The dUTPase of caprine arthritis-encephalitis virus negatively regulates interferon signaling pathway

Document Type : Full paper (Original article)

Authors

1 MSc Student in Biology, Department of Microbiology & Immunology, School of Life Sciences, Tianjin University, Tianjin, 300072, China

2 Departmet of Microbiology & Immunology, School of Life Sciences, Tianjin University, Tianjin, 300072, China

10.22099/ijvr.2021.38240.5568

Abstract

Background: Deoxyuracil triphosphate nucleotide (dUTP) pyrophosphatase (dUTPase, DU) is an enzyme of caprine arthritis-encephalitis virus (CAEV) that minimizes incorporation of dUTP into the DNA. Caprine arthritis-encephalitis virus relies partly on its ability to escape from innate immunity to cause persistent infections. Interferon β (IFN-β) is an important marker for evaluating the innate immune system, and it has a broad spectrum of antiviral activity. Aims: This study was conducted to investigate the details of the IFN-β response to CAEV infection. Methods: The expression of IFN-β and the proliferation of Sendai virus (SeV) and vesicular stomatitis virus (VSV) were determined by real-time quantitative polymerase chain reaction (qPCR). The effect of DU on the IFN signaling pathway was evaluated using luciferase reporter assays. Results: In our study, the expression of IFN-β was significantly inhibited and the proliferation of SeV and VSV was promoted in cells overexpressing CAEV-DU. DU affected interferon stimulated response element (ISRE) and IFN-β promoter activities induced by RIG-I/MDA5/MAVS/TBK1 pathway, while did not affect them induced by interferon regulatory factor 3 (IRF3-5D). Conclusion: DU protein downregulated the production of IFN-β by inhibiting the activity of the signal transduction molecules upstream of IRF3, thereby, helping CAEV escape innate immunity. Findings of this work provide an evidence to understand the persistent infection and multiple system inflammation of CAEV.

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Adedeji, AO; Barr, B; Gomez-Lucia, E and Murphy, B (2013). A polytropic caprine arthritis encephalitis virus promoter isolated from multiple tissues from a sheep with multisystemic lentivirus-associated inflammatory disease. Viruses. 5: 2005-2018.
Bakshi, S; Taylor, J; Strickson, S; McCartney, T and Cohen, P (2017). Identification of TBK1 complexes required for the phosphorylation of IRF3 and the production of interferon beta. Biochem. J., 474: 1163-1174.
Bandeira, DA; de Castro, RS; Azevedo, EO; de Souza Seixas Melo, L and de Melo, CB (2009). Seroprevalence of caprine arthritis-encephalitis virus in goats in the Cariri region, Paraiba state, Brazil. Vet. J., 180: 399-401.
Blacklaws, BA (2012). Small ruminant lentiviruses: immunopathogenesis of visna-maedi and caprine arthritis and encephalitis virus. Comp. Immunol. Microbiol. Infect. Dis., 35: 259-269.
Busca, A and Kumar, A (2014). Innate immune responses in hepatitis B virus (HBV) infection. Virol. J., 7: 11-22.
Cheevers, WP; Roberson, S; Klevjer-Anderson, P and Crawford, TB (1981). Characterization of caprine arthritis-encephalitis virus: a retrovirus of goats. Arch. Virol., 67: 111-117.
Chen, R; Wang, H and Mansky, LM (2002). Roles of uracil-DNA glycosylase and dUTPase in virus replication. J. Gen. Virol., 83: 2339-2345.
Crespo, H; Jauregui, P; Glaria, I; Sanjosé, L; Polledo, L; García-Marín, JF; Luján, L; de Andrés, D; Amorena, B and Reina, R (2012). Mannose receptor may be involved in small ruminant lentivirus pathogenesis. Vet. Res., 43: 1-6.
Cui, J; Chen, Y; Wang, HY and Wang, RF (2014). Mechanisms and pathways of innate immune activation and regulation in health and cancer. Hum. Vaccin Immunother., 10: 3270-3285.
de Pablo-Maiso, L; Domenech, A; Echeverria, I; Gomez-Arrebola, C; de Andres, D; Rosati, S; Gomez-Lucia, E and Reina, R (2018). Prospects in innate immune responses as potential control strategies against non-primate lentiviruses. Viruses. 10: 435-468.
Elder, JH; Lerner, DL; Hasselkus-Light, CS; Fontenot, DJ; Hunter, E; Luciw, PA; Montelaro, RC and Phillips, TR (1992). Distinct subsets of retroviruses encode dUTPase. J. Virol., 66: 1791-1794.
el-Hajj, HH; Zhang, H and Weiss, B (1988). Lethality of a dut (deoxyuridine triphosphatase) mutation in Escherichia coli. J. Bacteriolo., 170: 1069-1075.
Fensterl, V; Chattopadhyay, S and Sen, GC (2015). No love lost between viruses and interferons. Annu. Rev. Virol., 2: 549-572.
Fu, Y; Lu, D; Su, Y; Chi, H; Wang, J and Huang, J (2020). The Vif protein of caprine arthritis encephalitis virus inhibits interferon production. Arch. Virol., 165: 1557-1567.
Gadsden, MH; McIntosh, EM; Game, JC; Wilson, PJ and Haynes, RH (1993). dUTP pyrophosphatase is an essential enzyme in Saccharomyces cerevisiae. The EMBO J., 12: 4425-4431.
Greenwood, PL; North, RN and Kirkland, PD (1995). Prevalence, spread and control of caprine arthritis-encephalitis virus in dairy goat herds in New South Wales. Austr. Vet. J., 72: 341-345.
He, X; Ma, S; Tian, Y; Wei, C; Zhu, Y; Li, F; Zhang, P; Wang, P; Zhang, Y and Zhong, H (2017). ERRalpha negatively regulates type I interferon induction by inhibiting TBK1-IRF3 interaction. PLoS Pathog., 13: e1006347.
Hess, J; Pyper, JM and Clements, JE (1986). Nucleotide sequence and transcriptional activity of the caprine arthritis-encephalitis virus long terminal repeat. J. Virol., 60: 385-393.
Hizi, A and Herzig, E (2015). dUTPase: the frequently overlooked enzyme encoded by many retroviruses. Retrovirology. 12: 70-77.
Huang, J; Sun, Y; Liu, Y; Xiao, H and Zhuang, S (2012). Development of a loop-mediated isothermal amplification method for rapid detection of caprine arthritis-encephalitis virus proviral DNA. Arch. Virol., 157: 1463-1469.
Jonsson, SR and Andresdottir, V (2011). Propagating and detecting an infectious molecular clone of maedi-visna virus that expresses green fluorescent protein. J. Vis. Exp., 9: 3483-3485.
Juganaru, M; Reina, R; Grego, E; Profiti, M and Rosati, S (2010). LTR promoter activity of SRLV genotype E, strain Roccaverano. Vet. Res. Comm., 34: 47-51.
Juste, RA; Villoria, M; Leginagoikoa, I; Ugarte, E and Minguijon, E (2020). Milk production losses in Latxa dairy sheep associated with small ruminant lentivirus infection. Prev. Vet. Med., 176: 104886-104892.
Kaba, J; Strzałkowska, N; Jóźwik, A; Krzyżewski, J and Bagnicka, E (2012). Twelve-year cohort study on the influence of caprine arthritis-encephalitis virus infection on milk yield and composition. J. Dairy Sci., 95: 1617-1622.
Kato, A; Hirohata, Y; Arii, J and Kawaguchi, Y (2014). Phosphorylation of herpes simplex virus 1 dUTPase upregulated viral dUTPase activity to compensate for low cellular dUTPase activity for efficient viral replication. J. Virol., 88: 7776-7785.
Kato, H; Takeuchi, O; Mikamo-Satoh, E; Hirai, R; Kawai, T; Matsushita, K; Hiiragi, A; Dermody, TS; Fujita, T and Akira, S (2008). Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J. Exp. Med., 205: 1601-1610.
Klotz, D; Baumgartner, W and Gerhauser, I (2017). Type I interferons in the pathogenesis and treatment of canine diseases. Vet. Immunol. Immunopathol., 191: 80-93.
Lamara, A; Fieni, F; Chatagnon, G; Larrat, M; Dubreil, L and Chebloune, Y (2013). Caprine arthritis encephalitis virus (CAEV) replicates productively in cultured epididymal cells from goats. Comp. Immunol. Microbiol. Infect. Dis., 36: 397-404.
Leang, RS; Wu, TT; Hwang, S; Liang, LT; Tong, L; Truong, JT and Sun, R (2011). The anti-interferon activity of conserved viral dUTPase ORF54 is essential for an effective MHV-68 infection. PLoS Pathog., 7: e1002292.
Leitner, G; Krifucks, O; Weisblit, L; Lavi, Y; Bernstein, S and Merin, U (2010). The effect of caprine arthritis encephalitis virus infection on production in goats. Vet. J., 183: 328-331.
Li, Y; Zhou, F; Li, X; Wang, J; Zhao, X and Huang, J (2013). Development of TaqMan-based qPCR method for detection of caprine arthritis-encephalitis virus (CAEV) infection. Arch. Virol., 158: 2135-2141.
Liu, S; Cai, X; Wu, J; Cong, Q; Chen, X; Li, T; Du, F; Ren, J; Wu, YT; Grishin, NV and Chen, ZJ (2015). Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science. 347: aaa2630-1-2630-11.
Liu, C; Huang, S; Wang, X; Wen, M; Zheng, J; Wang, W; Fu, Y; Tian, S; Li, L; Li, Z andWang, X (2019). The otubain YOD1 suppresses aggregation and activation of the signaling adaptor MAVS through Lys63-linked deubiquitination. J. Immunol., 202: 2957-2970.
Loo, YM and Gale Jr, M (2011). Immune signaling by RIG-I-like receptors. Immunity. 34: 680-692.
McGeoch, DJ (1990). Protein sequence comparisons show that the ‘pseudoproteases’ encoded by poxviruses and certain retroviruses belong to the deoxyuridine triphosphatase family. Nuc. Acid Res., 18: 4105-4110.
McIntosh, EM and Haynes, RH (1997). dUTP pyrophosphatase as a potential target for chemotherapeutic drug development. Acta Biochim. Polo., 44: 159-171.
Michiels, R; Van Mael, E; Quinet, C; Welby, S; Cay, AB and De Regge, N (2018). Seroprevalence and risk factors related to small ruminant lentivirus infections in Belgian sheep and goats. Prev. Vet. Med., 151: 13-20.
Narayan, O; Kennedy-Stoskopf, S; Sheffer, D; Griffin, DE and Clements, JE (1983). Activation of caprine arthritis-encephalitis virus expression during maturation of monocytes to macrophages. Infect. Imm., 41: 67-73.
Narayan, O; Wolinsky, JS; Clements, JE; Strandberg, JD; Griffin, DE and Cork, LC (1982). Slow virus replication: the role of macrophages in the persistence and expression of visna viruses of sheep and goats. J. Gen. Virol., 59: 345-356.
Nardelli, S; Bettini, A; Capello, K; Bertoni, G and Tavella, A (2020). Eradication of caprine arthritis encephalitis virus in the goat population of South Tyrol, Italy: analysis of the tailing phenomenon during the 2016-2017 campaign. J. Vet. Diagn. Invest., 32: 589-593.
Oem, JK; Chung, JY; Byun, JW; Kim, HY; Kwak, D and Jung, BY (2012). Large-scale serological survey of caprine arthritis-encephalitis virus (CAEV) in Korean black goats (Capra hircus aegagrus). J. Vet. Med. Sci., 74: 1657-1659.
Pablo-Maiso, LD; Echeverría, I; Rius-Rocabert, S; Luján, L; Garcin, D; Andrés, DD; Nistal-Villán, E and Reina, R (2020). Sendai virus, a strong inducer of anti-lentiviral state in ovine cells. Vaccines. 8: 206-221.
Payne, SL and Elder, JH (2001). The role of retroviral dUTPases in replication and virulence. Curr. Protein Pept. Sci., 2: 381-388.
Peterhans, E; Greenland, T; Badiola, J; Harkiss, G; Bertoni, G; Amorena, B; Eliaszewicz, M; Juste, RA; Kraßnig, R and Lafont, JP (2004). Routes of transmission and consequences of small ruminant lentiviruses (SRLVs) infection and eradication schemes. Vet. Res., 35: 257-274.
Reina, R; Grego, E; Bertolotti, L; De Meneghi, D and Rosati, S (2009). Genome analysis of small-ruminant lentivirus genotype E: a caprine lentivirus with natural deletions of the dUTPase subunit, vpr-like accessory gene, and 70-base-pair repeat of the U3 region. J. Virol., 83: 1152-1155.
Saltarelli, M; Querat, G; Konings, DA; Vigne, R and Clements, JE (1990). Nucleotide sequence and transcriptional analysis of molecular clones of CAEV which generate infectious virus. Virology. 179: 347-364.
Sen, N; Sommer, M; Che, X; White, K; Ruyechan, WT and Arvin, AM (2010). Varicella-zoster virus immediate-early protein 62 blocks interferon regulatory factor 3 (IRF3) phosphorylation at key serine residues: a novel mechanism of IRF3 inhibition among herpesviruses. J. Virol., 84: 9240-9253.
Shi, P; Su, Y; Li, R; Zhang, L; Chen, C; Zhang, L; Faaberg, K and Huang, J (2018). Dual regulation of host TRAIP post-translation and nuclear/plasma distribution by porcine reproductive and respiratory syndrome virus non-structural protein 1α promotes viral proliferation. Front. Immunol., 9: 3023.
Sun, Y and Lopez, CB (2017). The innate immune response to RSV: Advances in our understanding of critical viral and host factors. Vaccine. 35: 481-488.
Tageldin, MH; Johnson, EH; Al-Busaidi, RM; Al-Habsi, KR and Al-Habsi, SS (2012). Serological evidence of caprine arthritis-encephalitis virus (CAEV) infection in indigenous goats in the Sultanate of Oman. Trop. Anim. Health Prod., 44: 1-3.
Tu, PA; Shiu, JS; Lee, SH; Pang, VF; Wang, DC and Wang, PH (2017). Development of a recombinase polymerase amplification lateral flow dipstick (RPA-LFD) for the field diagnosis of caprine arthritis-encephalitis virus (CAEV) infection. J. Virol. Methods. 243: 98-104.
Turelli, P; Guiguen, F; Mornex, JF; Vigne, R and Querat, G (1997). dUTPase-minus caprine arthritis-encephalitis virus is attenuated for pathogenesis and accumulates G-to-A substitutions. J. Virol., 71: 4522-4530.
Vertessy, BG and Toth, J (2009). Keeping uracil out of DNA: physiological role, structure and catalytic mechanism of dUTPases. Acc. Chem. Res., 42: 97-106.
Weil, AF; Ghosh, D; Zhou, Y; Seiple, L; McMahon, MA; Spivak, AM; Siliciano, RF and Stivers, JT (2013). Uracil DNA glycosylase initiates degradation of HIV-1 cDNA containing misincorporated dUTP and prevents viral integration. Proc. Natl. Acad. Sci. USA., 110: E448-E457.
Yang, S; Zhou, X; Li, R; Fu, X and Sun, P (2017). Optimized PEI-based transfection method for transient transfection and lentiviral production. Curr. Protoc. Chem. Biolo., 9: 147-157.
Zhang, R; Xu, A; Qin, C; Zhang, Q; Chen, S; Lang, Y; Wang, M; Li, C; Feng, W; Zhang, R; Jiang, Z and Tang, J (2017). Pseudorabies virus dUTPase UL50 induces lysosomal degradation of type I interferon receptor 1 and antagonizes the alpha interferon response. J. Virol., 91: e01148-17.
Zink, M and Narayan, O (1989). Lentivirus-induced interferon inhibits maturation and proliferation of monocytes and restricts the replication of caprine arthritis-encephalitis virus. J. Virol., 63: 2578-2584.