The online version of this article (doi:10.1186/2042-4280-5-1) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing of interest.
GL conceived of the study; GL, JPS and JTS designed the study. KG helped generate recombinant herpesviruses and conducted growth curve experiments and animal studies. GL coordinated all and conducted many of the experiments and wrote the manuscript. All authors have approved the final manuscript.
Many viral genes affect cytokine function within infected hosts, with interleukin 10 (IL-10) as a commonly targeted mediator. Epstein-Barr virus (EBV) encodes an IL-10 homologue (vIL-10) expressed during productive (lytic) infection and induces expression of cellular IL-10 (cIL-10) during latency. This study explored the role of vIL-10 in a murine gammaherpesvirus (MHV) model of viral infection.
The EBV vIL-10 gene was inserted into MHV-76, a strain which lacks the ability to induce cIL-10, by recombination in transfected mouse cells. Mice were infected intranasally with the recombinant, vIL-10-containing MHV-76 or control virus strains and assayed at various days post infection for lung virus titer, spleen cell number, percentage of latently infected spleen cells and ability to reactivate virus from spleen cells.
Recombinant murine gammaherpesvirus expressing EBV vIL-10 rose to significantly higher titers in lungs and promoted an increase in spleen cell number in infected mice in comparison to MHV strains lacking the vIL-10 gene. However, vIL-10 expression did not alter the quantity of latent virus in the spleen or its ability to reactivate.
In this mouse model of gammaherpesvirus infection, EBV vIL-10 appears to influence acute-phase pathogenicity. Given that EBV and MHV wild-type strains contain other genes that induce cIL-10 expression in latency (e.g. LMP-1 and M2, respectively), vIL-10 may have evolved to serve the specific role in acute infection of enlarging the permissive host cell population, perhaps to facilitate initial survival and dissemination of viral-infected cells.
Authors’ original file for figure 113276_2014_28_MOESM1_ESM.pdf
Authors’ original file for figure 213276_2014_28_MOESM2_ESM.pdf
Authors’ original file for figure 313276_2014_28_MOESM3_ESM.pdf
Authors’ original file for figure 413276_2014_28_MOESM4_ESM.pdf
Authors’ original file for figure 513276_2014_28_MOESM5_ESM.pdf
Authors’ original file for figure 613276_2014_28_MOESM6_ESM.pdf
Authors’ original file for figure 713276_2014_28_MOESM7_ESM.pdf
Kitagawa N, Goto M, Kurozumi K, Maruo S, Fukayama M, Naoe T, Yasukawa M, Hino K, Suzuki T, Todo S, Takada K: Epstein-Barr virus-encoded poly(A)(-) RNA supports Burkitt’s lymphoma growth through interleukin-10 induction. Embo J. 2000, 19: 6742-6750. 10.1093/emboj/19.24.6742. PubMedCentralCrossRefPubMed
Vieira P, de Waal-Malefyt R, Dang MN, Johnson KE, Kastelein R, Fiorentino DF, de Vries JE, Roncarolo MG, Mosmann TR, Moore KW: Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc Natl Acad Sci U S A. 1991, 88: 1172-1176. 10.1073/pnas.88.4.1172. PubMedCentralCrossRefPubMed
MacNeil IA, Suda T, Moore KW, Mosmann TR, Zlotnik A: IL-10, a novel growth cofactor for mature and immature T cells. J Immunol. 1990, 145: 4167-4173. PubMed
Liu Y, de Waal MR, Briere F, Parham C, Bridon JM, Banchereau J, Moore KW, Xu J: The EBV IL-10 homologue is a selective agonist with impaired binding to the IL-10 receptor. J Immunol. 1997, 158: 604-613. PubMed
Olivadoti M, Toth LA, Weinberg J, Opp MR: Murine gammaherpesvirus 68: a model for the study of Epstein-Barr virus infections and related diseases. Comp Med. 2007, 57: 44-50. PubMed
Tripp RA, Hamilton-Easton AM, Cardin RD, Nguyen P, Behm FG, Woodland DL, Doherty PC, Blackman MA: Pathogenesis of an infectious mononucleosis-like disease induced by a murine gamma-herpesvirus: role for a viral superantigen?. J Exp Med. 1997, 185: 1641-1650. 10.1084/jem.185.9.1641. PubMedCentralCrossRefPubMed
Macrae AI, Dutia BM, Milligan S, Brownstein DG, Allen DJ, Mistrikova J, Davison AJ, Nash AA, Stewart JP: Analysis of a novel strain of murine gammaherpesvirus reveals a genomic locus important for acute pathogenesis. J Virol. 2001, 75: 5315-5327. 10.1128/JVI.75.11.5315-5327.2001. PubMedCentralCrossRefPubMed
Husain SM, Usherwood EJ, Dyson H, Coleclough C, Coppola MA, Woodland DL, Blackman MA, Stewart JP, Sample JT: Murine gammaherpesvirus M2 gene is latency-associated and its protein a target for CD8(+) T lymphocytes. Proc Natl Acad Sci U S A. 1999, 96: 7508-7513. 10.1073/pnas.96.13.7508. PubMedCentralCrossRefPubMed
Madureira PA, Matos P, Soeiro I, Dixon LK, Simas JP, Lam EW: Murine gamma-herpesvirus 68 latency protein M2 binds to Vav signaling proteins and inhibits B-cell receptor-induced cell cycle arrest and apoptosis in WEHI-231 B cells. J Biol Chem. 2005, 280: 37310-37318. 10.1074/jbc.M507478200. CrossRefPubMed
Macrae AI, Usherwood EJ, Husain SM, Flano E, Kim IJ, Woodland DL, Nash AA, Blackman MA, Sample JT, Stewart JP: Murid herpesvirus 4 strain 68 M2 protein is a B-cell-associated antigen important for latency but not lymphocytosis. J Virol. 2003, 77: 9700-9709. 10.1128/JVI.77.17.9700-9709.2003. PubMedCentralCrossRefPubMed
Douglas J, Dutia B, Rhind S, Stewart JP, Talbot SJ: Expression in a recombinant murid herpesvirus 4 reveals the in vivo transforming potential of the K1 open reading frame of Kaposi’s sarcoma-associated herpesvirus. J Virol. 2004, 78: 8878-8884. 10.1128/JVI.78.16.8878-8884.2004. PubMedCentralCrossRefPubMed
Zeidler R, Eissner G, Meissner P, Uebel S, Tampe R, Lazis S, Hammerschmidt W: Downregulation of TAP1 in B lymphocytes by cellular and Epstein-Barr virus-encoded interleukin-10. Blood. 1997, 90: 2390-2397. PubMed
Brauner R, Wu L, Laks H, Nonoyama M, Scholl F, Shvarts O, Berk A, Drinkwater DC, Wang JL: Intracoronary gene transfer of immunosuppressive cytokines to cardiac allografts: method and efficacy of adenovirus-mediated transduction. J Thorac Cardiovasc Surg. 1997, 113: 1059-1066. 10.1016/S0022-5223(97)70293-9. discussion 1066–1057 CrossRefPubMed
Qin L, Chavin KD, Ding Y, Tahara H, Favaro JP, Woodward JE, Suzuki T, Robbins PD, Lotze MT, Bromberg JS: Retrovirus-mediated transfer of viral IL-10 gene prolongs murine cardiac allograft survival. J Immunol. 1996, 156: 2316-2323. PubMed
- Epstein-Barr virus IL-10 gene expression by a recombinant murine gammaherpesvirus in vivoenhances acute pathogenicity but does not affect latency or reactivation
Gary J Lindquester
Kimberly A Greer
James P Stewart
Jeffery T Sample
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II