All Title Author
Keywords Abstract

Viruses  2012 

Immune Evasion Strategies of Ranaviruses and Innate Immune Responses to These Emerging Pathogens

DOI: 10.3390/v4071075

Keywords: Iridovirus, ranavirus, FV3, frog virus 3, innate immunity, macrophage, anti-viral, immune-evasion, cytokines, inflammation

Full-Text   Cite this paper   Add to My Lib


Ranaviruses (RV, Iridoviridae) are large double-stranded DNA viruses that infect fish, amphibians and reptiles. For ecological and commercial reasons, considerable attention has been drawn to the increasing prevalence of ranaviral infections of wild populations and in aquacultural settings. Importantly, RVs appear to be capable of crossing species barriers of numerous poikilotherms, suggesting that these pathogens possess a broad host range and potent immune evasion mechanisms. Indeed, while some of the 95–100 predicted ranavirus genes encode putative evasion proteins (e.g., vIFα, vCARD), roughly two-thirds of them do not share significant sequence identity with known viral or eukaryotic genes. Accordingly, the investigation of ranaviral virulence and immune evasion strategies is promising for elucidating potential antiviral targets. In this regard, recombination-based technologies are being employed to knock out gene candidates in the best-characterized RV member, Frog Virus (FV3). Concurrently, by using animal infection models with extensively characterized immune systems, such as the African clawed frog, Xenopus laevis, it is becoming evident that components of innate immunity are at the forefront of virus-host interactions. For example, cells of the macrophage lineage represent important combatants of RV infections while themselves serving as targets for viral infection, maintenance and possibly dissemination. This review focuses on the recent advances in the understanding of the RV immune evasion strategies with emphasis on the roles of the innate immune system in ranaviral infections.


[1]  Stuart, S.N.; Chanson, J.S.; Cox, N.A.; Young, B.E.; Rodrigues, A.S.; Fischman, D.L.; Waller, R.W. Status and trends of amphibian declines and extinctions worldwide. Science 2004, 306, 1783–1786.
[2]  Collins, J.P. Amphibian decline and extinction: What we know and what we need to learn. Dis. Aquat. Organ. 2010, 92, 93–99, doi:10.3354/dao02307.
[3]  Daszak, P.; Berger, L.; Cunningham, A.A.; Hyatt, A.D.; Green, D.E.; Speare, R. Emerging infectious diseases and amphibian population declines. Emerg. Infect. Dis. 1999, 5, 735–748, doi:10.3201/eid0506.990601.
[4]  Green, D.E.; Converse, K.A.; Schrader, A.K. Epizootiology of sixty-four amphibian morbidity and mortality events in the USA, 1996–2001. Ann. N. Y. Acad. Sci. 2002, 969, 323–339, doi:10.1111/j.1749-6632.2002.tb04400.x.
[5]  Gray, M.J.; Miller, D.L.; Hoverman, J.T. Ecology and pathology of amphibian ranaviruses. Dis. Aquat. Organ. 2009, 87, 243–266, doi:10.3354/dao02138.
[6]  Jancovich, J.K.; Jacobs, B.L. Innate immune evasion mediated by the Ambystoma tigrinum virus eukaryotic translation initiation factor 2alpha homologue. J. Virol. 2011, 85, 5061–5069, doi:10.1128/JVI.01488-10.
[7]  Chinchar, V.G.; Hyatt, A.; Miyazaki, T.; Williams, T. Family iridoviridae: Poor viral relations no longer. Curr. Top. Microbiol. Immunol. 2009, 328, 123–170.
[8]  Robert, J.; Ohta, Y. Comparative and developmental study of the immune system in Xenopus. Dev. Dyn. 2009, 238, 1249–1270, doi:10.1002/dvdy.21891.
[9]  Gordon, S.; Martinez, F.O. Alternative activation of macrophages: Mechanism and functions. Immunity 2010, 32, 593–604, doi:10.1016/j.immuni.2010.05.007.
[10]  Coiras, M.; Lopez-Huertas, M.R.; Perez-Olmeda, M.; Alcami, J. Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs. Nat. Rev. Microbiol. 2009, 7, 798–812, doi:10.1038/nrmicro2223.
[11]  Gousset, K.; Ablan, S.D.; Coren, L.V.; Ono, A.; Soheilian, F.; Nagashima, K.; Ott, D.E.; Freed, E.O. Real-time visualization of HIV-1 GAG trafficking in infected macrophages. PLoS Pathog. 2008, 4.
[12]  Groot, F.; Welsch, S.; Sattentau, Q.J. Efficient HIV-1 transmission from macrophages to T cells across transient virological synapses. Blood 2008, 111, 4660–4663, doi:10.1182/blood-2007-12-130070.
[13]  Kawai, T.; Akira, S. Antiviral signaling through pattern recognition receptors. J. Biochem. 2007, 141, 137–145, doi:10.1093/jb/mvm032.
[14]  Kawai, T.; Akira, S. SnapShot: Pattern-recognition receptors. Cell 2007, 129.
[15]  Thompson, A.J.; Locarnini, S.A. Toll-like receptors, RIG-I-like RNA helicases and the antiviral innate immune response. Immunol. Cell. Biol. 2007, 85, 435–445, doi:10.1038/sj.icb.7100100.
[16]  Gut, J.P.; Anton, M.; Bingen, A.; Vetter, J.M.; Kirn, A. Frog virus 3 induces a fatal hepatitis in rats. Lab. Invest. 1981, 45, 218–228.
[17]  Kirn, A.; Bingen, A.; Steffan, A.M.; Wild, M.T.; Keller, F.; Cinqualbre, J. Endocytic capacities of Kupffer cells isolated from the human adult liver. Hepatology 1982, 2, 216–222.
[18]  Kirn, A.; Steffan, A.M.; Bingen, A. Inhibition of erythrophagocytosis by cultured rat Kupffer cells infected with frog virus 3. J. Reticuloendothel. Soc. 1980, 28, 381–388.
[19]  Hagmann, W.; Steffan, A.M.; Kirn, A.; Keppler, D. Leukotrienes as mediators in frog virus 3-induced hepatitis in rats. Hepatology 1987, 7, 732–736, doi:10.1002/hep.1840070419.
[20]  Aubertin, A.M.; Hirth, C.; Travo, C.; Nonnenmacher, H.; Kirn, A. Preparation and properties of an inhibitory extract from frog virus 3 particles. J. Virol. 1973, 11, 694–701.
[21]  Gendrault, J.L.; Steffan, A.M.; Bingen, A.; Kirn, A. Penetration and uncoating of frog virus 3 (FV3) in cultured rat Kupffer cells. Virology 1981, 112, 375–384, doi:10.1016/0042-6822(81)90284-1.
[22]  Elharrar, M.; Hirth, C.; Blanc, J.; Kirn, A. Pathogenesis of the toxic hepatitis of mice provoked by FV3 (frog virus 3): Inhibition of the liver macromolecular synthesis. Biochem. Biophys. Acta. 1973, 319, 91–102.
[23]  Kirn, A.; Gut, J.P.; Elharrar, M. FV3 (Frog Virus 3) toxicity for the mouse. Nouv. Presse. Med. 1972, 1, 19–43.
[24]  Robert, J.; Abramowitz, L.; Gantress, J.; Morales, H.D. Xenopus laevis: A possible vector of Ranavirus infection? J. Wildl. Dis. 2007, 43, 645–652.
[25]  Morales, H.D.; Abramowitz, L.; Gertz, J.; Sowa, J.; Vogel, A.; Robert, J. Innate immune responses and permissiveness to ranavirus infection of peritoneal leukocytes in the frog Xenopus laevis. J. Virol. 2010, 84, 4912–4922, doi:10.1128/JVI.02486-09.
[26]  Siwicki, A.K.; Pozet, F.; Morand, M.; Volatier, C.; Terech-Majewska, E. Effects of iridovirus-like agent on the cell-mediated immunity in sheatfish (Silurus glanis)—An in vitro study. Virus. Res. 1999, 63, 115–119, doi:10.1016/S0168-1702(99)00064-7.
[27]  Chao, C.B.; Chen, C.Y.; Lai, Y.Y.; Lin, C.S.; Huang, H.T. Histological, ultrastructural, and in situ hybridization study on enlarged cells in grouper Epinephelus hybrids infected by grouper iridovirus in Taiwan (TGIV). Dis. Aquat. Organ. 2004, 58, 127–142, doi:10.3354/dao058127.
[28]  Chinchar, V.G.; Wang, J.; Murti, G.; Carey, C.; Rollins-Smith, L. Inactivation of frog virus 3 and channel catfish virus by esculentin-2P and ranatuerin-2P, two antimicrobial peptides isolated from frog skin. Virology 2001, 288, 351–357, doi:10.1006/viro.2001.1080.
[29]  Huang, X.; Huang, Y.; Ouyang, Z.; Cai, J.; Yan, Y.; Qin, Q. Roles of stress-activated protein kinases in the replication of Singapore grouper iridovirus and regulation of the inflammatory responses in grouper cells. J. Gen. Virol. 2010, 92, 1292–1301.
[30]  Maniero, G.D.; Morales, H.; Gantress, J.; Robert, J. Generation of a long-lasting, protective, and neutralizing antibody response to the ranavirus FV3 by the frog Xenopus. Dev. Comp. Immunol. 2006, 30, 649–657, doi:10.1016/j.dci.2005.09.007.
[31]  Gantress, J.; Maniero, G.D.; Cohen, N.; Robert, J. Development and characterization of a model system to study amphibian immune responses to iridoviruses. Virology 2003, 311, 254–262, doi:10.1016/S0042-6822(03)00151-X.
[32]  Morales, H.D.; Robert, J. Characterization of primary and memory CD8 T-cell responses against ranavirus (FV3) in Xenopus laevis. J. Virol. 2007, 81, 2240–2248, doi:10.1128/JVI.01104-06.
[33]  Cuthbertson, R.A.; Lang, R.A.; Coghlan, J.P. Macrophage products IL-1 alpha, TNF alpha and bFGF may mediate multiple cytopathic effects in the developing eyes of GM-CSF transgenic mice. Exp. Eye Res. 1990, 51, 335–344, doi:10.1016/0014-4835(90)90030-X.
[34]  Ferreri, N.R.; Millet, I.; Paliwal, V.; Herzog, W.; Solomon, D.; Ramabhadran, R.; Askenase, P.W. Induction of macrophage TNF alpha, IL-1, IL-6, and PGE2 production by DTH-initiating factors. Cell. Immunol. 1991, 137, 389–405, doi:10.1016/0008-8749(91)90088-S.
[35]  Itoh, A.; Iizuka, K.; Natori, S. Induction of TNF-like factor by murine macrophage-like cell line J774.1 on treatment with Sarcophaga lectin. FEBS Lett. 1984, 175, 59–62, doi:10.1016/0014-5793(84)80569-4.
[36]  Liew, F.Y.; Li, Y.; Millott, S. Tumour necrosis factor (TNF-alpha) in leishmaniasis. II. TNF-alpha-induced macrophage leishmanicidal activity is mediated by nitric oxide from L-arginine. Immunology 1990, 71, 556–559.
[37]  McMasters, K.M.; Cheadle, W.G. Regulation of macrophage TNF alpha, IL-1 beta, and Ia (I-A alpha) mRNA expression during peritonitis is site dependent. J. Surg. Res. 1993, 54, 426–430, doi:10.1006/jsre.1993.1067.
[38]  Myers, M.J.; Pullen, J.K.; Ghildyal, N.; Eustis-Turf, E.; Schook, L.B. Regulation of IL-1 and TNF-alpha expression during the differentiation of bone marrow derived macrophage. J. Immunol. 1989, 142, 153–160.
[39]  Shimoda, O.; Takeda, Y.; Woo, H.J.; Shimada, S.; Higuchi, M.; Osawa, T. A human macrophage hybridoma producing a cytotoxic factor distinct from TNF, LT, and IL-1. Cancer Immunol. Immunother. 1988, 26, 101–108.
[40]  Cassatella, M.A.; Bazzoni, F.; Flynn, R.M.; Dusi, S.; Trinchieri, G.; Rossi, F. Molecular basis of interferon-gamma and lipopolysaccharide enhancement of phagocyte respiratory burst capability. Studies on the gene expression of several NADPH oxidase components. J. Biol. Chem. 1990, 265, 20241–20246.
[41]  Cassatella, M.A.; Cappelli, R.; Della Bianca, V.; Grzeskowiak, M.; Dusi, S.; Berton, G. Interferon-gamma activates human neutrophil oxygen metabolism and exocytosis. Immunology 1988, 63, 499–506.
[42]  Corradin, S.B.; Buchmuller-Rouiller, Y.; Mauel, J. Phagocytosis enhances murine macrophage activation by interferon-gamma and tumor necrosis factor-alpha. Eur. J. Immunol. 1991, 21, 2553–2558, doi:10.1002/eji.1830211036.
[43]  Fremond, C.M.; Togbe, D.; Doz, E.; Rose, S.; Vasseur, V.; Maillet, I.; Jacobs, M.; Ryffel, B.; Quesniaux, V.F. IL-1 receptor-mediated signal is an essential component of MyD88-dependent innate response to Mycobacterium tuberculosis infection. J. Immunol. 2007, 179, 1178–1189.
[44]  Grayfer, L.; Belosevic, M. Molecular characterization, expression and functional analysis of goldfish (Carassius auratus L.) interferon gamma. Dev. Comp. Immunol. 2009, 33, 235–246, doi:10.1016/j.dci.2008.09.001.
[45]  Grayfer, L.; Garcia, E.G.; Belosevic, M. Comparison of macrophage antimicrobial responses induced by type II interferons of the goldfish (Carassius auratus L.). J. Biol. Chem. 2010, 285, 23537–23547.
[46]  Grayfer, L.; Walsh, J.G.; Belosevic, M. Characterization and functional analysis of goldfish (Carassius auratus L.) tumor necrosis factor-alpha. Dev. Comp. Immunol. 2008, 32, 532–543, doi:10.1016/j.dci.2007.09.009.
[47]  Ishibe, K.; Yamanishi, T.; Wang, Y.; Osatomi, K.; Hara, K.; Kanai, K.; Yamaguchi, K.; Oda, T. Comparative analysis of the production of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) from macrophages exposed to high virulent and low virulent strains of Edwardsiella tarda. Fish. Shellfish. Immunol. 2009, 27, 386–389, doi:10.1016/j.fsi.2009.06.002.
[48]  Nathan, C.F.; Murray, H.W.; Wiebe, M.E.; Rubin, B.Y. Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J. Exp. Med. 1983, 158, 670–689, doi:10.1084/jem.158.3.670.
[49]  Ordas, M.C.; Costa, M.M.; Roca, F.J.; Lopez-Castejon, G.; Mulero, V.; Meseguer, J.; Figueras, A.; Novoa, B. Turbot TNFalpha gene: Molecular characterization and biological activity of the recombinant protein. Mol. Immunol. 2007, 44, 389–400.
[50]  Purcell, M.K.; Kurath, G.; Garver, K.A.; Herwig, R.P.; Winton, J.R. Quantitative expression profiling of immune response genes in rainbow trout following infectious haematopoietic necrosis virus (IHNV) infection or DNA vaccination. Fish Shellfish Immunol. 2004, 17, 447–462, doi:10.1016/j.fsi.2004.04.017.
[51]  Purcell, M.K.; Nichols, K.M.; Winton, J.R.; Kurath, G.; Thorgaard, G.H.; Wheeler, P.; Hansen, J.D.; Herwig, R.P.; Park, L.K. Comprehensive gene expression profiling following DNA vaccination of rainbow trout against infectious hematopoietic necrosis virus. Mol. Immunol. 2006, 43, 2089–2106, doi:10.1016/j.molimm.2005.12.005.
[52]  Xiao, J.; Zhou, Z.C.; Chen, C.; Huo, W.L.; Yin, Z.X.; Weng, S.P.; Chan, S.M.; Yu, X.Q.; He, J.G. Tumor necrosis factor-alpha gene from mandarin fish, Siniperca chuatsi: Molecular cloning, cytotoxicity analysis and expression profile. Mol. Immunol. 2007, 44, 3615–3622.
[53]  Bird, S.; Wang, T.; Zou, J.; Cunningham, C.; Secombes, C.J. The first cytokine sequence within cartilaginous fish: IL-1 beta in the small spotted catshark (Scyliorhinus canicula). J. Immunol. 2002, 168, 3329–3340.
[54]  Hirono, I.; Nam, B.H.; Kurobe, T.; Aoki, T. Molecular cloning, characterization, and expression of TNF cDNA and gene from Japanese flounder Paralychthys olivaceus. J. Immunol. 2000, 165, 4423–4427.
[55]  Igawa, D.; Sakai, M.; Savan, R. An unexpected discovery of two interferon gamma-like genes along with interleukin (IL)-22 and -26 from teleost: IL-22 and -26 genes have been described for the first time outside mammals. Mol. Immunol. 2006, 43, 999–1009, doi:10.1016/j.molimm.2005.05.009.
[56]  Nishikawa, A.; Murata, E.; Akita, M.; Kaneko, K.; Moriya, O.; Tomita, M.; Hayashi, H. Roles of macrophages in programmed cell death and remodeling of tail and body muscle of Xenopus laevis during metamorphosis. Histochem. Cell Biol. 1998, 109, 11–17.
[57]  Auffray, C.; Fogg, D.; Garfa, M.; Elain, G.; Join-Lambert, O.; Kayal, S.; Sarnacki, S.; Cumano, A.; Lauvau, G.; Geissmann, F. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 2007, 317, 666–670.
[58]  Nahrendorf, M.; Swirski, F.K.; Aikawa, E.; Stangenberg, L.; Wurdinger, T.; Figueiredo, J.L.; Libby, P.; Weissleder, R.; Pittet, M.J. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J. Exp. Med. 2007, 204, 3037–3047.
[59]  Zhao, C.; Zhang, H.; Wong, W.C.; Sem, X.; Han, H.; Ong, S.M.; Tan, Y.C.; Yeap, W.H.; Gan, C.S.; Ng, K.Q.; et al. Identification of novel functional differences in monocyte subsets using proteomic and transcriptomic methods. J. Proteome Res. 2009, 8, 4028–4038.
[60]  Ziegler-Heitbrock, L. The CD14+ CD16+ blood monocytes: Their role in infection and inflammation. J. Leukoc. Biol. 2007, 81, 584–592, doi:10.1189/jlb.0806510.
[61]  Flajnik, M.F.; Kaufman, J.F.; Hsu, E.; Manes, M.; Parisot, R.; Du Pasquier, L. Major histocompatibility complex-encoded class I molecules are absent in immunologically competent Xenopus before metamorphosis. J. Immunol. 1986, 137, 3891–3899.
[62]  Kerr, I.M.; Brown, R.E.; Hovanessian, A.G. Nature of inhibitor of cell-free protein synthesis formed in response to interferon and double-stranded RNA. Nature 1977, 268, 540–542.
[63]  Meurs, E.; Chong, K.; Galabru, J.; Thomas, N.S.; Kerr, I.M.; Williams, B.R.; Hovanessian, A.G. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell 1990, 62, 379–390, doi:10.1016/0092-8674(90)90374-N.
[64]  Roberts, W.K.; Hovanessian, A.; Brown, R.E.; Clemens, M.J.; Kerr, I.M. Interferon-mediated protein kinase and low-molecular-weight inhibitor of protein synthesis. Nature 1976, 264, 477–480.
[65]  George, C.X.; Thomis, D.C.; McCormack, S.J.; Svahn, C.M.; Samuel, C.E. Characterization of the heparin-mediated activation of PKR, the interferon-inducible RNA-dependent protein kinase. Virology 1996, 221, 180–188, doi:10.1006/viro.1996.0364.
[66]  Ruvolo, P.P.; Gao, F.; Blalock, W.L.; Deng, X.; May, W.S. Ceramide regulates protein synthesis by a novel mechanism involving the cellular PKR activator RAX. J. Biol. Chem. 2001, 276, 11754–11758.
[67]  Gil, J.; Alcami, J.; Esteban, M. Induction of apoptosis by double-stranded-RNA-dependent protein kinase (PKR) involves the alpha subunit of eukaryotic translation initiation factor 2 and NF-kappaB. Mol. Cell. Biol. 1999, 19, 4653–4663.
[68]  Langland, J.O.; Cameron, J.M.; Heck, M.C.; Jancovich, J.K.; Jacobs, B.L. Inhibition of PKR by RNA and DNA viruses. Virus. Res. 2006, 119, 100–110, doi:10.1016/j.virusres.2005.10.014.
[69]  Essbauer, S.; Bremont, M.; Ahne, W. Comparison of the eIF-2alpha homologous proteins of seven ranaviruses (Iridoviridae). Virus Genes 2001, 23, 347–359, doi:10.1023/A:1012533625571.
[70]  Chen, G.; Ward, B.M.; Yu, K.H.; Chinchar, V.G.; Robert, J. Improved knockout methodology reveals that frog virus 3 mutants lacking either the 18K immediate-early gene or the truncated vIF-2alpha gene are defective for replication and growth in vivo. J. Virol. 2011, 85, 11131–11138, doi:10.1128/JVI.05589-11.
[71]  Rothenburg, S.; Chinchar, V.G.; Dever, T.E. Characterization of a ranavirus inhibitor of the antiviral protein kinase PKR. BMC Microbiol. 2011, 11.
[72]  Majji, S.; Thodima, V.; Sample, R.; Whitley, D.; Deng, Y.; Mao, J.; Chinchar, V.G. Transcriptome analysis of Frog virus 3, the type species of the genus Ranavirus, family Iridoviridae. Virology 2009, 391, 293–303, doi:10.1016/j.virol.2009.06.022.
[73]  Whitley, D.S.; Sample, R.C.; Sinning, A.R.; Henegar, J.; Chinchar, V.G. Antisense approaches for elucidating ranavirus gene function in an infected fish cell line. Dev. Comp. Immunol. 2011, 35, 937–948, doi:10.1016/j.dci.2010.12.002.


comments powered by Disqus