Friend retrovirus drives cytotoxic effectors through Toll-like receptor 3

Retrovirology

Ulf Dittmer³  Mario L Santiago¹  Mengji Lu³  Carsten J Kirchning²  Bradley S Barrett¹  Michael S Harper¹  Anna M Sigmund²  Sandra Francois³  Kathrin Gibbert³ 

[1] Department of Medicine, University of Colorado Denver, Aurora 80045, CO, USA;Institute for Medical Microbiology of the University Hospital in Essen, University of Duisburg-Essen, Essen, Germany;Institute for Virology of the University Hospital in Essen, University of Duisburg-Essen, Essen, Germany

关键词: Pathogen recognition;    Cytotoxic T cells;    NK cells;    Dendritic cells;    Friend Retrovirus;    Toll-like receptor 3;   

Others  :  1132008
DOI  :  10.1186/s12977-014-0126-4

 received in 2014-10-24, accepted in 2014-12-05,  发布年份 2014

【 摘 要 】

Background

Pathogen recognition drives host defense towards viral infections. Specific groups rather than single members of the protein family of pattern recognition receptors (PRRs) such as membrane spanning Toll-like receptors (TLRs) and cytosolic helicases might mediate sensing of replication intermediates of a specific virus species. TLR7 mediates host sensing of retroviruses and could significantly influence retrovirus-specific antibody responses. However, the origin of efficient cell-mediated immunity towards retroviruses is unknown. Double-stranded RNA intermediates produced during retroviral replication are good candidates for immune stimulatory viral products. Thus, we considered TLR3 as primer of cell-mediated immunity against retroviruses in vivo.

Results

Infection of mice deficient in TLR3 (TLR3^−/−) with Friend retrovirus (FV) complex revealed higher viral loads during acute retroviral infection compared to wild type mice. TLR3^−/− mice exhibited significantly lower expression levels of type I interferons (IFNs) and IFN-stimulated genes like Pkr or Ifi44, as well as reduced numbers of activated myeloid dendritic cells (DCs) (CD86⁺ and MHC-II⁺). DCs generated from FV-infected TLR3^−/− mice were less capable of priming virus-specific CD8⁺ T cell proliferation. Moreover, cytotoxicity of natural killer (NK) cells as well as CD8⁺ T cells were reduced in vitro and in vivo, respectively, in FV-infected TLR3^-/- mice.

Conclusions

TLR3 mediates antiretroviral cytotoxic NK cell and CD8⁺ T cell activity in vivo. Our findings qualify TLR3 as target of immune therapy against retroviral infections.

【 授权许可】

   
2014 Gibbert et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Akira S, Takeda K: Toll-like receptor signalling. Nat Rev Immunol 2004, 4:499-511.
• [2]Gao D, Wu J, Wu YT, Du F, Aroh C, Yan N, Sun L, Chen ZJ: Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science 2013, 341:903-906.
• [3]Sun L, Wu J, Du F, Chen X, Chen ZJ: Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 2013, 339:786-791.
• [4]Cai X, Chiu YH, Chen ZJ: The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. Molecular cell 2014, 54:289-296.
• [5]Randall RE, Goodbourn S: Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol 2008, 89:1-47.
• [6]Gringhuis SI, van der Vlist M, van den Berg LM, den Dunnen J, Litjens M, Geijtenbeek TB: HIV-1 exploits innate signaling by TLR8 and DC-SIGN for productive infection of dendritic cells. Nat Immunol 2010, 11:419-426.
• [7]Mogensen TH, Melchjorsen J, Larsen CS, Paludan SR: Innate immune recognition and activation during HIV infection. Retrovirology 2010, 7:54. BioMed Central Full Text
• [8]Beignon AS, McKenna K, Skoberne M, Manches O, DaSilva I, Kavanagh DG, Larsson M, Gorelick RJ, Lifson JD, Bhardwaj N: Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions. J Clin Invest 2005, 115:3265-3275.
• [9]Lepelley A, Louis S, Sourisseau M, Law HK, Pothlichet J, Schilte C, Chaperot L, Plumas J, Randall RE, Si-Tahar M, Mammano F, Albert ML, Schwartz O: Innate sensing of HIV-infected cells. PLoS Pathog 2011, 7:e1001284.
• [10]Pertel T, Hausmann S, Morger D, Zuger S, Guerra J, Lascano J, Reinhard C, Santoni FA, Uchil PD, Chatel L, Bisiaux A, Albert ML, Strambio-De-Castillia C, Mothes W, Pizzato M, Grutter MG, Luban J: TRIM5 is an innate immune sensor for the retrovirus capsid lattice. Nature 2011, 472:361-365.
• [11]Browne EP, Littman DR: Myd88 is required for an antibody response to retroviral infection. PLoS pathogens 2009, 5:e1000298.
• [12]Kane M, Case LK, Wang C, Yurkovetskiy L, Dikiy S, Golovkina TV: Innate immune sensing of retroviral infection via Toll-like receptor 7 occurs upon viral entry. Immunity 2011, 35:135-145.
• [13]Gibbert K, Joedicke JJ, Meryk A, Trilling M, Francois S, Duppach J, Kraft A, Lang KS, Dittmer U: Interferon-alpha Subtype 11 Activates NK Cells and Enables Control of Retroviral Infection. PLoS pathogens 2012, 8:e1002868.
• [14]Littwitz E, Francois S, Dittmer U, Gibbert K: Distinct roles of NK cells in viral immunity during different phases of acute Friend retrovirus infection. Retrovirology 2013, 10:127. BioMed Central Full Text
• [15]Alexopoulou L, Holt AC, Medzhitov R, Flavell RA: Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001, 413:732-738.
• [16]Hajjar AM, Linial ML: Modification of retroviral RNA by double-stranded RNA adenosine deaminase. J Virol 1995, 69:5878-5882.
• [17]Tounekti N, Mougel M, Roy C, Marquet R, Darlix JL, Paoletti J, Ehresmann B, Ehresmann C: Effect of dimerization on the conformation of the encapsidation Psi domain of Moloney murine leukemia virus RNA. J Mol Biol 1992, 223:205-220.
• [18]Alford RL, Honda S, Lawrence CB, Belmont JW: RNA secondary structure analysis of the packaging signal for Moloney murine leukemia virus. Virology 1991, 183:611-619.
• [19]Kabat D: Molecular biology of Friend viral erythroleukemia. Curr Top Microbiol Immunol 1989, 148:1-42.
• [20]Hasenkrug KJ, Dittmer U: The role of CD4 and CD8 T cells in recovery and protection from retroviral infection: lessons from the Friend virus model. Virology 2000, 272:244-249.
• [21]Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M, Okabe M, Takeda K, Akira S: Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 2003, 301:640-643.
• [22]Yoneyama M, Suhara W, Fukuhara Y, Fukuda M, Nishida E, Fujita T: Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300. EMBO J 1998, 17:1087-1095.
• [23]Doyle S, Vaidya S, O'Connell R, Dadgostar H, Dempsey P, Wu T, Rao G, Sun R, Haberland M, Modlin R, Cheng G: IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 2002, 17:251-263.
• [24]Barchet W, Wimmenauer V, Schlee M, Hartmann G: Accessing the therapeutic potential of immunostimulatory nucleic acids. Curr Opin Immunol 2008, 20:389-395.
• [25]Barbalat R, Ewald SE, Mouchess ML, Barton GM: Nucleic acid recognition by the innate immune system. Annu Rev Immunol 2011, 29:185-214.
• [26]Gerlach N, Schimmer S, Weiss S, Kalinke U, Dittmer U: Effects of Type I Interferons on Friend Retrovirus Infection (Erratum). J Virol 2007, 81:6160.
• [27]Gerlach N, Schimmer S, Weiss S, Kalinke U, Dittmer U: Effects of type I interferons on Friend retrovirus infection. J Virol 2006, 80:3438-3444.
• [28]Zelinskyy G, Dietze KK, Husecken YP, Schimmer S, Nair S, Werner T, Gibbert K, Kershaw O, Gruber AD, Sparwasser T, Dittmer U: The regulatory T-cell response during acute retroviral infection is locally defined and controls the magnitude and duration of the virus-specific cytotoxic T-cell response. Blood 2009, 114:3199-3207.
• [29]Zelinskyy G, Kraft AR, Schimmer S, Arndt T, Dittmer U: Kinetics of CD8+ effector T cell responses and induced CD4+ regulatory T cell responses during Friend retrovirus infection. Eur J Immunol 2006, 36:2658-2670.
• [30]Browne EP: Toll-like receptor 7 inhibits early acute retroviral infection through rapid lymphocyte responses. J Virol 2013, 87:7357-7366.
• [31]Marques R, Antunes I, Eksmond U, Stoye J, Hasenkrug K, Kassiotis G: B lymphocyte activation by coinfection prevents immune control of friend virus infection. J Immunol 2008, 181:3432-3440.
• [32]Gururajan M, Jacob J, Pulendran B: Toll-like receptor expression and responsiveness of distinct murine splenic and mucosal B-cell subsets. PloS one 2007, 2:e863.
• [33]Mandl JN, Barry AP, Vanderford TH, Kozyr N, Chavan R, Klucking S, Barrat FJ, Coffman RL, Staprans SI, Feinberg MB: Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nat Med 2008, 14:1077-1087.
• [34]Lee H, Komano J, Saitoh Y, Yamaoka S, Kozaki T, Misawa T, Takahama M, Satoh T, Takeuchi O, Yamamoto N, Matsuura Y, Saitoh T, Akira S: Zinc-finger antiviral protein mediates retinoic acid inducible gene I-like receptor-independent antiviral response to murine leukemia virus. Proc Natl Acad Sci U S A 2013, 110:12379-12384.
• [35]Iwasaki A, Medzhitov R: Toll-like receptor control of the adaptive immune responses. Nat Immunol 2004, 5:987-995.
• [36]Kawai T, Akira S: Antiviral signaling through pattern recognition receptors. J Biochem 2007, 141:137-145.
• [37]Akira S, Takeda K, Kaisho T: Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001, 2:675-680.
• [38]Iwasaki A, Pillai PS: Innate immunity to influenza virus infection. Nat Rev Immunol 2014, 14:315-328.
• [39]Koyama S, Ishii KJ, Kumar H, Tanimoto T, Coban C, Uematsu S, Kawai T, Akira S: Differential role of TLR- and RLR-signaling in the immune responses to influenza A virus infection and vaccination. J Immunol 2007, 179:4711-4720.
• [40]Heer AK, Shamshiev A, Donda A, Uematsu S, Akira S, Kopf M, Marsland BJ: TLR signaling fine-tunes anti-influenza B cell responses without regulating effector T cell responses. J Immunol 2007, 178:2182-2191.
• [41]Xia J, Winkelmann ER, Gorder SR, Mason PW, Milligan GN: TLR3- and MyD88-dependent signaling differentially influences the development of West Nile virus-specific B cell responses in mice following immunization with RepliVAX WN, a single-cycle flavivirus vaccine candidate. J Virol 2013, 87:12090-12101.
• [42]Lazear HM, Pinto AK, Ramos HJ, Vick SC, Shrestha B, Suthar MS, Gale M Jr, Diamond MS: Pattern recognition receptor MDA5 modulates CD8+ T cell-dependent clearance of West Nile virus from the central nervous system. J Virol 2013, 87:11401-11415.
• [43]Errett JS, Suthar MS, McMillan A, Diamond MS, Gale M Jr: The essential, nonredundant roles of RIG-I and MDA5 in detecting and controlling West Nile virus infection. J Virol 2013, 87:11416-11425.
• [44]Suthar MS, Ma DY, Thomas S, Lund JM, Zhang N, Daffis S, Rudensky AY, Bevan MJ, Clark EA, Kaja MK, Diamond MS, Gale M Jr: IPS-1 is essential for the control of West Nile virus infection and immunity. PLoS Pathog 2010, 6:e1000757.
• [45]Szretter KJ, Daffis S, Patel J, Suthar MS, Klein RS, Gale M Jr, Diamond MS: The innate immune adaptor molecule MyD88 restricts West Nile virus replication and spread in neurons of the central nervous system. J Virol 2010, 84:12125-12138.
• [46]Daffis S, Samuel MA, Suthar MS, Gale M Jr, Diamond MS: Toll-like receptor 3 has a protective role against West Nile virus infection. J Virol 2008, 82:10349-10358.
• [47]Jin YH, Kim SJ, So EY, Meng L, Colonna M, Kim BS: Melanoma differentiation-associated gene 5 is critical for protection against Theiler's virus-induced demyelinating disease. J Virol 2012, 86:1531-1543.
• [48]Jin YH, Kaneyama T, Kang MH, Kang HS, Koh CS, Kim BS: TLR3 signaling is either protective or pathogenic for the development of Theiler's virus-induced demyelinating disease depending on the time of viral infection. J Neuroinflammation 2011, 8:178. BioMed Central Full Text
• [49]Tabeta K, Georgel P, Janssen E, Du X, Hoebe K, Crozat K, Mudd S, Shamel L, Sovath S, Goode J, Alexopoulou L, Flavell RA, Beutler B: Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc Natl Acad Sci U S A 2004, 101:3516-3521.
• [50]Moore MD, Hu WS: HIV-1 RNA dimerization: It takes two to tango. AIDS Rev 2009, 11:91-102.
• [51]Russell RS, Liang C, Wainberg MA: Is HIV-1 RNA dimerization a prerequisite for packaging? Yes, no, probably? Retrovirology 2004, 1:23. BioMed Central Full Text
• [52]Greatorex J: The retroviral RNA dimer linkage: different structures may reflect different roles. Retrovirology 2004, 1:22. BioMed Central Full Text
• [53]Watts JM, Dang KK, Gorelick RJ, Leonard CW, Bess JW Jr, Swanstrom R, Burch CL, Weeks KM: Architecture and secondary structure of an entire HIV-1 RNA genome. Nature 2009, 460:711-716.
• [54]Tatematsu M, Nishikawa F, Seya T, Matsumoto M: Toll-like receptor 3 recognizes incomplete stem structures in single-stranded viral RNA. Nat Commun 2013, 4:1833.
• [55]Gibbert K, Dietze KK, Zelinskyy G, Lang KS, Barchet W, Kirschning CJ, Dittmer U: Polyinosinic-polycytidylic acid treatment of Friend retrovirus-infected mice improves functional properties of virus-specific T cells and prevents virus-induced disease. J Immunol 2010, 185:6179-6189.
• [56]Wang X, Chao W, Saini M, Potash MJ: A common path to innate immunity to HIV-1 induced by Toll-like receptor ligands in primary human macrophages. PLoS One 2011, 6:e24193.
• [57]Zhou Y, Wang X, Liu M, Hu Q, Song L, Ye L, Zhou D, Ho W: A critical function of toll-like receptor-3 in the induction of anti-human immunodeficiency virus activities in macrophages. Immunology 2010, 131:40-49.
• [58]Tsang J, Chain BM, Miller RF, Webb BL, Barclay W, Towers GJ, Katz DR, Noursadeghi M: HIV-1 infection of macrophages is dependent on evasion of innate immune cellular activation. AIDS 2009, 23:2255-2263.
• [59]Suh HS, Zhao ML, Choi N, Belbin TJ, Brosnan CF, Lee SC: TLR3 and TLR4 are innate antiviral immune receptors in human microglia: role of IRF3 in modulating antiviral and inflammatory response in the CNS. Virology 2009, 392:246-259.
• [60]Swaminathan G, Rossi F, Sierra LJ, Gupta A, Navas-Martin S, Martin-Garcia J: A role for microRNA-155 modulation in the anti-HIV-1 effects of Toll-like receptor 3 stimulation in macrophages. PLoS Pathog 2012, 8:e1002937.
• [61]Breckpot K, Escors D, Arce F, Lopes L, Karwacz K, Van Lint S, Keyaerts M, Collins M: HIV-1 lentiviral vector immunogenicity is mediated by Toll-like receptor 3 (TLR3) and TLR7. J Virol 2010, 84:5627-5636.
• [62]Kariko K, Ni H, Capodici J, Lamphier M, Weissman D: mRNA is an endogenous ligand for Toll-like receptor 3. J Biol Chem 2004, 279:12542-12550.
• [63]Sironi M, Biasin M, Cagliani R, Forni D, De Luca M, Saulle I, Lo Caputo S, Mazzotta F, Macias J, Pineda JA, Caruz A, Clerici M: A common polymorphism in TLR3 confers natural resistance to HIV-1 infection. J Immunol 2012, 188:818-823.
• [64]Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S: Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 2002, 3:196-200.
• [65]Dittmer U, Brooks DM, Hasenkrug KJ: Characterization of a live-attenuated retroviral vaccine demonstrates protection via immune mechanisms. J Virol 1998, 72:6554-6558.
• [66]Smith DS, Guo K, Barrett BS, Heilman KJ, Evans LH, Hasenkrug KJ, Greene WC, Santiago ML: Noninfectious retrovirus particles drive the APOBEC3/Rfv3 dependent neutralizing antibody response. PLoS Pathog 2011, 7:e1002284.
• [67]Balkow S, Krux F, Loser K, Becker JU, Grabbe S, Dittmer U: Friend retrovirus infection of myeloid dendritic cells impairs maturation, prolongs contact to naive T cells, and favors expansion of regulatory T cells. Blood 2007, 110:3949-3958.