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Non-redundant and Redundant Roles of Cytomegalovirus gH/gL Complexes in Host Organ Entry and Intra-tissue Spread


The role of viral glycoprotein entry complexes in viral tropism in vivo is a question central to understanding virus pathogenesis and transmission for any virus. Studies were limited by the difficulty in distinguishing between viral entry into first-hit target cells and subsequent cell-to-cell spread within tissues. Employing the murine cytomegalovirus entry complex gH/gL/gO as a paradigm for a generally applicable strategy to dissect these two events experimentally, we used a gO-transcomplemented ΔgO mutant for providing the complex exclusively for the initial cell entry step. In immunocompromised mice as a model for recipients of hematopoietic cell transplantation, our studies revealed an irreplaceable role for gH/gL/gO in initiating infection in host organs relevant to pathogenesis, whereas subsequent spread within tissues and infection of the salivary glands, the site relevant to virus host-to-host transmission, are double-secured by the entry complexes gH/gL/gO and gH/gL/MCK-2. As an important consequence, interventional strategies targeting only gO might be efficient in preventing organ manifestations after a primary viremia, whereas both gH/gL complexes need to be targeted for preventing intra-tissue spread of virus reactivated from latency within tissues as well as for preventing the salivary gland route of host-to-host transmission.


Vyšlo v časopise: Non-redundant and Redundant Roles of Cytomegalovirus gH/gL Complexes in Host Organ Entry and Intra-tissue Spread. PLoS Pathog 11(2): e32767. doi:10.1371/journal.ppat.1004640
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004640

Souhrn

The role of viral glycoprotein entry complexes in viral tropism in vivo is a question central to understanding virus pathogenesis and transmission for any virus. Studies were limited by the difficulty in distinguishing between viral entry into first-hit target cells and subsequent cell-to-cell spread within tissues. Employing the murine cytomegalovirus entry complex gH/gL/gO as a paradigm for a generally applicable strategy to dissect these two events experimentally, we used a gO-transcomplemented ΔgO mutant for providing the complex exclusively for the initial cell entry step. In immunocompromised mice as a model for recipients of hematopoietic cell transplantation, our studies revealed an irreplaceable role for gH/gL/gO in initiating infection in host organs relevant to pathogenesis, whereas subsequent spread within tissues and infection of the salivary glands, the site relevant to virus host-to-host transmission, are double-secured by the entry complexes gH/gL/gO and gH/gL/MCK-2. As an important consequence, interventional strategies targeting only gO might be efficient in preventing organ manifestations after a primary viremia, whereas both gH/gL complexes need to be targeted for preventing intra-tissue spread of virus reactivated from latency within tissues as well as for preventing the salivary gland route of host-to-host transmission.


Zdroje

1. Connolly SA, Jackson JO, Jardetzky TS, Longnecker R (2011) Fusing structure and function: a structural view of the herpesvirus entry machinery. Nat Rev Microbiol 9:369–381. doi: 10.1038/nrmicro2548 21478902

2. Eisenberg RJ, Atanasiu D, Cairns TM, Gallagher JR, Krummenacher C, et al. (2012) Herpes virus fusion and entry: a story with many characters. Viruses 4:800–832. doi: 10.3390/v4050800 22754650

3. Hutt-Fletcher LM (2007) Epstein-Barr virus entry. J Virol 81:7825–7832. 17459936

4. Pedersen SM Hollsberg P (2006) Complexities in human herpesvirus-6A and-6B binding to host cells. Virology 356:1–3. 16959284

5. Adler B, Sinzger C (2013) Cytomegalovirus inter-strain variance in cell-type tropism. In: Reddehase, editor. Cytomegaloviruses: from molecular pathogenesis to intervention. Caister Academic Press, Norfolk, UK. Vol. II, pp. 297–322.

6. Hahn G, Revello MG, Patrone M, Percivalle E, Campanini G, et al. (2004) Human cytomegalovirus UL131–128 genes are indispensable for virus growth in endothelial cells and virus transfer to leukocytes. J Virol 78:10023–10033. 15331735

7. Gerna G, Percivalle E, Lilleri D, Lozza L., Fornara C., et al. (2005) Dendritic-cell infection by human cytomegalovirus is restricted to strains carrying functional UL131–128 genes and mediates efficient viral antigen presentation to CD8+ T cells. J Gen Virol 86:275–284. 15659746

8. Wang D, Shenk T (2005) Human cytomegalovirus virion protein complex required for epithelial and endothelial cell tropism. Proc Natl Acad Sci USA 102:18153–18158. 16319222

9. Adler B, Scrivano L, Ruzcics Z, Rupp B, Sinzger C., et al. (2006) Role of human cytomegalovirus UL131A in cell type-specific virus entry and release. J Gen Virol 87:2451–2460. 16894182

10. Sinzger C, Eberhardt K, Cavignac Y, Weinstock C, Kessler T, et al. (2006) Macrophage cultures are susceptible to lytic productive infection by endothelial-cell-propagated human cytomegalovirus strains and present viral IE1 protein to CD4+ T cells despite late downregulation of MHC class II molecules. J Gen Virol 87:1853–1862. 16760387

11. Ryckman BJ, Chase MC, Johnson DC (2008) HCMV gH/gL/UL128–131 interferes with virus entry into epithelial cells: evidence for cell type-specific receptors. Proc Natl Acad Sci USA 105:14118–14123. doi: 10.1073/pnas.0804365105 18768787

12. Vanarsdall AL, Chase MC, Johnson DC (2011) Human cytomegalovirus glycoprotein gO complexes with gH/gL, promoting interference with viral entry into human fibroblasts but not entry into epithelial cells. J Virol 85:11638–11645. doi: 10.1128/JVI.05659-11 21880752

13. Jiang XJ, Adler B, Sampaio KL, Digel M, Jahn G, et al. (2008) UL74 of human cytomegalovirus contributes to virus release by promoting secondary envelopment of virions. J Virol 82:2802–2812. doi: 10.1128/JVI.01550-07 18184717

14. Wille PT, Knoche AJ, Nelson JA, Jarvis MA, Johnson DC (2010) An HCMV gO-null mutant fails to incorporate gH/gL into the virion envelope and is unable to enter fibroblasts, epithelial, and endothelial cells. J Virol 84:2585–2596. doi: 10.1128/JVI.02249-09 20032184

15. Borza CM, Hutt-Fletcher LM (2002) Alternate replication in B cells and epithelial cells switches tropism of Epstein-Barr virus. Nat Med 8:594–599. 12042810

16. Scrivano L, Sinzger C, Nitschko H, Koszinowski UH, Adler B (2011) HCMV spread and cell tropism are determined by distinct virus populations. PLoS Pathog 7:e1001256. doi: 10.1371/journal.ppat.1001256 21249233

17. Scrivano L, Esterlechner J, Muhlbach H, Ettischer N, Hagen C, et al. (2010) The m74 gene product of murine cytomegalovirus (MCMV) is a functional homolog of human CMV gO and determines the entry pathway of MCMV. J Virol 84:4469–4480. doi: 10.1128/JVI.02441-09 20181688

18. Wagner FM, Brizic I, Prager A, Trsan T, Arapovic M, et al. (2013). The viral chemokine MCK-2 of murine cytomegalovirus promotes infection as part of a gH/gL/MCK-2 complex. PLoS Pathog. 9:e1003493. doi: 10.1371/journal.ppat.1003493 23935483

19. Stahl FR, Keyser KA, Heller K, Bischoff Y, Halle S., et al. (2014) Mck2-dependent infection of alveolar macrophages promotes replication of MCMV in nodular inflammatory foci of the neonatal lung. Mucosal Immunol. doi: 10.1038/mi.2014.42 25515629

20. Nogalski MT, Chan GC, Stevenson EV, Collins-McMillen DK, Yurochko AD (2013). The HCMV gH/gL/UL128–131 complex triggers the specific cellular activation required for efficient viral internalization into target monocytes. PLoS Pathog 9:e1003463. doi: 10.1371/journal.ppat.1003463 23853586

21. Noda S., Aguirre SA, Bitmansour A, Brown JM, Sparer TE, et al. (2006) Cytomegalovirus MCK-2 controls mobilization and recruitment of myeloid progenitor cells to facilitate dissemination. Blood 107:30–38. 16046529

22. Straschewski S, Patrone M, Walther P, Gallina A., Mertens T, et al. (2011) Protein pUL128 of human cytomegalovirus is necessary for monocyte infection and blocking of migration. J Virol 85:5150–5158. doi: 10.1128/JVI.02100-10 21367908

23. Fleming P, Davis-Poynter N, Degli-Esposti M, Densley E, Papadimitriou J, et al. (1999) The murine cytomegalovirus chemokine homolog, m131/129, is a determinant of viral pathogenicity. J Virol 73:6800–6809. 10400778

24. Saederup N, Aguirre SA, Sparer TE, Bouley DM, Mocarski ES (2001) Murine cytomegalovirus CC chemokine homolog MCK-2 (m131–129) is a determinant of dissemination that increases inflammation at initial sites of infection. J Virol 75:9966–9976. 11559829

25. Daley-Bauer LP, Roback LJ, Wynn GM, Mocarski ES (2014) Cytomegalovirus hijacks CX3CR1(hi) patrolling monocytes as immune-privileged vehicles for dissemination in mice. Cell Host Microbe 15:351–362. doi: 10.1016/j.chom.2014.02.002 24629341

26. Daley-Bauer LP, Wynn GM, and Mocarski ES (2012) Cytomegalovirus impairs antiviral CD8+ T cell immunity by recruiting inflammatory monocytes. Immunity 37:122–133. doi: 10.1016/j.immuni.2012.04.014 22840843

27. Wikstrom ME, Fleming P, Comerford I, McColl SR, Andoniou CE, et al. (2013) A chemokine-like viral protein enhances alpha interferon production by plasmacytoid dendritic cells but delays CD8+ T cell activation and impairs viral clearance. J Virol 87:7911–7920. doi: 10.1128/JVI.00187-13 23658453

28. Jordan S, Krause J, Prager A, Mitrovic M, Jonjic S, et al. (2011) Virus progeny of murine cytomegalovirus bacterial artificial chromosome pSM3fr show reduced growth in salivary glands due to a fixed mutation of MCK-2. J Virol 85:10346–10353. doi: 10.1128/JVI.00545-11 21813614

29. Wirtz N, Schader SI, Holtappels R, Simon CO, Lemmermann NA, et al. (2008) Polyclonal cytomegalovirus-specific antibodies not only prevent virus dissemination from the portal of entry but also inhibit focal virus spread within target tissues. Med Microbiol Immunol 197:151–158. doi: 10.1007/s00430-008-0095-0 18365251

30. Cekinovic D, Lisnic VJ, Jonjic S (2014) Rodent models of congenital cytomegalovirus infection. Methods Mol Biol 1119:289–310. doi: 10.1007/978-1-62703-788-4_16 24639229

31. Holtappels R, Ebert S, Podlech J, Fink A, Böhm V, et al. (2013) Murine model for cytoimmunotherapy of CMV disease after haematopoietic cell transplantation. In: MJ Reddehase, editor. Cytomegaloviruses: from molecular pathogenesis to intervention. Caister Academic Press, Norfolk, UK. Vol. II, pp.354–381.

32. Murrell I, Tomasec P, Wilkie GS, Dargan DJ, Davison AJ, et al. (2013) Impact of sequence variation in the UL128 locus on production of human cytomegalovirus in fibroblast and epithelial cells. J Virol 87:10489–10500. doi: 10.1128/JVI.01546-13 23885075

33. Zhou M, Yu Q, Wechsler A, Ryckman BJ (2013) Comparative analysis of gO isoforms reveals that strains of human cytomegalovirus differ in the ratio of gH/gL/gO and gH/gL/UL128–131 in the virion envelope. J Virol 87:9680–9690. doi: 10.1128/JVI.01167-13 23804643

34. Seo S, Boeckh MClinical Cytomegalovirus Research: Haematopoietic Cell Transplantation In: MJ Reddehase, editor. Cytomegaloviruses: from molecular pathogenesis to intervention. Caister Academic Press, Norfolk, UK. Vol. II, pp.337–353.

35. Keil GM, Fibi MR, Koszinowski UH (1985) Characterization of the major immediate-early polypeptides encoded by murine cytomegalovirus. J Virol 54:422–428. 2985805

36. Bühler B, Keil GM, Weiland F, Koszinowski UH (1990) Characterization of the murine cytomegalovirus early transcription unit e1 that is induced by immediate-early proteins. J Virol 64:1907–1919. 2157860

37. Ciocco-Schmitt GM, Karabekian Z, Godfrey EW, Stenberg RM, Campbell AE, et al. (2002) Identification and characterization of novel murine cytomegalovirus M112–113 (e1) gene products. Virology 294:199–208. 11886278

38. Frevert U, Engelmann S, Zougbédé S, Stange J, Ng B, et al. (2005) Intravital observation of Plasmodium berghei sporozoite infection of the liver. PLoS Biol 3:e192. 15901208

39. Sacher T, Podlech J, Mohr CA, Jordan S, Ruzsics Z, et al. (2008) The major virus-producing cell type during murine cytomegalovirus infection, the hepatocyte, is not the source of virus dissemination in the host. Cell Host Microbe 3:263–272. doi: 10.1016/j.chom.2008.02.014 18407069

40. Seckert CK, Renzaho A, Tervo HM, Krause C., Deegen P.,et al. (2009) Liver sinusoidal endothelial cells are a site of murine cytomegalovirus latency and reactivation. J Virol 83:8869–8884. doi: 10.1128/JVI.00870-09 19535440

41. Lemmermann NA, Podlech J, Seckert CK, Kropp KA, Grzimek NK, et al. (2010) CD8 T-cell immunotherapy of cytomegalovirus disease in the murine model. In D Kabelitz, SHE Kaufmann, editors. Methods in Microbiology: Immunology of Infection, Academic Press, London UK, pp. 369–420.

42. Jonjić S, Mutter W, Weiland F, Reddehase MJ, Koszinowski UH (1989) Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4+ T lymphocytes. J Exp Med 169:1199–1212. 2564415

43. Plachter B, Sinzger C, Jahn G (1996) Cell types involved in replication and distribution of human cytomegalovirus. Adv Virus Res 46:195–261. 8824701

44. Ebert S, Becker M, Lemmermann NA, Büttner JK, Michel A, et al. (2014). Mast cells expedite control of pulmonary murine cytomegalovirus infection by enhancing the recruitment of protective CD8 T cells to the lungs. PLoS Pathog 10:e1004100. doi: 10.1371/journal.ppat.1004100 24763809

45. Hsu KM, Pratt JR, Akers WJ, Achilefu SI, Yokoyama WM (2009) Murine cytomegalovirus displays selective infection of cells within hours after systemic administration. J Gen Virol 90:33–43. doi: 10.1099/vir.0.006668-0 19088270

46. Manning WC, Stoddart CA, Lagenaur LA, Abenes GB, Mocarski ES (1992) Cytomegalovirus determinant of replication in salivary glands. J Virol 66:3794–3802. 1316482

47. Lagenaur LA, Manning WC, Vieira J, Martens CL, Mocarski ES (1994) Structure and function of the murine cytomegalovirus sgg1 gene: a determinant of viral growth in salivary gland acinar cells. J Virol. 68:7717–7727. 7966561

48. Wagner M, Jonjic S, Koszinowski UH, Messerle M (1999) Systematic excision of vector sequences from the BAC-cloned herpesvirus genome during virus reconstitution. J Virol 73:7056–7060. 10400809

49. Igakura T, Stinchcombe JC, Goon PK, Taylor GP, Weber JN, et al. (2003) Spread of HTLV-I between lymphocytes by virus-induced polarization of the cytoskeleton. Science 299:1713–1716. 12589003

50. Sattentau Q. (2008) Avoiding the void: cell-to-cell spread of human viruses. Nat Rev Microbiol 6:815–826. doi: 10.1038/nrmicro1972 18923409

51. Dingwell KS, Brunetti CR, Hendricks RL, Tang Q, Tang M, Rainbow AJ, Johnson DC et al. (1994) Herpes simplex virus glycoproteins E and I facilitate cell-to-cell spread in vivo and across junctions of cultured cells. J Virol 68:834–845. 8289387

52. Mulder W, Pol J, Kimman T, Kok G, Priem J, et al. (1996) Glycoprotein D-negative pseudorabies virus can spread transneuronally via direct neuron-to-neuron transmission in its natural host, the pig, but not after additional inactivation of gE or gI. J Virol 70:2191–2200. 8642642

53. Johnson DC, Webb M, Wisner TW, Brunetti C (2001) Herpes simplex virus gE/gI sorts nascent virions to epithelial cell junctions, promoting virus spread. J Virol 75:821–833. 11134295

54. Gill MB, Edgar R, May JS, Stevenson PG (2008) A gamma-herpesvirus glycoprotein complex manipulates actin to promote viral spread. PLoS ONE 3:e1808. doi: 10.1371/journal.pone.0001808 18350146

55. Becker M, Lemmermann NA, Ebert S, Baars P, Renzaho A, et al. (2014) Mast cells as rapid innate sensors of cytomegalovirus by TLR3/TRIF signaling-dependent and-independent mechanisms. Cell Mol Immunol doi: 10.1038/cmi.2014.73 25544504

56. Plendl J, Sinowatz F, Auerbach R (1995) A transformed murine myocardial vascular endothelial cell clone: characterization of cells in vitro and of tumours derived from clone in situ. Virchows Arch 426:619–628. 7655744

57. Cox GW, Mathieson BJ, Gandino L, Blasi E, Radzioch D, et al. (1989) Heterogeneity of hematopoietic cells immortalized by v-myc/v-raf recombinant retrovirus infection of bone marrow or fetal liver. J Natl Cancer Inst 81:1492–1496. 2778838

58. Cekinovic D, Golemac M, Pugel EP, Tomac J, Cicin-Sain L, et al. (2008) Passive immunization reduces murine cytomegalovirus-induced brain pathology in newborn mice. J Virol 82:12172–12180. doi: 10.1128/JVI.01214-08 18842707

59. MacDonald MR, Burney MW, Resnick SB, Virgin HW IV (1999) Spliced mRNA encoding the murine cytomegalovirus chemokine homolog predicts a beta chemokine of novel structure. J Virol 73:3682–3691. 10196260

60. Tischer BK, von Einem J, Kaufer B, Osterrieder N (2006) Two-step red-mediated recombination for versatile high-efficiency markerless DNA manipulation in Escherichia coli. Biotechniques 40:191–197. 16526409

61. Podlech J, Holtappels R, Wirtz N, Steffens HP, Reddehase MJ (1998) Reconstitution of CD8 T cells is essential for the prevention of multiple-organ cytomegalovirus histopathology after bone marrow transplantation. J Gen Virol 79:2099–2104. 9747717

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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