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Establishment of Murine Gammaherpesvirus Latency in B Cells Is Not a Stochastic Event


Murid γ-herpesvirus-4 (MuHV-4) is a good model to study infectious mononucleosis in mice, in which the virus ultimately establishes life-long latency in B cells. Whereas several viral proteins have been shown to modulate B cell behavior, in the present study we aimed at clarifying the parameters that dictate the establishment of viral latency from the B cell perspective. Indeed, the B cell repertoire is highly diverse and it remains unknown whether latency takes place randomly in B cells. To study this question, we isolated latently infected B cells in which we observed a low frequency of virus-specific B cells, suggesting that viral latency is not restricted to this population. To better understand MuHV-4 influence on non-virus specific B cells, we then followed the fate of B cells specific for a foreign antigen, hen egg lysozyme (HEL). While in vitro experiments showed that HEL-specific B cells could be acutely infected by MuHV-4, these cells were resistant to MuHV-4 latent infection in vivo. These results suggest that while establishment of γ-herpesvirus latency is not restricted to virus-specific B cells, it does not take place randomly in B cells and relies on mechanisms that remain to be identified.


Vyšlo v časopise: Establishment of Murine Gammaherpesvirus Latency in B Cells Is Not a Stochastic Event. PLoS Pathog 10(7): e32767. doi:10.1371/journal.ppat.1004269
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004269

Souhrn

Murid γ-herpesvirus-4 (MuHV-4) is a good model to study infectious mononucleosis in mice, in which the virus ultimately establishes life-long latency in B cells. Whereas several viral proteins have been shown to modulate B cell behavior, in the present study we aimed at clarifying the parameters that dictate the establishment of viral latency from the B cell perspective. Indeed, the B cell repertoire is highly diverse and it remains unknown whether latency takes place randomly in B cells. To study this question, we isolated latently infected B cells in which we observed a low frequency of virus-specific B cells, suggesting that viral latency is not restricted to this population. To better understand MuHV-4 influence on non-virus specific B cells, we then followed the fate of B cells specific for a foreign antigen, hen egg lysozyme (HEL). While in vitro experiments showed that HEL-specific B cells could be acutely infected by MuHV-4, these cells were resistant to MuHV-4 latent infection in vivo. These results suggest that while establishment of γ-herpesvirus latency is not restricted to virus-specific B cells, it does not take place randomly in B cells and relies on mechanisms that remain to be identified.


Zdroje

1. BartonE, MandalP, SpeckSH (2011) Pathogenesis and host control of gammaherpesviruses: lessons from the mouse. Annu Rev Immunol 29: 351–397 doi:10.1146/annurev-immunol-072710-081639

2. Thorley-LawsonDA, GrossA (2004) Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med 350: 1328–1337 doi:10.1056/NEJMra032015

3. MarquesS, EfstathiouS, SmithKG, HauryM, SimasJP (2003) Selective gene expression of latent murine gammaherpesvirus 68 in B lymphocytes. J Virol 77: 7308–7318 doi:10.1128/JVI.77.13.7308-7318.2003

4. CollinsCM, BossJM, SpeckSH (2009) Identification of Infected B-Cell Populations by Using a Recombinant Murine Gammaherpesvirus 68 Expressing a Fluorescent Protein. J Virol 83: 6484–6493 doi:10.1128/JVI.00297-09

5. StevensonPG, SimasJP, EfstathiouS (2009) Immune control of mammalian gamma-herpesviruses: lessons from murid herpesvirus-4. J Gen Virol 90: 2317–2330 doi:10.1099/vir.0.013300-0

6. FredericoB, ChaoB, MayJS, BelzGT, StevensonPG (2014) A Murid Gamma-Herpesviruses Exploits Normal Splenic Immune Communication Routes for Systemic Spread. Cell Host Microbe 15: 457–470 doi:10.1016/j.chom.2014.03.010

7. StevensonPG, DohertyPC (1999) Non-antigen-specific B-cell activation following murine gammaherpesvirus infection is CD4 independent in vitro but CD4 dependent in vivo. J Virol 73: 1075–1079.

8. SangsterMY, TophamDJ, DCostaS, CardinRD, MarionTN, et al. (2000) Analysis of the virus-specific and nonspecific B cell response to a persistent B-lymphotropic gammaherpesvirus. J Immunol 164: 1820–1828.

9. Sunil-ChandraNP, ArnoJ, FazakerleyJ, NashAA (1994) Lymphoproliferative disease in mice infected with murine gammaherpesvirus 68. Am J Pathol 145: 818–826.

10. CollinsCM, SpeckSH (2014) Expansion of Murine Gammaherpesvirus Latently Infected B Cells Requires T Follicular Help. PLoS Pathog 10: e1004106 doi:10.1371/journal.ppat.1004106

11. EhtishamS, Sunil-ChandraNP, NashAA (1993) Pathogenesis of murine gammaherpesvirus infection in mice deficient in CD4 and CD8 T cells. J Virol 67: 5247–5252.

12. DutiaBM, ClarkeCJ, AllenDJ, NashAA (1997) Pathological changes in the spleens of gamma interferon receptor-deficient mice infected with murine gammaherpesvirus: a role for CD8 T cells. J Virol 71: 4278–4283.

13. CardinRD, BrooksJW, SarawarSR, DohertyPC (1996) Progressive loss of CD8+ T cell-mediated control of a gamma-herpesvirus in the absence of CD4+ T cells. J Exp Med 184: 863–871.

14. SimasJP, MarquesS, BridgemanA, EfstathiouS, AdlerH (2004) The M2 gene product of murine gammaherpesvirus 68 is required for efficient colonization of splenic follicles but is not necessary for expansion of latently infected germinal centre B cells. J Gen Virol 85: 2789–2797 doi:10.1099/vir.0.80138-0

15. JacobyMA, VirginHW, SpeckSH (2002) Disruption of the M2 gene of murine gammaherpesvirus 68 alters splenic latency following intranasal, but not intraperitoneal, inoculation. J Virol 76: 1790–1801 doi:10.1128/JVI.76.4.1790-1801.2002

16. Pires de MirandaM, AlenquerM, MarquesS, RodriguesL, LopesF, et al. (2008) The Gammaherpesvirus m2 protein manipulates the Fyn/Vav pathway through a multidocking mechanism of assembly. PLoS ONE 3: e1654 doi:10.1371/journal.pone.0001654

17. RodriguesL, Pires de MirandaM, CalocaMJ, BusteloXR, SimasJP (2006) Activation of Vav by the gammaherpesvirus M2 protein contributes to the establishment of viral latency in B lymphocytes. J Virol 80: 6123–6135 doi:10.1128/JVI.02700-05

18. Pires de MirandaM, LopesFB, McVeyCE, BusteloXR, SimasJP (2013) Role of Src Homology Domain Binding in Signaling Complexes Assembled by the Murid γ-Herpesvirus M2 Protein. J Biol Chem 288: 3858–3870 doi:10.1074/jbc.M112.439810

19. LiangX, CollinsCM, MendelJB, IwakoshiNN, SpeckSH (2009) Gammaherpesvirus-driven plasma cell differentiation regulates virus reactivation from latently infected B lymphocytes. PLoS Pathog 5: e1000677 doi:10.1371/journal.ppat.1000677

20. RodriguesL, PopovN, KayeKM, SimasJP (2013) Stabilization of Myc through heterotypic poly-ubiquitination by mLANA is critical for γ-herpesvirus lymphoproliferation. PLoS Pathog 9: e1003554 doi:10.1371/journal.ppat.1003554

21. PhanTG, AmesburyM, GardamS, CrosbieJ, HasboldJ, et al. (2003) B Cell Receptor-independent Stimuli Trigger Immunoglobulin (Ig) Class Switch Recombination and Production of IgG Autoantibodies by Anergic Self-Reactive B Cells. J Exp Med 197: 845–860 doi:10.1084/jem.20022144

22. BrinkR, PhanTG, PausD, ChanTD (2008) Visualizing the effects of antigen affinity on T-dependent B-cell differentiation. Immunol Cell Biol 86: 31–39 doi:10.1038/sj.icb.7100143

23. PausD, PhanTG, ChanTD, GardamS, BastenA, et al. (2006) Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation. J Exp Med 203: 1081–1091 doi:10.1084/jem.20060087

24. ChanTD, GardamS, GattoD, TurnerVM, SilkeJ, et al. (2010) In vivo control of B-cell survival and antigen-specific B-cell responses. Immunol Rev 237: 90–103 doi:10.1111/j.1600-065X.2010.00942.x

25. GoodnowCC, CrosbieJ, AdelsteinS, LavoieTB, Smith-GillSJ, et al. (1988) Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334: 676–682 doi:10.1038/334676a0

26. WangJ, TaniuchiI, MaekawaY, MaureenH, CooperMD, et al. (1996) Expression and function of Fas antigen on activated murine B cells. Eur J Immunol 26: 92–96.

27. BaumgarthN (2010) The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat Rev Immunol 11: 34–46 doi:10.1038/nri2901

28. DutiaBM, StewartJP, ClaytonRA, DysonH, NashAA (1999) Kinetic and phenotypic changes in murine lymphocytes infected with murine gammaherpesvirus-68 in vitro. J Gen Virol 80 (Pt 10) 2729–2736.

29. FredericoB, MilhoR, MayJS, GilletL, StevensonPG (2012) Myeloid Infection Links Epithelial and B Cell Tropisms of Murid Herpesvirus-4. PLoS Pathog 8 doi:10.1371/journal.ppat.1002935

30. UsherwoodEJ, RossAJ, AllenDJ, NashAA (1996) Murine gammaherpesvirus-induced splenomegaly: a critical role for CD4 T cells. J Gen Virol 77: 627–630.

31. PhanTG, GrayEE, CysterJG (2009) The microanatomy of B cell activation. Curr Opin Immunol 21: 258–265 doi:10.1016/j.coi.2009.05.006

32. CollinsCM, SpeckSH (2012) Tracking murine gammaherpesvirus 68 infection of germinal center B cells in vivo. PLoS ONE 7: e33230 doi:10.1371/journal.pone.0033230

33. MoserJM, UptonJW, AllenRD, WilsonCB, SpeckSH (2005) Role of B-cell proliferation in the establishment of gammaherpesvirus latency. J Virol 79: 9480–9491 doi:10.1128/JVI.79.15.9480-9491.2005

34. McClellanKB, GangappaS, SpeckSH, VirginHW (2006) Antibody-independent control of gamma-herpesvirus latency via B cell induction of anti-viral T cell responses. PLoS Pathog 2: e58 doi:10.1371/journal.ppat.0020058

35. KimI-J, FlañoE, WoodlandDL, LundFE, RandallTD, et al. (2003) Maintenance of Long Term γ-Herpesvirus B Cell Latency Is Dependent on CD40-Mediated Development of Memory B Cells. J Immunol 171: 886–892.

36. WardemannH, YurasovS, SchaeferA, YoungJW, MeffreE, et al. (2003) Predominant autoantibody production by early human B cell precursors. Science 301: 1374–1377 doi:10.1126/science.1086907

37. KoelschK, ZhengN-Y, ZhangQ, DutyA, HelmsC, et al. (2007) Mature B cells class switched to IgD are autoreactive in healthy individuals. J Clin Invest 117: 1558–1565 doi:10.1172/JCI27628

38. CambierJC, GauldSB, MerrellKT, VilenBJ (2007) B-cell anergy: from transgenic models to naturally occurring anergic B cells? Nat Rev Immunol 7: 633–643 doi:10.1038/nri2133

39. ZikhermanJ, ParameswaranR, WeissA (2012) Endogenous antigen tunes the responsiveness of naive B cells but not T cells. Nature 1–6 doi:10.1038/nature11311

40. TracySI, KakalachevaK, LunemannJD, LuzuriagaK, MiddeldorpJ, et al. (2012) Persistence of Epstein-Barr Virus in Self-Reactive Memory B Cells. J Virol 86: 12330–12340 doi:10.1128/JVI.01699-12

41. LarsonJD, ThurmanJM, RubtsovAV, ClaypoolD, MarrackP, et al. (2012) Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity. Proc Natl Acad Sci U S A 109: E1092–E1110 doi:10.1073/pnas.1203019109

42. GetahunA, SmithMJ, KogutI, van DykLF, CambierJC (2012) Retention of Anergy and Inhibition of Antibody Responses during Acute Gammaherpesvirus 68 Infection. J Immunol doi:10.4049/jimmunol.1201407

43. GauldSB, De SantisJL, KulinskiJM, McGrawJA, LeonardoSM, et al. (2013) Modulation of B-cell tolerance by Murine Gammaherpesvirus 68 infection: requirement for Orf73 viral gene expression and follicular helper T cells. Immunology 139: 197–204 doi:10.1111/imm.12069

44. de LimaBD, MayJS, MarquesS, SimasJP, StevensonPG (2005) Murine gammaherpesvirus 68 bcl-2 homologue contributes to latency establishment in vivo. J Gen Virol 86: 31–40 doi:10.1099/vir.0.80480-0

45. SimasJP, BowdenRJ, PaigeV, EfstathiouS (1998) Four tRNA-like sequences and a serpin homologue encoded by murine gammaherpesvirus 68 are dispensable for lytic replication in vitro and latency in vivo. J Gen Virol 79: 149–153.

46. McLeanIW, NakanePK (1974) Periodate-lysine-paraformaldehyde fixative. A new fixation for immunoelectron microscopy. J Histochem Cytochem 22: 1077–1083 doi:10.1177/22.12.1077

47. BeuneuH, DeguineJ, BreartB, MandelboimO, Di SantoJP, et al. (2009) Dynamic behavior of NK cells during activation in lymph nodes. Blood 114: 3227–3234 doi:10.1182/blood-2009-06-228759

48. MarquesS, AlenquerM, StevensonPG, SimasJP (2008) A single CD8+ T cell epitope sets the long-term latent load of a murid herpesvirus. PLoS Pathog 4: e1000177 doi:10.1371/journal.ppat.1000177

49. BonnefoixT, BonnefoixP, CallananM, VerdielP, SottoJ-J (2001) Graphical Representation of a Generalized Linear Model-Based Statistical Test Estimating the Fit of the Single-Hit Poisson Model to Limiting Dilution Assays. J Immunol 167: 5725–5730.

50. PhanTG, GardamS, BastenA, BrinkR (2005) Altered migration, recruitment, and somatic hypermutation in the early response of marginal zone B cells to T cell-dependent antigen. J Immunol 174: 4567–4578.

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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