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01-12-2019 | Rabies | Original Article

Cholesterol 25-hydroxylase suppresses rabies virus infection by inhibiting viral entry

Authors: Yueming Yuan, Zongmei Wang, Bin Tian, Ming Zhou, Zhen F. Fu, Ling Zhao

Published in: Archives of Virology | Issue 12/2019

Abstract

Cholesterol-25-hydroxylase (CH25H) is a reticulum-associated membrane protein that catalyzes the oxidation of cholesterol to 25-hydroxycholesterol (25HC). Recent studies have revealed that CH25H is an interferon-stimulated gene (ISG) that suppresses infection by several viruses. In the present study, we found that overexpression of both human and murine CH25H inhibited rabies virus (RABV) infection in HEK-293T (293T) cells. In contrast, silencing of CH25H enhanced RABV replication in 293T cells, and a catalytic mutant of CH25H lost its ability to inhibit RABV infection. Treatment with the oxysterol 25-hydroxycholesterol (25HC), the product of CH25H, dramatically decreased RABV replication in 293T, BSR and N2a cells by inhibiting viral membrane penetration. These data provide insights into the antiviral function of CH25H against RABV infection, which can potentially be used as a therapeutic agent for rabies.

Hampson K, Coudeville L, Lembo T et al (2015) Estimating the global burden of endemic canine rabies. PLoS Negl Trop Dis 9:e0003709. https://doi.org/10.1371/journal.pntd.0003709 CrossRefPubMedPubMedCentral

Hidaka Y, Lim C-K, Takayama-Ito M et al (2018) Segmentation of the rabies virus genome. Virus Res 252:68–75. https://doi.org/10.1016/j.virusres.2018.05.017 CrossRefPubMed

Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820. https://doi.org/10.1016/j.cell.2010.01.022 CrossRefPubMed

Schoggins JW, Rice CM (2011) Interferon-stimulated genes and their antiviral effector functions. Curr Opin Virol 1:519–525. https://doi.org/10.1016/j.coviro.2011.10.008 CrossRefPubMedPubMedCentral

Sen GC, Peters GA (2007) Viral stress-inducible genes. Advances in virus research. Elsevier, Amsterdam, pp 233–263

Blondel D, Maarifi G, Nisole S, Chelbi-Alix M (2015) Resistance to rhabdoviridae infection and subversion of antiviral responses. Viruses 7:3675–3702. https://doi.org/10.3390/v7072794 CrossRefPubMedPubMedCentral

Faul EJ, Wanjalla CN, Suthar MS et al (2010) Rabies virus infection induces type I interferon production in an IPS-1 dependent manner while dendritic cell activation relies on IFNAR signaling. PLoS Pathog 6:e1001016. https://doi.org/10.1371/journal.ppat.1001016 CrossRefPubMedPubMedCentral

Tian B, Zhou M, Yang Y et al (2018) Lab-Attenuated rabies virus causes abortive infection and induces cytokine expression in astrocytes by activating mitochondrial antiviral-signaling protein signaling pathway. Front Immunol 8:2011. https://doi.org/10.3389/fimmu.2017.02011 CrossRefPubMedPubMedCentral

Davis BM, Fensterl V, Lawrence TM et al (2017) Ifit2 is a restriction factor in rabies virus pathogenicity. J Virol 91:e00889-17. https://doi.org/10.1128/JVI.00889-17 CrossRefPubMedPubMedCentral

10.

Blondel D, Regad T, Poisson N et al (2002) Rabies virus P and small P products interact directly with PML and reorganize PML nuclear bodies. Oncogene 21:7957–7970. https://doi.org/10.1038/sj.onc.1205931 CrossRefPubMed

11.

Tang H-B, Lu Z-L, Wei X-K et al (2016) Viperin inhibits rabies virus replication via reduced cholesterol and sphingomyelin and is regulated upstream by TLR4. Sci Rep 6:30529. https://doi.org/10.1038/srep30529 CrossRefPubMedPubMedCentral

12.

Lund EG, Kerr TA, Sakai J et al (1998) cDNA cloning of mouse and human cholesterol 25-hydroxylases, polytopic membrane proteins that synthesize a potent oxysterol regulator of lipid metabolism. J Biol Chem 273:34316–34327. https://doi.org/10.1074/jbc.273.51.34316 CrossRefPubMed

13.

Song Z, Zhang Q, Liu X et al (2017) Cholesterol 25-hydroxylase is an interferon-inducible factor that protects against porcine reproductive and respiratory syndrome virus infection. Vet Microbiol 210:153–161. https://doi.org/10.1016/j.vetmic.2017.09.011 CrossRefPubMed

14.

Liu S-Y, Aliyari R, Chikere K et al (2013) Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity 38:92–105. https://doi.org/10.1016/j.immuni.2012.11.005 CrossRefPubMed

15.

Civra A, Cagno V, Donalisio M et al (2015) Inhibition of pathogenic non-enveloped viruses by 25-hydroxycholesterol and 27-hydroxycholesterol. Sci Rep 4:7487. https://doi.org/10.1038/srep07487 CrossRef

16.

Wang ZW, Sarmento L, Wang Y et al (2005) Attenuated rabies virus activates, while pathogenic rabies virus evades, the host innate immune responses in the central nervous system. J Virol 79:12554–12565. https://doi.org/10.1128/JVI.79.19.12554-12565.2005 CrossRefPubMedPubMedCentral

17.

Jiang Y, Luo Y, Michel F et al (2010) Characterization of conformation-specific monoclonal antibodies against rabies virus nucleoprotein. Arch Virol 155:1187–1192. https://doi.org/10.1007/s00705-010-0709-x CrossRefPubMedPubMedCentral

18.

Zhou M, Wang L, Zhou S et al (2015) Recombinant rabies virus expressing dog GM-CSF is an efficacious oral rabies vaccine for dogs. Oncotarget. https://doi.org/10.18632/oncotarget.5904 CrossRefPubMedPubMedCentral

19.

Meslin F-X, Kaplan MM, Koprowski H (1996) The fluorescent antibody test. Laboratory techniques in rabies, 4th edn. World Health Organization, Geneva, pp 88–91

20.

Ma Y, Wei Y, Zhang X et al (2014) mRNA cap methylation influences pathogenesis of vesicular stomatitis virus in vivo. J Virol 88:2913–2926. https://doi.org/10.1128/JVI.03420-13 CrossRefPubMedPubMedCentral

21.

Ke W, Fang L, Jing H et al (2017) Cholesterol 25-hydroxylase inhibits porcine reproductive and respiratory syndrome virus replication through enzyme activity-dependent and -independent mechanisms. J Virol 91:e00827-17. https://doi.org/10.1128/JVI.00827-17 CrossRefPubMedPubMedCentral

22.

Schneider WM, Chevillotte MD, Rice CM (2014) Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol 32:513–545. https://doi.org/10.1146/annurev-immunol-032713-120231 CrossRefPubMedPubMedCentral

23.

Wiltzer L, Okada K, Yamaoka S et al (2014) Interaction of rabies virus P-protein with STAT proteins is critical to lethal rabies disease. J Infect Dis 209:1744–1753. https://doi.org/10.1093/infdis/jit829 CrossRefPubMed

24.

Lieu KG, Brice A, Wiltzer L et al (2013) The rabies virus interferon antagonist P protein interacts with activated STAT3 and inhibits Gp130 receptor signaling. J Virol 87:8261–8265. https://doi.org/10.1128/JVI.00989-13 CrossRefPubMedPubMedCentral

25.

Vidy A, Chelbi-Alix M, Blondel D (2005) Rabies virus P protein interacts with STAT1 and inhibits interferon signal transduction pathways. J Virol 79:14411–14420. https://doi.org/10.1128/JVI.79.22.14411-14420.2005 CrossRefPubMedPubMedCentral

26.

Fouquet B, Nikolic J, Larrous F et al (2015) Focal adhesion kinase is involved in rabies virus infection through its interaction with viral phosphoprotein P. J Virol 89:1640–1651. https://doi.org/10.1128/JVI.02602-14 CrossRefPubMed

27.

Raux H, Flamand A, Blondel D (2000) Interaction of the rabies virus P protein with the LC8 dynein light chain. J Virol 74:10212–10216. https://doi.org/10.1128/JVI.74.21.10212-10216.2000 CrossRefPubMedPubMedCentral

28.

Zhang Y, Wang L, Huang X et al (2019) Fish cholesterol 25-hydroxylase inhibits virus replication via regulating interferon immune response or affecting virus entry. Front Immunol 10:322. https://doi.org/10.3389/fimmu.2019.00322 CrossRefPubMedPubMedCentral

29.

Li C, Deng Y-Q, Wang S et al (2017) 25-Hydroxycholesterol protects host against Zika virus infection and its associated microcephaly in a mouse model. Immunity 46:446–456. https://doi.org/10.1016/j.immuni.2017.02.012 CrossRefPubMedPubMedCentral

30.

Xiang Y, Tang J-J, Tao W et al (2015) Identification of cholesterol 25-hydroxylase as a novel host restriction factor and a part of the primary innate immune responses against hepatitis C virus infection. J Virol 89:6805–6816. https://doi.org/10.1128/JVI.00587-15 CrossRefPubMedPubMedCentral

31.

Blanc M, Hsieh WY, Robertson KA et al (2013) The transcription factor STAT-1 couples macrophage synthesis of 25-hydroxycholesterol to the interferon antiviral response. Immunity 38:106–118. https://doi.org/10.1016/j.immuni.2012.11.004 CrossRefPubMedPubMedCentral

32.

You H, Yuan H, Fu W et al (2017) Herpes simplex virus type 1 abrogates the antiviral activity of Ch25h via its virion host shutoff protein. Antivir Res 143:69–73. https://doi.org/10.1016/j.antiviral.2017.04.004 CrossRefPubMed

33.

Song Z, Bai J, Nauwynck H et al (2019) 25-Hydroxycholesterol provides antiviral protection against highly pathogenic porcine reproductive and respiratory syndrome virus in swine. Vet Microbiol 231:63–70. https://doi.org/10.1016/j.vetmic.2019.02.035 CrossRefPubMed

34.

Civra A, Francese R, Gamba P et al (2018) 25-Hydroxycholesterol and 27-hydroxycholesterol inhibit human rotavirus infection by sequestering viral particles into late endosomes. Redox Biol 19:318–330. https://doi.org/10.1016/j.redox.2018.09.003 CrossRefPubMedPubMedCentral

35.

van Lier JE, Mast N, Pikuleva IA (2015) Cholesterol hydroperoxides as substrates for cholesterol-metabolizing cytochrome P450 enzymes and alternative sources of 25-hydroxycholesterol and other oxysterols. Angew Chem Int Ed 54:11138–11142. https://doi.org/10.1002/anie.201505002 CrossRef

Title: Cholesterol 25-hydroxylase suppresses rabies virus infection by inhibiting viral entry
Authors: Yueming Yuan
Zongmei Wang
Bin Tian
Ming Zhou
Zhen F. Fu
Ling Zhao
Publication date: 01-12-2019
Publisher: Springer Vienna
Keyword: Rabies
Published in: Archives of Virology / Issue 12/2019
Print ISSN: 0304-8608
Electronic ISSN: 1432-8798
DOI: https://doi.org/10.1007/s00705-019-04415-6

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