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Current Proteomics

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ISSN (Print): 1570-1646
ISSN (Online): 1875-6247

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Research Article

Interaction of Human Herpesvirus 8 Viral Interleukin-6 with Human Interleukin-6 Receptor Using In Silico Approach: The Potential Role in HHV-8 Pathogenesis

Author(s): Behzad Dehghani, Tayebeh Hashempour* and Zahra Hasanshahi

Volume 17, Issue 2, 2020

Page: [107 - 116] Pages: 10

DOI: 10.2174/1570164616666190626151949

Price: $65

Abstract

Introduction: Human Herpesvirus 8 (HHV-8) causes classical, endemic (African), and Acquired Immunodeficiency Syndrome (AIDS)-related Kaposi’s Sarcoma (KS), Body Cavity-Based Primary Effusion Lymphomas (BCBL), HHV-8-associated peritoneal Primary Effusion Lymphoma (PEL), and Multicentric Castleman’s Disease (MCD). HHV8 genome encodes several structural and non-structural proteins, among which vIL6 is a functional homologue of Interleukin-6 (IL-6). It has been established that vIL6 plays a vital role in HHV8 infections; also, it has been suggested that its function was mediated through gp130, rather than the gp80 (IL-6 receptor [IL-6R]). This study aimed to investigate the physicochemical and structural properties as well as the immunological features, and finally the interaction between vIL6 and IL6 receptor (IL6R) by using several bioinformatics tools which could provide both valuable insight into vIL6 protein and advantageous data for further studies on HHV8 inhibitors and new vaccines.

Material and Methods: vIL6, human IL6 (hIL6), and IL6R were obtained from NCBI GenBank and Uniport, which were aligned by The CLC Genomics Workbench. "Signal-BLAST" and “predisi" were employed to define signal peptide; also, “Expasy’sProtParam” was used to predict physicochemical properties as well as "DiANNA", and "SCRATCH" predicted the disulfide bonds. “NetPhosK”, “DISPHOS”, “NetPhos”, ”NetNGlyc”, and ”GlycoEP” were involved to determine post-modification sites. To define immunoinformatics analysis, “BcePred”, “ABCpred”, “Bepipred”, “AlgPred”, and "VaxiJen" were used. “SOPMA”, “I-TASSER”, “GalaxyRefine”, and “3D-Refine” predicted and refined the secondary and tertiary structures. TM-align server was used to align 3D structures. In addition, docking analysis was done by “Hex 5.0.”, and finally the results were illustrated by “Discovery Studio”.

Results: A signal peptide (1-22) was defined in the vIL6 sequences and analysis has shown that vIL6 is an acidic protein which is significantly stable in all organisms. Three Disulfide bonds were predicted and immunoinformatics analysis showed 5 distinct B-cell epitopes. vIL6 is predicted as a non-allergen protein and the majority of its structure consists of Alpha helix. TM-align pointed the significant similarity between vIL6 and hIL6 in protein folding. The high energy value between vIL6 protein and IL6R was calculated and further analysis illustrated 5 conserved regions as well as 4 conserved amino acids which had a significant role in vIL6 and IL6R interaction.

Discussion: An in silico study by numerous software determined the possible interaction between vIL6 and IL6R and the possible role of this interaction in HHV8 pathogenesis and the progress of infection. These have been overlooked by previous studies and will be beneficial to gain a more comprehensive understanding of vIL6 function during HHV8 lifecycle and infections. Structural analysis showed the significant similarity between vIL6 and hIL6 folding which can describe the similarity of the functions or interactions of both proteins. Furthermore, several conserved regions in the interaction site which interestingly were highly conserved among all vIL6 sequences can be used as new target for vIL6 inhibitors. Moreover, our results could predict immunological properties of vIL6 which suggested the ability of this protein in induction of the humoral immune response. Such a protein may be used for further studies on therapeutic vaccine fields.

Keywords: HHV-8, vIL6, human IL6, IL6R, bioinformatics, MCD.

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[1]
Blauvelt, A. Skin diseases associated with human herpesvirus 6, 7, and 8 infection. J. Investig. Dermatol. Symp. Proc., 2001, 6(3), 197-202.
[2]
Campbell, D.M.; Rappocciolo, G.; Jenkins, F.J.; Rinaldo, C.R. Dendritic cells: key players in human herpesvirus 8 infection and pathogenesis. Front. Microbiol., 2014, 5, 452.
[http://dx.doi.org/10.3389/fmicb.2014.00452] [PMID: 25221546]
[3]
Grayson, W.; Pantanowitz, L. Histological variants of cutaneous Kaposi sarcoma. Diagn. Pathol., 2008, 3(1), 31.
[http://dx.doi.org/10.1186/1746-1596-3-31] [PMID: 18655700]
[4]
Al-Kzayer, L.F.; Keizer, P.; Abdulraheem, F.T.; Sano, K.; Kamata, M.; Sakashita, K.; Habbaba, L.A.; Koike, K. Rapidly progressive Kaposi’s Sarcoma in an Iraqi boy received valproic acid: A case report and review of literature. BMC Pediatr., 2016, 16(1), 111.
[http://dx.doi.org/10.1186/s12887-016-0653-3] [PMID: 27459853]
[5]
Dow, D.E.; Cunningham, C.K.; Buchanan, A.M. A review of human herpesvirus 8, the Kaposi’s sarcoma-associated herpesvirus, in the pediatric population. J. Pediatric Infect. Dis. Soc., 2014, 3(1), 66-76.
[http://dx.doi.org/10.1093/jpids/pit051] [PMID: 24567845]
[6]
Wu, W.; Vieira, J.; Fiore, N.; Banerjee, P.; Sieburg, M.; Rochford, R.; Harrington, W., Jr; Feuer, G. KSHV/HHV-8 infection of human hematopoietic progenitor (CD34+) cells: persistence of infection during hematopoiesis in vitro and in vivo. Blood, 2006, 108(1), 141-151.
[http://dx.doi.org/10.1182/blood-2005-04-1697] [PMID: 16543476]
[7]
Gregory, S.M.; Wang, L.; West, J.A.; Dittmer, D.P.; Damania, B. Latent Kaposi’s sarcoma-associated herpesvirus infection of monocytes downregulates expression of adaptive immune response costimulatory receptors and proinflammatory cytokines. J. Virol., 2012, 86(7), 3916-3923.
[http://dx.doi.org/10.1128/JVI.06437-11] [PMID: 22278234]
[8]
Starita, N.; Di Monta, G.; Cerasuolo, A.; Marone, U.; Anniciello, A.M.; Botti, G.; Buonaguro, L.; Buonaguro, F.M.; Tornesello, M.L. Effect of electrochemotherapy on human herpesvirus 8 kinetics in classic Kaposi sarcoma. Infect. Agent. Cancer, 2017, 12(1), 35.
[http://dx.doi.org/10.1186/s13027-017-0147-4] [PMID: 28649271]
[9]
Campbell, T.B.; Borok, M.; Gwanzura, L.; MaWhinney, S.; White, I.E.; Ndemera, B.; Gudza, I.; Fitzpatrick, L.; Schooley, R.T. Relationship of human herpesvirus 8 peripheral blood virus load and Kaposi’s sarcoma clinical stage. AIDS, 2000, 14(14), 2109-2116.
[http://dx.doi.org/10.1097/00002030-200009290-00006] [PMID: 11061651]
[10]
Sakakibara, S.; Tosato, G. Viral interleukin-6: role in Kaposi’s sarcoma-associated herpesvirus: associated malignancies. J. Interferon Cytokine Res., 2011, 31(11), 791-801.
[http://dx.doi.org/10.1089/jir.2011.0043] [PMID: 21767154]
[11]
Cousins, E.; Gao, Y.; Sandford, G.; Nicholas, J. Human herpesvirus 8 viral interleukin-6 signaling through gp130 promotes virus replication in primary effusion lymphoma and endothelial cells. J.Virol.,, 2014, JVI, 01751-14.
[http://dx.doi.org/10.1128/JVI.01751-14]
[12]
Staskus, K.A.; Sun, R.; Miller, G.; Racz, P.; Jaslowski, A.; Metroka, C.; Brett-Smith, H.; Haase, A.T. Cellular tropism and viral interleukin-6 expression distinguish human herpesvirus 8 involvement in Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. J. Virol., 1999, 73(5), 4181-4187.
[PMID: 10196314]
[13]
Suthaus, J.; Stuhlmann-Laeisz, C.; Tompkins, V. S.; Rosean, T. R.; Klapper, W.; Tosato, G.; Janz, S.; Scheller, J.; Rose-John, S. HHV8 encoded viral IL-6 collaborates with mouse IL-6 in MCD-like development in mice. Blood,, 2012. blood-2011-09-377705.
[14]
Dehghani, B.; Ghasabi, F.; Hashempoor, T.; Joulaei, H.; Hasanshahi, Z.; Halaji, M.; Chatrabnous, N.; Mousavi, Z.; Moayedi, J. Functional and structural characterization of Ebola virus glycoprotein (1976-2015)-an in silico study. Int. J. Biomath., 2017, 10(08)1750108
[http://dx.doi.org/10.1142/S179352451750108X]
[15]
Negahdaripour, M.; Nezafat, N.; Eslami, M.; Ghoshoon, M.B.; Shoolian, E.; Najafipour, S.; Morowvat, M.H.; Dehshahri, A.; Erfani, N.; Ghasemi, Y. Structural vaccinology considerations for in silico designing of a multi-epitope vaccine. Infect. Genet. Evol., 2018, 58, 96-109.
[http://dx.doi.org/10.1016/j.meegid.2017.12.008] [PMID: 29253673]
[16]
Farhadi, T.; Nezafat, N.; Ghasemi, Y.; Karimi, Z.; Hemmati, S.; Erfani, N. Designing of complex multi-epitope peptide vaccine based on omps of Klebsiella pneumoniae: An in silico approach. Int. J. Pept. Res. Ther., 2015, 21(3), 325-341.
[http://dx.doi.org/10.1007/s10989-015-9461-0]
[17]
Hajighahramani, N.; Nezafat, N.; Eslami, M.; Negahdaripour, M.; Rahmatabadi, S.S.; Ghasemi, Y. Immunoinformatics analysis and in silico designing of a novel multi-epitope peptide vaccine against Staphylococcus aureus. Infect. Genet. Evol., 2017, 48, 83-94.
[http://dx.doi.org/10.1016/j.meegid.2016.12.010] [PMID: 27989662]
[18]
Moattari, A.; Dehghani, B.; Khodadad, N.; Tavakoli, F. In silico functional and structural characterization of H1N1 influenza a viruses hemagglutinin, 2010-2013, Shiraz, Iran. Acta Biotheor., 2015, 63(2), 183-202.
[http://dx.doi.org/10.1007/s10441-015-9260-1] [PMID: 25963671]
[19]
Dehghani, B.; Rasooli, I.; Jalali-Nadoushan, M.; Owlia, P.; Rasooli, Z. Immunoprotectivity of Salmonella enterica serovar Enteritidis virulence protein, InvH, against Salmonella typhi. Iran. J. Basic Med. Sci., 2014, 17(8), 560-565.
[PMID: 25422747]
[20]
Dehghani, B.; Rasooli, I.; Gargari, S.L.M.; Nadooshan, M.R.J.; Owlia, P.; Nazarian, S. Immunogenicity of Salmonella enterica serovar Enteritidis virulence protein, InvH, and cross-reactivity of its antisera with Salmonella strains. Microbiol. Res., 2013, 168(2), 84-90.
[http://dx.doi.org/10.1016/j.micres.2012.09.002] [PMID: 23141708]
[21]
Frank, K.; Sippl, M.J. High-performance signal peptide prediction based on sequence alignment techniques. Bioinformatics, 2008, 24(19), 2172-2176.
[http://dx.doi.org/10.1093/bioinformatics/btn422] [PMID: 18697773]
[22]
Tanaka, T.; Narazaki, M.; Kishimoto, T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb. Perspect. Biol., 2014, 6(10)a016295
[http://dx.doi.org/10.1101/cshperspect.a016295] [PMID: 25190079]
[23]
Wan, X.; Wang, H.; Nicholas, J. Human herpesvirus 8 interleukin-6 (vIL-6) signals through gp130 but has structural and receptor-binding properties distinct from those of human IL-6. J. Virol., 1999, 73(10), 8268-8278.
[PMID: 10482577]
[24]
Cannon, J.S.; Nicholas, J.; Orenstein, J.M.; Mann, R.B.; Murray, P.G.; Browning, P.J.; DiGiuseppe, J.A.; Cesarman, E.; Hayward, G.S.; Ambinder, R.F. Heterogeneity of viral IL-6 expression in HHV-8-associated diseases. J. Infect. Dis., 1999, 180(3), 824-828.
[http://dx.doi.org/10.1086/314956] [PMID: 10438372]
[25]
Giffin, L.; Damania, B. KSHV: pathways to tumorigenesis and persistent infection. Adv. Virus Res., 2014, 88, 111-159.
[26]
Neipel, F.; Albrecht, J-C.; Ensser, A.; Huang, Y-Q.; Li, J.J.; Friedman-Kien, A.E.; Fleckenstein, B. Human herpesvirus 8 encodes a homolog of interleukin-6. J. Virol., 1997, 71(1), 839-842.
[PMID: 8985427]
[27]
Cousins, E.; Nicholas, J. Role of human herpesvirus 8 interleukin-6-activated gp130 signal transducer in primary effusion lymphoma cell growth and viability. J. Virol., 2013, 87(19), 10816-10827.
[http://dx.doi.org/10.1128/JVI.02047-13]
[28]
Adam, N.; Rabe, B.; Suthaus, J.; Grötzinger, J.; Rose-John, S.; Scheller, J. Unraveling viral interleukin-6 binding to gp130 and activation of STAT-signaling pathways independently of the interleukin-6 receptor. J. Virol., 2009, 83(10), 5117-5126.
[http://dx.doi.org/10.1128/JVI.01601-08] [PMID: 19264784]
[29]
Burger, R.; Neipel, F.; Fleckenstein, B.; Savino, R.; Ciliberto, G.; Kalden, J.R.; Gramatzki, M. Human herpesvirus type 8 interleukin-6 homologue is functionally active on human myeloma cells. Blood, 1998, 91(6), 1858-1863.
[PMID: 9490667]
[30]
Grötzinger, J.; Kurapkat, G.; Wollmer, A.; Kalai, M.; Rose-John, S. The family of the IL-6-type cytokines: Specificity and promiscuity of the receptor complexes. Proteins, 1997, 27(1), 96-109.
[http://dx.doi.org/10.1002/(SICI)1097-0134(199701)27:1<96:AID-PROT10>3.0.CO;2-D] [PMID: 9037715]
[31]
Dela Cruz, C.S.; Lee, Y.; Viswanathan, S.R.; El-Guindy, A.S.; Gerlach, J.; Nikiforow, S.; Shedd, D.; Gradoville, L.; Miller, G. N-linked glycosylation is required for optimal function of Kaposi’s sarcoma herpesvirus-encoded, but not cellular, interleukin 6. J. Exp. Med., 2004, 199(4), 503-514.
[http://dx.doi.org/10.1084/jem.20031205] [PMID: 14970177]
[32]
Parekh, R.B.; Dwek, R.A.; Rademacher, T.W.; Opdenakker, G.; Van Damme, J. Glycosylation of interleukin-6 purified from normal human blood mononuclear cells. Eur. J. Biochem., 1992, 203(1-2), 135-141.
[http://dx.doi.org/10.1111/j.1432-1033.1992.tb19838.x] [PMID: 1730219]
[33]
Clogston, C.L.; Boone, T.C.; Crandall, B.C.; Mendiaz, E.A.; Lu, H.S. Disulfide structures of human interleukin-6 are similar to those of human granulocyte colony stimulating factor. Arch. Biochem. Biophys., 1989, 272(1), 144-151.
[http://dx.doi.org/10.1016/0003-9861(89)90205-1] [PMID: 2472117]
[34]
Fontaine, V.; Savino, R.; Arcone, R.; de Wit, L.; Brakenhoff, J.P.; Content, J.; Ciliberto, G. Involvement of the Arg179 in the active site of human IL-6. Eur. J. Biochem., 1993, 211(3), 749-755.
[http://dx.doi.org/10.1111/j.1432-1033.1993.tb17605.x] [PMID: 8436132]
[35]
Li, X.; Rock, F.; Chong, P.; Cockle, S.; Keating, A.; Ziltener, H.; Klein, M. Structure-function analysis of the C-terminal segment of human interleukin-6. J. Biol. Chem., 1993, 268(30), 22377-22384.
[PMID: 7693665]
[36]
Weiergräber, O.; Schneider-Mergener, J.; Grötzinger, J.; Wollmer, A.; Küster, A.; Exner, M.; Heinrich, P.C. Use of immobilized synthetic peptides for the identification of contact sites between human interleukin-6 and its receptor. FEBS Lett., 1996, 379(2), 122-126.
[http://dx.doi.org/10.1016/0014-5793(95)01482-9] [PMID: 8635575]
[37]
Aoki, Y.; Yarchoan, R.; Wyvill, K.; Okamoto, S.; Little, R.F.; Tosato, G. Detection of viral interleukin-6 in Kaposi sarcoma-associated herpesvirus-linked disorders. Blood, 2001, 97(7), 2173-2176.
[http://dx.doi.org/10.1182/blood.V97.7.2173] [PMID: 11264189]
[38]
Zhang, Y-J.; Bonaparte, R.S.; Patel, D.; Stein, D.A.; Iversen, P.L. Blockade of viral interleukin-6 expression of Kaposi’s sarcoma-associated herpesvirus. Mol. Cancer Ther., 2008, 7(3), 712-720.
[http://dx.doi.org/10.1158/1535-7163.MCT-07-2036] [PMID: 18347156]
[39]
Kovaleva, M.; Bussmeyer, I.; Rabe, B.; Grötzinger, J.; Sudarman, E.; Eichler, J.; Conrad, U.; Rose-John, S.; Scheller, J. Abrogation of viral interleukin-6 (vIL-6)-induced signaling by intracellular retention and neutralization of vIL-6 with an anti-vIL-6 single-chain antibody selected by phage display. J. Virol., 2006, 80(17), 8510-8520.
[http://dx.doi.org/10.1128/JVI.00420-06] [PMID: 16912301]

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