nuclease (Li et al., 2002; Li et al., 2004; Lu et al., 2005; Aliyari et al., 2008; Ding, 2010). We have shown that infection of suckling mice by mutants of NoV expressing no B2 protein (NoVDB2) or a B2 mutant (B2-R59Q) unable to suppress Dicer processing of long dsRNA triggers production of highly abundant virus-derived siRNAs. These mouse viral siRNAs are predominantly 22 nucleotides long and perfect base-paired duplexes with 2-nt 3’ overhangs. Similar to plant and insect virus mutants defective in the expression of the cognate VSR, the VSR-defective mutants of NoV become non-virulent and are rapidly cleared in suckling mice (Li et al., 2013). Mouse embryonic stem cells (mESCs) also produce abundant vsiRNAs in response to NoVDB2 infection, which is defective in wild type mESCs but is partially rescued in mESCs knockout for all of the four Argonaute genes (Maillard et al., 2013). Since Dicer-mediated biogenesis and Argonaute loading of abundant vsiRNAs have been demonstrated in Encephalomyocarditis virus-infected mESCs (Maillard et al., 2013), these studies together reveal a conserved RNAi response to RNA viruses in mammals.

Induction of antiviral RNAi depends on the host immune detection of viral dsRNA in the cytoplasm, which also is critical in the initiation of the interferon (IFN)-dependent innate immunity targeting RNA viruses by RIG-I-like receptors (Aliyari et al., 2009). Therefore, mouse infection by NoV provides a unique model to investigate the function and mechanism as well as viral suppression of antiviral RNAi, and to characterize the interactions of dsRNA-sensing pathways in mammals. Recently, we have developed systems in cultured somatic cells to investigate the mammalian RNAi response to Influenza A virus infection. We are currently recruiting postdocs with research experience on mammalian RNA viruses and the mouse model.

Li Y, Lu JF, Han YH, Fan XX and Ding SW. 2013. RNA interference functions as an antiviral immunity mechanism in mammals. Science 342:231-234.

Maillard PV, Ciaudo C, Marchais A, Li Y, Jay F, Ding SW, Voinnet O. Antiviral RNA interference in mammalian cells. Science 342:235-238.

Ding SW and Voinnet O. 2014. Antiviral RNA silencing is mammals: No news is not good news. Cell Rep 9: 795-797.

Gaulke C, Porter M, Han YH, Sankaran-Walters S, Grishina I, George M, Dang A, Ding SW, Jiang G, Korf I, Dandekar S 2014. Intestinal epithelial barrier disruption through altered mucosal microRNA expression in human immunodeficiency virus and simian immunodeficiency virus infections. J Virol 88:6268–6280

Ding SW. RNA-based viral immunity. 2010. Nature Rev Immunol 10:632-44.

Aliyari R, and Ding SW. 2009. RNA-based viral immunity initiated by the Dicer family of host immune receptors. Immunol Rev 227: 176-188.

Aliyari R, Wu QF, L HW, Wang XH, Li F, Green LD Han CS, Li WX, and Ding SW. 2008. Mechanism of induction and suppression of antiviral immunity directed by virus-derived small RNAs in DrosophilaCell Host & Microbe 4:387-397.

Ding SW and Voinnet O. 2007. Antiviral immunity directed by small RNAs. Cell 130:413-426

Lu R, Maduro M, Li F, Li HW, Maduro G, Li WX and Ding SW. 2005. Animal virus replication and RNAi-mediated antiviralin Caenorhabditis elegans.Nature 436:1040-1043.

Li WX, Li HW, Lu R, Li F, Dus M, Atkinson P, Johnson KL, Garcia-Sastre A, Brydon E, Ball LA, Palese P & Ding SW. (2004) Interferon antagonist proteins of influenza and vaccinia viruses are suppressors of RNA silencing. Proc Natl Acad Sci USA101:1350-1355.

Ding SW, Li HW, Lu R, Li F and Li WX. 2004. RNA silencing: A conserved antiviral immunity of plants and animals. Virus Res 102, 109-115.

Li HW, Li WX, & Ding SW. 2002. Induction and suppression of RNA silencing by an animal virus. Science 296, 1319-1321.

2. Antiviral RNAi in insects. We began to investigate the antiviral function of RNAi in the animal kingdom in late 2000 when I relocated to UC Riverside. The B2 and 2b genes encoded by FHV and Cucumber mosaic virus (CMV) respectively shared key features despite lack of sequence similarity (Ding et al, 1995). Because 2b was later identified as a VSR (Brigneti et al., 1998; Li et al., 1999), we characterized the infection of wild type and RNAi-defective Drosophila cells by FHV. Our first paper (Li et al., 2002) showed that B2 of FHV is a VSR in plant and Drosophila cells, FHV infection triggers production of abundant viral siRNAs, and a B2-deficient mutant of FHV is rapidly cleared by an Argonaute2-dependent pathway of RNAi in Drosophila cells. These results provided the first evidence for an antiviral role of RNAi in the animal kingdom. My lab has subsequently made several key discoveries on antiviral RNAi using the Drosophila model. For example, we 1) demonstrated a universal antiviral function of RNAi against evolutionary diverse RNA viruses and identified Dicer-2, Argonaute-2 and R2D2 in the dsRNA-siRNA pathway of RNAi as the key components of Drosophila antiviral RNAi; 2) established RNAi as the major antiviral mechanism in insects because Drosophila RNAi-defective mutants are defective in antiviral defense but are not compromised in innate immune signaling by Toll and Imd pathways; 3) identified the first insect VSRs in Nodaviruses and Cricket paralysis virus and revealed a highly conserved VSR mechanism by binding to long dsRNA and suppressing its dicing into siRNAs; 4) demonstrated that antiviral RNAi is sufficient to terminate virus infection in adult flies in the absence of VSR expression; 5) reported the first deep sequencing and identified the first dsRNA precursor of viral siRNAs; 6) illustrated the importance and necessity of using VSR-defective virus mutants in dissecting host antiviral responses; 7) were the first to detect the induction of antiviral RNAi in mosquito cells in 2004 and the production of virus-derived PIWI-interacting RNAs (piRNAs) in 2010, and 8) developed a bioinformatics approach for the discovery of viruses by deep sequencing and assembly of the total small RNAs from host cells.

Li HW, Li WX, & Ding SW. 2002. Induction and suppression of RNA silencing by an animal virus. Science 296, 1319-1321

Li WX, Li HW, Lu R, Li F, Dus M, Atkinson P, Johnson KL, Garcia-Sastre A, Brydon E, Ball LA, Palese P & Ding SW. (2004) Interferon antagonist proteins of influenza and vaccinia viruses are suppressors of RNA silencing. Proc Natl Acad Sci USA101:1350-1355.

Ding SW*, Li WX & Symons RH*. 1995. A novel naturally occurring hybrid gene encoded by a plant RNA virus facilitates long-distance virus movement. EMBO J14, 5762-5772 (co-corresponding authors).

Li HW, and Ding SW. 2005. Antiviral silencing in animals. FEBS Lett 579, 5965-5973

Lu R, Maduro M, Li F, Li HW, Maduro G, Li WX and Ding SW. 2005. Animal virus replication and RNAi-mediated antiviralin Caenorhabditis elegans.Nature 436:1040-1043.

Wang XH, Aliyari R, Li WX, Li HW, Kim K, Carthew R, Atkinson P, and Ding SW. 2006. RNA interference directs innate immunity against viruses in adult  Drosophila. Science 312:452-454.

Aliyari R, Wu QF, L HW, Wang XH, Li F, Green LD Han CS, Li WX, and Ding SW. 2008. Mechanism of induction and suppression of antiviral immunity directed by virus-derived small RNAs in DrosophilaCell Host & Microbe 4:387-397.

Wu Q, Luo Y, Lu R, Lau N, Lai EC, Li WX, and Ding SW. 2010. Virus discovery by deep sequencing and assembly of virus-derived small silencing RNAs. Proc Natl Acad Sci USA. 107, 1606-1611.

Han YH, Luo YJ, Wu Q, Jovel J, Wang XH, Aliyari R, Han C, Li WX and Ding SW. 2011. RNA-based immunity terminates viral infection in adult Drosophila in absence of viral suppression of RNAi: Characterization of viral siRNA populations in wildtype and mutant flies. J Virol 85(24):13153-63.

3.  Genetic studies of antiviral RNA in C. elegans.  The desire to identify host genes required for antiviral RNAi by forward genetic screens led us to the Caenorhabditis elegans model. Because C. elegans was not known to support replication of any virus at that time, we constructed stable nematode strains carrying an inducible transgene integrated into the animal chromosome that is transcribed to yield the genomic RNAs of FHV, which is known to replicate in insect, yeast, plant, and mammalian cells. Our 2005 paper demonstrated replication of the complete FHV genome, detected induction of antiviral RNAi by the canonical RNAi pathway of C. elegans, and illustrated an essential role of RNAi suppression by B2 for FHV accumulation in the whole animals (Lu et al., 2005). Virus replication and antiviral RNAi were also independently demonstrated by two other groups in cultured primary cells of C. elegans. We have carried out a pilot genetic screen in C. elegans and identified an essential component of antiviral RNAi, Dicer-related helicase 1 (DRH-1), which is highly homologous to mammalian RIG-I-like receptors (Lu et al., 2009). Similar genetic requirements have been demonstrated for antiviral RNAi induced by the FHV replicon and a natural virus of C. elegans discovered in 2011 by others, Orsay virus, which is most closely related to the Nodaviruses. Notably, DRH-1 acts to enhance production of viral siRNAs and both the helicase and C-terminal domains of human RIG-I can functionally replace the corresponding domains of DRH-1 to mediate antiviral RNAi in C. elegans. These studies establish a new small animal model for antiviral immunity and suggest a possible role for the classic mammalian innate immunity in antiviral RNAi.

Lu R, Maduro M, Li F, Li HW, Maduro G, Li WX and Ding SW. 2005. Animal virus replication and RNAi-mediated antiviralin Caenorhabditis elegans.Nature 436:1040-1043.

Lu R, Yigit E, Li WX and Ding SW. 2009. An RIG-I-like RNA helicase mediates antiviral RNAi downstream of viral siRNA biogenesis in Caenorhabditis elegans. PLoS Pathogens 5(2): e1000286

Ding SW and Lu R. 2011. Virus-derived siRNAs and piRNAs in immunity and pathogenesis. Curr Opin Virol 1, 533-544

Guo X, Zhang R, Wang J, Ding SW, Lu R. 2013. Homologous RIG-I-like helicase proteins direct RNAi-mediated antiviral immunity in C. elegans by distinct mechanisms. Proc Natl Acad Sci USA. 110:16085-90

4. Mechanisms of induction and suppression of antiviral RNAi in plants. We began to test the hypothesis that the 2b protein of CMV and other Cucumoviruses is a VSR following the early studies demonstrating that 2b facilitates virus systemic spread and is responsible for the severe synergistic disease phenotype in diverse host plants (Ding et al., 1995; Ding et al., 1996). After the publication of the first papers on the identification and characterization of the cucumoviral 2b proteins as VSRs (Brigneti et al., 1998; Li et al., 1999; Lucy et al., 2000; Ji et al., 2001; Guo et al., 2002; Chen et al., 2004; Lu et al., 2004), we have focused on the genetic characterization of antiviral RNAi using Arabidopsis thaliana as the model plants. Our studies have revealed the redundant and overlapping functions of the Arabidopsis multigene families encoding Dicer-like proteins (DCLs), Argonaute proteins and RNA-dependent RNA polymerases (RDRs) in antiviral RNAi (Diaz-Pendon et al., 2007; Wang et al., 2010; Wang et al., 2011). One of our recent studies (Cao et al., 2014) has discovered a novel class of host endogenous siRNAs induced by virus infection, designated as virus-activated siRNAs (vasiRNAs). vasiRNAs are produced by DCL4 and RDR1 to direct widespread silencing of host genes by Argonaute-2.

Ding SW*, Li WX & Symons RH*. 1995. A novel naturally occurring hybrid gene encoded by a plant RNA virus facilitates long-distance virus movement. EMBO J14, 5762-5772 (co-corresponding authors).

Ding SW*, Shi BJ, Li WX & Symons RH*. 1996. An interspecies hybrid RNA virus is significantly more virulent that either parental virus. Proc Natl Acad Sci USA 93, 7470-7474 (co-corresponding authors).

Brigneti G, Voinnet O, Li WX, Ji LH, Ding SW & Baulcombe DC. 1998. Viral pathogenicity determinants are suppressors of transgene silencing in Nicotiana benthamiana. EMBO J17, 6739-6746.

Li HW, Lucy AP, Guo HS, Li WX, Ji LH, Wong SM, & Ding SW. 1999. Strong host resistance targeted against a viral suppressor of the plant gene silencing defence mechanism. EMBO J 18, 2683-2691.

Lucy AP, Guo HS, Li WX, & Ding SW.  2000. Suppression of post-transcriptional gene silencing by a plant viral protein localised in the nucleus. EMBO J 19, 1672-1680.

Ding SW. RNA silencing. 2000. Curr Opin Biotechnol 11, 152-156.Guo HS & Ding SW. 2002. A viral protein inhibits the long-range signaling activity of the gene silencing signal. EMBO J 21, 398-407.

Ji LH & Ding SW. 2001. The suppressor of transgene RNA silencing encoded by cucumber mosaic virus interferes with salicylic acid-mediated virus resistance. Mol Plant-Microbe Interact 14, 715-724.

Li WX and Ding SW. 2001. Viral suppressors of RNA silencing. Curr Opin Biotechnol 12, 150-154

Chen J, Li WX, Xie DX, Peng JR & Ding SW. 2004. Viral virulence protein suppresses RNA silencing-mediated defense but upregulates the role of miRNA in host gene expression. Plant Cell 16:1302-1313.

Lu R, Folimonov A, Shintaku M, Li WX, Falk BW, Dawson WO, and Ding SW. 2004. Three distinct suppressors of RNA silencing encoded by a 20-kb viral RNA genome. Proc Natl Acad Sci USA101:15742-15747.

Li F, and Ding SW. 2006. Virus counterdefense: Diverse strategies for evading the RNA silencing immunity. Ann Rev Microbiol 60:503-531.

Diaz-Pendon JA, Li F, Li WX, and Ding SW. 2007. Suppression of antiviral silencing by cucumber mosaic virus 2b protein in Arabidopsis is associated with drastically reduced accumulation of three classes of viral small interfering RNAs. Plant Cell 19:2053-2063.

Diaz-Pendon JA and Ding SW. 2008. Direct and indirect roles of viral suppressors of RNA silencing in pathogenesis. Ann Rev Phytopath 46:303-326

Wang XB, Wu Q, Ito T, Cillo F, Li WX, Chen X, Yu JL, and Ding SW. 2010. RNAi-mediated viral immunity requires amplification of virus-derived siRNAs in Arabidopsis thaliana. Proc Natl Acad Sci USA 107, 484-489

Wu QF, Wang XB and Ding SW. 2010. Viral suppressors of RNA-based viral immunity: Host targets. Cell Host & Microbe 8:12-15.

Wang XB, Jovel J, Udomporn P, Wang Y, Wu Q, Li WX, Gasciolli V, Vaucheret H and Ding SW. 2011. The 21-nucleotide, but not 22-nucleotide, viral secondary small interfering RNAs direct potent antiviral defense by two cooperative Argonautes in Arabidopsis thaliana. Plant Cell 23:1625-38.

Duan CG, Fang YY, Zhou BJ, Zhao JH, Hou WN, Zhu H, Ding SW, Guo HS. 2012. Suppression of Arabidopsis ARGONAUTE1-mediated slicing, transgene-induced RNA silencing, and DNA methylation by distinct domains of the cucumber mosaic virus 2b protein. Plant Cell 24:259-274.

Cao MJ, Du P, Wang XB, Yu YQ, Qiu YH, Li WX, Gal-On A, Zhou CY, Li Y, Ding SW. 2014. Virus infection triggers widespread silencing of host genes by a distinct class of endogenous siRNAs in Arabidopsis. Proc Natl Acad Sci USA111(40):14613-8

5.   Discovery of viruses and viroids by deep sequencing. Our deep sequencing of small RNAs has revealed that in contrast to previous observations made by low throughput sequencing, viral siRNAs produced by the host RNAi machinery in fact overlap extensively in sequence (Aliyari et al., 2008). According to this property of viral siRNAs, we have developed a culture-independent approach for the discovery of viruses by deep sequencing and assembly of total small RNAs (vdSAR) isolated from a host organism (Wu et al., 2010). For example, vdSAR analysis of small RNAs sequenced from Drosophila Schneider 2 (S2) and ovary somatic sheet (OSS) cell lines uncovered co-infection of the widely used cell lines with five and six RNA viruses, respectively. Moreover, we have developed a unique computational algorithm, progressive filtering of overlapping small RNAs (PFOR), for homology-independent discovery of viroids (Wu et al., 2012), which are non-coding single-stranded circular RNA molecules 246–401 nt in length known to cause diseases only in plants. Viroid infection triggers production of overlapping viroid-derived siRNAs that cover the entire genome with high densities. PFOR retains viroid-specific siRNAs for genome assembly by progressively eliminating nonoverlapping small RNAs and others that overlap but cannot be assembled into a direct repeat RNA, which is synthesized from circular RNA templates during viroid replication. Recent development of a new computational program and its incorporation into PFOR further allows the identification of viroids and other circular RNAs regardless of whether they replicate and/or induce the in vivo accumulation of small RNAs. (Zhang et al., 2014).

Wu Q, Luo Y, Lu R, Lau N, Lai EC, Li WX, and Ding SW. 2010. Virus discovery by deep sequencing and assembly of virus-derived small silencing RNAs. Proc Natl Acad Sci USA. 107, 1606-1611.

Wu Q, Wang Y, Cao MJ, Pantaleo V, Burgyan J, Li WX and Ding SW. 2012. Homology-independent discovery of replicating pathogenic circular RNAs by deep sequencing and a new computational algorithm. Proc Natl Acad Sci USA 109:3938-3943.

Jiang H, Lei R, Ding SW, Zhu S. 2014. Skewer: A fast and accurate adapter trimmer for Next-Generation Sequencing (NGS) paired-end reads. BMC Bioinformatics 15:182. doi:10.1186/1471-2105-15-182

Zhang Z, Qi S, Tang N, Zhang X, Chen S, Zhu P, Ma L, Cheng J, Xu Y, Lu M, Wang H, Ding SW, Li S, and Wu Q. (2014) Discovery of Replicating Circular RNAs by RNA-Seq and Computational Algorithms. PLoS Pathog 10(12): e1004553. doi:10.1371/journal.ppat.100455.

Wu Q, Ding SW, Zhang Y and Zhu SF. 2015. Identification of viruses and viroids by next-generation sequencing and homology-dependent and homology-independent algorithms. Annu Rev Phytopath In press.


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