Virus-derived small interfering RNAs serve as new intercellular immune modulators against viral infection in mammals

Shengkai Zhou; Ye Xu; Yu Zhou; Fangfang Jin

doi:10.55092/exrna20240008

Abstract

RNA silencing serves as the primary antiviral immune system in plants, fungi, and invertebrates. Upon virus invasion, its replication intermediates act as pathogen-associated molecular patterns (PAMPs), promptly recognized and processed by Dicer into siRNAs. These virus-derived small interfering RNAs (vsiRNAs) then guide specific cleavage of the viral genome. In mammalian cells, the presence of vsiRNAs has been difficult to detect. However, recent studies indicate that vsiRNA expression can be detected when viruses infect undifferentiated mammalian cells. These findings complement new antiviral mechanisms in mammalian cells, but also face several controversies. Therefore, we will briefly discuss the current research status of vsiRNAs in mammals and analyze the controversies existing in this field.

Keywords

virus-derived small interfering RNAs; antiviral immunity; mammal

Preview

view pdf

References

[1] Takeuchi O, Akira S. Innate immunity to virus infection. Immunol. Rev. 2009, 227(1):75–86.
[2] Hu MM, Shu HB. Cytoplasmic Mechanisms of Recognition and Defense of Microbial Nucleic Acids. Annu. Rev. Cell Dev. Biol. 2018, 34:357–379.
[3] Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: a complex web of host defenses. Annu. Rev. Immunol. 2014, 32:513–545.
[4] Ding SW, Voinnet O. Antiviral immunity directed by small RNAs. Cell 2007, 130(3):413–426.
[5] Bronkhorst AW, van Rij RP. The long and short of antiviral defense: small RNA-based immunity in insects. Curr. Opin. Virol. 2014, 7:19–28.
[6] Ding SW. RNA-based antiviral immunity. Nat. Rev. Immunol. 2010, 10(9):632–644.
[7] Samuel GH, Adelman ZN, Myles KM. Antiviral Immunity and Virus-Mediated Antagonism in Disease Vector Mosquitoes. Trends Microbiol. 2018, 26(5):447–461.
[8] Sparmann A, Vogel J. RNA-based medicine: from molecular mechanisms to therapy. EMBO J. 2023, 42(21):e114760.
[9] Setten RL, Rossi JJ, Han SP. The current state and future directions of RNAi-based therapeutics. Nat. Rev. Drug Discov. 2019;18(6):421–446.
[10] Jadhav V, Vaishnaw A, Fitzgerald K, Maier MA. RNA interference in the era of nucleic acid therapeutics. Nat. Biotechnol. 2024, 42(3):394–405.
[11] Li Y, Lu J, Han Y, Fan X, Ding SW. RNA interference functions as an antiviral immunity mechanism in mammals. Science 2013, 342(6155):231–234.
[12] Maillard PV, Ciaudo C, Marchais A, Li Y, Jay F, et al. Antiviral RNA interference in mammalian cells. Science 2013, 342(6155):235–238.
[13] Hamilton AJ, Baulcombe DC. A species of small antisense RNA in posttranscriptional gene silencing in plants. Science 1999, 286(5441):950–952.
[14] Hammond SM, Bernstein E, Beach D, Hannon GJ. An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature 2000, 404(6775):293–296.
[15] Li H, Li WX, Ding SW. Induction and suppression of RNA silencing by an animal virus. Science 2002, 296(5571):1319–1321.
[16] Wang XH, Aliyari R, Li WX, Li HW, Kim K, et al. RNA interference directs innate immunity against viruses in adult Drosophila. Science 2006, 312(5772):452–454.
[17] Wang XB, Wu Q, Ito T, Cillo F, Li WX, et al. RNAi-mediated viral immunity requires amplification of virus-derived siRNAs in Arabidopsis thaliana. Proc. Natl. Acad. Sci. U. S. A. 2010, 107(1):484–489.
[18] Zhang X, Segers GC, Sun Q, Deng F, Nuss DL. Characterization of hypovirus-derived small RNAs generated in the chestnut blight fungus by an inducible DCL-2-dependent pathway. J. Virol. 2008, 82(6):2613–2619.
[19] Brodersen P, Voinnet O. The diversity of RNA silencing pathways in plants. Trends Genet. 2006, 22(5):268–280.
[20] Hammond SM. Dicing and slicing: the core machinery of the RNA interference pathway. FEBS Lett. 2005, 579(26):5822–5829.
[21] Vaucheret H. Post-transcriptional small RNA pathways in plants: mechanisms and regulations. Genes Dev. 2006, 20(7):759–771.
[22] Chen X. A marked end. Nat. Struct. Mol. Biol. 2007,14(4):259–260.
[23] Aliyari R, Wu Q, Li HW, Wang XH, Li F, et al. Mechanism of induction and suppression of antiviral immunity directed by virus-derived small RNAs in Drosophila. Cell Host Microbe 2008, 4(4):387–397.
[24] Mérai Z, Kerényi Z, Molnár A, Barta E, Válóczi A, et al. Aureusvirus P14 is an efficient RNA silencing suppressor that binds double-stranded RNAs without size specificity. J. Virol. 2005, 79(11):7217–7226.
[25] Love AJ, Laird J, Holt J, Hamilton AJ, Sadanandom A, et al. Cauliflower mosaic virus protein P6 is a suppressor of RNA silencing. J. Gen. Virol. 2007, 88(Pt 12):3439–3444.
[26] Mérai Z, Kerényi Z, Kertész S, Magna M, Lakatos L, et al. Double-stranded RNA binding may be a general plant RNA viral strategy to suppress RNA silencing. J. Virol. 2006, 80(12):5747–5756.
[27] Giner A, Lakatos L, García-Chapa M, López-Moya JJ, Burgyán J. Viral protein inhibits RISC activity by argonaute binding through conserved WG/GW motifs. PLoS Pathog. 2010, 6(7):e1000996.
[28] Li F, Ding SW. Virus counterdefense: diverse strategies for evading the RNA-silencing immunity. Annu. Rev. Microbiol. 2006, 60:503–531.
[29] Deleris A, Gallego-Bartolome J, Bao J, Kasschau KD, Carrington JC, et al. Hierarchical action and inhibition of plant Dicer-like proteins in antiviral defense. Science 2006, 313(5783):68–71.
[30] Azevedo J, Garcia D, Pontier D, Ohnesorge S, Yu A, et al. Argonaute quenching and global changes in Dicer homeostasis caused by a pathogen-encoded GW repeat protein. Genes Dev. 2010, 24(9):904–915.
[31] Vargason JM, Szittya G, Burgyán J, Hall TM. Size selective recognition of siRNA by an RNA silencing suppressor. Cell. 2003;115(7):799-811.
[32] Ye K, Malinina L, Patel DJ. Recognition of small interfering RNA by a viral suppressor of RNA silencing. Nature 2003, 426(6968):874–878.
[34] Parameswaran P, Sklan E, Wilkins C, Burgon T, Samuel MA, et al. Six RNA viruses and forty-one hosts: viral small RNAs and modulation of small RNA repertoires in vertebrate and invertebrate systems. PLoS Pathog. 2010, 6(2):e1000764.
[35] Grundhoff A, Sullivan CS. Virus-encoded microRNAs. Virology 2011, 411(2):325–343.
[36] Weng KF, Hung CT, Hsieh PT, Li ML, Chen GW, et al. A cytoplasmic RNA virus generates functional viral small RNAs and regulates viral IRES activity in mammalian cells. Nucleic Acids Res. 2014, 42(20):12789–12805.
[37] Benitez AA, Spanko LA, Bouhaddou M, Sachs D, tenOever BR. Engineered Mammalian RNAi Can Elicit Antiviral Protection that Negates the Requirement for the Interferon Response. Cell Rep. 2015, 13(7):1456–1466.
[38] Li Y, Basavappa M, Lu J, Dong S, Cronkite DA, et al. Induction and suppression of antiviral RNA interference by influenza A virus in mammalian cells. Nat. Microbiol. 2016, 2:16250.
[39] Qiu Y, Xu Y, Zhang Y, Zhou H, Deng YQ, et al. Human Virus-Derived Small RNAs Can Confer Antiviral Immunity in Mammals. Immunity 2018;49(4):780–781.
[40] Qiu Y, Xu YP, Wang M, Miao M, Zhou H, et al. Flavivirus induces and antagonizes antiviral RNA interference in both mammals and mosquitoes. Sci. Adv. 2020, 6(6):eaax7989.
[41] Zeng J, Luo Z, Dong S, Xie X, Liang X, et al. Functional Mapping of AGO-Associated Zika Virus-Derived Small Interfering RNAs in Neural Stem Cells. Front. Cell. Infect. Microbiol. 2021, 11:628887.
[42] Zhang Y, Li Z, Ye Z, Xu Y, Wang B, et al. The antiviral RNA interference not only exists in neural progenitor cells but also in somatic cells in mammals. Emerg. Microbes Infect. 2020, 9(1):1580–1589.
[43] Xu YP, Qiu Y, Zhang B, Chen G, Chen Q, et al. Zika virus infection induces RNAi-mediated antiviral immunity in human neural progenitors and brain organoids. Cell Res. 2019, 29(4):265–273.
[44] Díaz-Pendón JA, Ding SW. Direct and indirect roles of viral suppressors of RNA silencing in pathogenesis. Annu. Rev. Phytopathol. 2008, 46:303–326.
[45] Wu Q, Wang X, Ding SW. Viral suppressors of RNA-based viral immunity: host targets. Cell Host Microbe 2010, 8(1):12–15.
[46] Girardi E, Chane-Woon-Ming B, Messmer M, Kaukinen P, Pfeffer S. Identification of RNase L-dependent, 3'-end-modified, viral small RNAs in Sindbis virus-infected mammalian cells. mBio 2013, 4(6):e00698-13.
[47] Wang J, Li Y. Current advances in antiviral RNA interference in mammals. FEBS J. 2024, 291(2):208–216.
[48] Flemr M, Malik R, Franke V, Nejepinska J, Sedlacek R, et al. A retrotransposon-driven dicer isoform directs endogenous small interfering RNA production in mouse oocytes. Cell 2013, 155(4):807–816.
[49] Kennedy EM, Whisnant AW, Kornepati AV, Marshall JB, Bogerd HP, et al. Production of functional small interfering RNAs by an amino-terminal deletion mutant of human Dicer. Proc. Natl. Acad. Sci. U. S. A. 2016, 113(12):E6547.
[50] Seo GJ, Kincaid RP, Phanaksri T, Burke JM, Pare JM, et al. Reciprocal inhibition between intracellular antiviral signaling and the RNAi machinery in mammalian cells. Cell Host Microbe 2013, 14(4):435–445.
[51] van der Veen AG, Maillard PV, Schmidt JM, Lee SA, Deddouche-Grass S, et al. The RIG-I-like receptor LGP2 inhibits Dicer-dependent processing of long double-stranded RNA and blocks RNA interference in mammalian cells. EMBO J. 2018, 37(4):e97479.
[52] Maillard PV, Van der Veen AG, Deddouche-Grass S, Rogers NC, Merits A, et al. Inactivation of the type I interferon pathway reveals long double-stranded RNA-mediated RNA interference in mammalian cells. EMBO J. 2016, 35(23):2505–2518.
[53] Zhang Y, Xu Y, Dai Y, Li Z, Wang J, et al. Efficient Dicer processing of virus-derived double-stranded RNAs and its modulation by RIG-I-like receptor LGP2. PLoS Pathog. 2021, 17(8):e1009790.
[54] Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J. Extracell. Vesicles 2018, 7(1):1535750.
[55] Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 2014, 30:255–289.
[56] Kouwaki T, Okamoto M, Tsukamoto H, Fukushima Y, Oshiumi H. Extracellular Vesicles Deliver Host and Virus RNA and Regulate Innate Immune Response. Int. J. Mol. Sci. 2017, 18(3):666.
[57] Buzas EI. The roles of extracellular vesicles in the immune system. Nat. Rev. Immunol. 2023, 23(4):236–250.
[58] Kouwaki T, Fukushima Y, Daito T, Sanada T, Yamamoto N, et al. Extracellular Vesicles Including Exosomes Regulate Innate Immune Responses to Hepatitis B Virus Infection. Front. Immunol. 2016, 7:335.
[59] Hsu M, Zhang J, Flint M, Logvinoff C, Cheng-Mayer C, et al. Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles. Proc. Natl. Acad. Sci. U. S. A. 2003, 100(12):7271–7276.
[60] Naqvi AR. Immunomodulatory roles of human herpesvirus-encoded microRNA in host-virus interaction. Rev. Med. Virol. 2020, 30(1):e2081.
[61] Tassetto M, Kunitomi M, Andino R. Circulating Immune Cells Mediate a Systemic RNAi-Based Adaptive Antiviral Response in Drosophila. Cell 2017, 169(2):314–325.
[62] Zhang Y, Dai Y, Wang J, Xu Y, Li Z, et al. Mouse circulating extracellular vesicles contain virus-derived siRNAs active in antiviral immunity. EMBO J. 2022, 41(11):e109902.
[63] Lee SR, Roh JY, Ryu J, Shin HJ, Hong EJ. Activation of TCA cycle restrains virus-metabolic hijacking and viral replication in mouse hepatitis virus-infected cells. Cell Biosci. 2022, 12(1):7.
[64] Zou L, Wang X, Zhao F, Wu K, Li X, et al. Viruses Hijack ERAD to Regulate Their Replication and Propagation. Int. J. Mol. Sci. 2022, 23(16):9398.
[65] Racicot K, VanOeveren S, Alberts A. Viral Hijacking of Formins in Neurodevelopmental Pathologies. Trends Mol. Med. 2017, 23(9):778–785.
[66] Cullen BR, Cherry S, tenOever BR. Is RNA interference a physiologically relevant innate antiviral immune response in mammals?. Cell Host Microbe 2013, 14(4):374–378.
[67] Cullen BR. Viruses and RNA interference: issues and controversies. J. Virol. 2014, 88(22):12934–12936.
[68] Gantier MP. Processing of double-stranded RNA in mammalian cells: a direct antiviral role?. J. Interferon Cytokine Res. 2014, 34(6):469–477.
[69] Tsai K, Courtney DG, Kennedy EM, Cullen BR. Influenza A virus-derived siRNAs increase in the absence of NS1 yet fail to inhibit virus replication. RNA 2018, 24(9):1172–1182.
[70] Schuster S, Tholen LE, Overheul GJ, van Kuppeveld FJM, van Rij RP. Deletion of Cytoplasmic Double-Stranded RNA Sensors Does Not Uncover Viral Small Interfering RNA Production in Human Cells. mSphere 2017, 2(4):e00333-17.