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The Cytoplasmic Domain of Varicella-Zoster Virus Glycoprotein H Regulates Syncytia Formation and Skin Pathogenesis


Varicella zoster virus (VZV) infects the human population globally, causing chickenpox in children and shingles in adults. While those afflicted with shingles experience severe pain that might last from weeks to months, the cause is not known. Biopsies of VZV infected skin and specimens of nerve ganglia collected at autopsy from patients with shingles at the time of death contain multi-nucleated cells, indicating that the virus is able to cause fusion between infected cells. Since the destruction of nerve cells that results from this process is likely to contribute to the pain associated with shingles, it is important to understand how the virus causes infected cells to fuse. We find that VZV cell-cell fusion is regulated by the intracellular facing domain of glycoprotein H (gH), a viral protein present on the surface of infected cells. This regulation was dependent upon the physical length of the domain, not a specific sequence. Loss of this regulation increased cell-cell fusion causing the formation of larger multi-nucleated cells that limited the ability of the virus to effectively spread in human skin. Our study provides new insight into how VZV manipulates host cells during infection and controls the spread of the virus in tissues.


Vyšlo v časopise: The Cytoplasmic Domain of Varicella-Zoster Virus Glycoprotein H Regulates Syncytia Formation and Skin Pathogenesis. PLoS Pathog 10(5): e32767. doi:10.1371/journal.ppat.1004173
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004173

Souhrn

Varicella zoster virus (VZV) infects the human population globally, causing chickenpox in children and shingles in adults. While those afflicted with shingles experience severe pain that might last from weeks to months, the cause is not known. Biopsies of VZV infected skin and specimens of nerve ganglia collected at autopsy from patients with shingles at the time of death contain multi-nucleated cells, indicating that the virus is able to cause fusion between infected cells. Since the destruction of nerve cells that results from this process is likely to contribute to the pain associated with shingles, it is important to understand how the virus causes infected cells to fuse. We find that VZV cell-cell fusion is regulated by the intracellular facing domain of glycoprotein H (gH), a viral protein present on the surface of infected cells. This regulation was dependent upon the physical length of the domain, not a specific sequence. Loss of this regulation increased cell-cell fusion causing the formation of larger multi-nucleated cells that limited the ability of the virus to effectively spread in human skin. Our study provides new insight into how VZV manipulates host cells during infection and controls the spread of the virus in tissues.


Zdroje

1. Arvin AM, Gilden D (2013) Varicella-Zoster Virus In: Knipe DM, Howley PM, editors. Fields Virology. 6th edition. Philadelphia (Pennsylvania): Lippincott Williams & Wilkins. pp. 2015–2184.

2. GroseC (1981) Variation on a theme by Fenner: the pathogenesis of chickenpox. Pediatrics 68: 735–737.

3. KuCC, PadillaJA, GroseC, ButcherEC, ArvinAM (2002) Tropism of varicella-zoster virus for human tonsillar CD4(+) T lymphocytes that express activation, memory, and skin homing markers. J Virol 76: 11425–11433.

4. Zerboni L, Arvin AM, Zerboni L, Arvin AM (2008) The pathogenesis of varicella-zoster virus neurotropism and infection. In: Neurotropic Viral Infections. Cambridge University Press.

5. Hope-SimpsonRE (1975) Postherpetic neuralgia. J R Coll Gen Pract 25: 571–575.

6. DuelliD, LazebnikY (2007) Cell-to-cell fusion as a link between viruses and cancer. Nat Rev Cancer 7: 968–976.

7. HogganMD, RoizmanB, RoanePRJr (1961) Further studies of variants of herpes simplex virus that produce syncytia or pocklike lesions in cell cultures. Am J Hyg 73: 114–122.

8. McNamaraPS, SmythRL (2002) The pathogenesis of respiratory syncytial virus disease in childhood. Br Med Bull 61: 13–28.

9. EsiriMM, TomlinsonAH (1972) Herpes Zoster. Demonstration of virus in trigeminal nerve and ganglion by immunofluorescence and electron microscopy. J Neurol Sci 15: 35–48.

10. CheathamWJ, DolanTFJr, DowerJC, WellerTH (1956) Varicella: report of two fatal cases with necropsy, virus isolation, and serologic studies. Am J Pathol 32: 1015–1035.

11. ReicheltM, ZerboniL, ArvinAM (2008) Mechanisms of varicella-zoster virus neuropathogenesis in human dorsal root ganglia. J Virol 82: 3971–3983.

12. MoffatJF, SteinMD, KaneshimaH, ArvinAM (1995) Tropism of varicella-zoster virus for human CD4+ and CD8+ T lymphocytes and epidermal cells in SCID-hu mice. J Virol 69: 5236–5242.

13. EisenbergRJ, AtanasiuD, CairnsTM, GallagherJR, KrummenacherC, et al. (2012) Herpes virus fusion and entry: a story with many characters. Viruses 4: 800–832.

14. KluppBG, NixdorfR, MettenleiterTC (2000) Pseudorabies virus glycoprotein M inhibits membrane fusion. J Virol 74: 6760–6768.

15. SuenagaT, SatohT, SomboonthumP, KawaguchiY, MoriY, et al. (2010) Myelin-associated glycoprotein mediates membrane fusion and entry of neurotropic herpesviruses. Proc Natl Acad Sci U S A 107: 866–871.

16. WangX, KenyonWJ, LiQ, MullbergJ, Hutt-FletcherLM (1998) Epstein-Barr virus uses different complexes of glycoproteins gH and gL to infect B lymphocytes and epithelial cells. J Virol 72: 5552–5558.

17. GianniT, AmasioM, Campadelli-FiumeG (2009) Herpes simplex virus gD forms distinct complexes with fusion executors gB and gH/gL in part through the C-terminal profusion domain. J Biol Chem 284: 17370–17382.

18. RuyechanWT, MorseLS, KnipeDM, RoizmanB (1979) Molecular genetics of herpes simplex virus. II. Mapping of the major viral glycoproteins and of the genetic loci specifying the social behavior of infected cells. J Virol 29: 677–697.

19. BzikDJ, FoxBA, DeLucaNA, PersonS (1984) Nucleotide sequence of a region of the herpes simplex virus type 1 gB glycoprotein gene: mutations affecting rate of virus entry and cell fusion. Virology 137: 185–190.

20. GroseC, CarpenterJE, JacksonW, DuusKM (2010) Overview of varicella-zoster virus glycoproteins gC, gH and gL. Curr Top Microbiol Immunol 342: 113–128.

21. HeldweinEE, LouH, BenderFC, CohenGH, EisenbergRJ, et al. (2006) Crystal structure of glycoprotein B from herpes simplex virus 1. Science 313: 217–220.

22. ChowdaryTK, CairnsTM, AtanasiuD, CohenGH, EisenbergRJ, et al. (2010) Crystal structure of the conserved herpesvirus fusion regulator complex gH-gL. Nat Struct Mol Biol 17: 882–888.

23. AvitabileE, ForghieriC, Campadelli-FiumeG (2009) Cross talk among the glycoproteins involved in herpes simplex virus entry and fusion: the interaction between gB and gH/gL does not necessarily require gD. J Virol 83: 10752–10760.

24. VleckSE, OliverSL, ReicheltM, RajamaniJ, ZerboniL, et al. (2010) Anti-glycoprotein H antibody impairs the pathogenicity of varicella-zoster virus in skin xenografts in the SCID mouse model. J Virol 84: 141–152.

25. ZhangZ, SelariuA, WardenC, HuangG, HuangY, et al. (2010) Genome-wide mutagenesis reveals that ORF7 is a novel VZV skin-tropic factor. PLoS Pathog 6: e1000971.

26. DrewPD, MossMT, PasiekaTJ, GroseC, HarrisWJ, et al. (2001) Multimeric humanized varicella-zoster virus antibody fragments to gH neutralize virus while monomeric fragments do not. J Gen Virol 82: 1959–1963.

27. VleckSE, OliverSL, BradyJJ, BlauHM, RajamaniJ, et al. (2011) Structure-function analysis of varicella-zoster virus glycoprotein H identifies domain-specific roles for fusion and skin tropism. Proc Natl Acad Sci U S A 108: 18412–18417.

28. GershonAA, ShermanDL, ZhuZ, GabelCA, AmbronRT, et al. (1994) Intracellular transport of newly synthesized varicella-zoster virus: final envelopment in the trans-Golgi network. J Virol 68: 6372–6390.

29. PasiekaTJ, MaresovaL, GroseC (2003) A functional YNKI motif in the short cytoplasmic tail of varicella-zoster virus glycoprotein gH mediates clathrin-dependent and antibody-independent endocytosis. J Virol 77: 4191–4204.

30. MaresovaL, PasiekaTJ, HomanE, GerdayE, GroseC (2005) Incorporation of three endocytosed varicella-zoster virus glycoproteins, gE, gH, and gB, into the virion envelope. J Virol 79: 997–1007.

31. WangZ, GershonMD, LunguO, PanagiotidisCA, ZhuZ, et al. (1998) Intracellular transport of varicella-zoster glycoproteins. J Infect Dis 178 Suppl 1: S7–12.

32. MaresovaL, KutinovaL, LudvikovaV, ZakR, MaresM, et al. (2000) Characterization of interaction of gH and gL glycoproteins of varicella-zoster virus: their processing and trafficking. J Gen Virol 81: 1545–1552.

33. PasiekaTJ, MaresovaL, ShirakiK, GroseC (2004) Regulation of varicella-zoster virus-induced cell-to-cell fusion by the endocytosis-competent glycoproteins gH and gE. J Virol 78: 2884–2896.

34. OliverSL, BradyJJ, SommerMH, ReicheltM, SungP, et al. (2013) An immunoreceptor tyrosine-based inhibition motif in varicella-zoster virus glycoprotein B regulates cell fusion and skin pathogenesis. Proc Natl Acad Sci U S A 110: 1911–1916.

35. TischerBK, KauferBB, SommerM, WussowF, ArvinAM, et al. (2007) A self-excisable infectious bacterial artificial chromosome clone of varicella-zoster virus allows analysis of the essential tegument protein encoded by ORF9. J Virol 81: 13200–13208.

36. ChaudhuriV, SommerM, RajamaniJ, ZerboniL, ArvinAM (2008) Functions of Varicella-zoster virus ORF23 capsid protein in viral replication and the pathogenesis of skin infection. J Virol 82: 10231–10246.

37. OliverSL, ZerboniL, SommerM, RajamaniJ, ArvinAM (2008) Development of recombinant varicella-zoster viruses expressing luciferase fusion proteins for live in vivo imaging in human skin and dorsal root ganglia xenografts. J Virol Methods 154: 182–193.

38. BernselA, ViklundH, HennerdalA, ElofssonA (2009) TOPCONS: consensus prediction of membrane protein topology. Nucleic Acids Res 37: W465–468.

39. UjikeM, NakajimaK, NobusawaE (2006) A point mutation at the C terminus of the cytoplasmic domain of influenza B virus haemagglutinin inhibits syncytium formation. J Gen Virol 87: 1669–1676.

40. CrosetA, DelafosseL, GaudryJP, ArodC, GlezL, et al. (2012) Differences in the glycosylation of recombinant proteins expressed in HEK and CHO cells. J Biotechnol 161: 336–348.

41. Ngounou WetieAG, SokolowskaI, WoodsAG, RoyU, LooJA, et al. (2013) Investigation of stable and transient protein-protein interactions: Past, present, and future. Proteomics 13: 538–557.

42. AtanasiuD, SawWT, GallagherJR, HannahBP, MatsudaZ, et al. (2013) Dual Split Protein-Based Fusion Assay Reveals that Mutations to Herpes Simplex Virus (HSV) Glycoprotein gB Alter the Kinetics of Cell-Cell Fusion Induced by HSV Entry Glycoproteins. J Virol 87: 11332–11345.

43. WilsonDW, Davis-PoynterN, MinsonAC (1994) Mutations in the cytoplasmic tail of herpes simplex virus glycoprotein H suppress cell fusion by a syncytial strain. J Virol 68: 6985–6993.

44. LoretS, GuayG, LippeR (2008) Comprehensive characterization of extracellular herpes simplex virus type 1 virions. J Virol 82: 8605–8618.

45. LiuST, Sharon-FrilingR, IvanovaP, MilneSB, MyersDS, et al. (2011) Synaptic vesicle-like lipidome of human cytomegalovirus virions reveals a role for SNARE machinery in virion egress. Proc Natl Acad Sci U S A 108: 12869–12874.

46. EjercitoPM, KieffED, RoizmanB (1968) Characterization of herpes simplex virus strains differing in their effects on social behaviour of infected cells. J Gen Virol 2: 357–364.

47. Roizman BK, David M., Whitley, Richard J (2007) Herpes Simplex Viruses. In: Knipe DMH, Peter M, editors. Fields Virology. 5th ed. Philadelphia (Pennsylvania): Lippincott Williams & Wilkins. pp. 2502–2601.

48. BrowneHM, BruunBC, MinsonAC (1996) Characterization of herpes simplex virus type 1 recombinants with mutations in the cytoplasmic tail of glycoprotein H. J Gen Virol 77(Pt 10): 2569–2573.

49. BalanP, Davis-PoynterN, BellS, AtkinsonH, BrowneH, et al. (1994) An analysis of the in vitro and in vivo phenotypes of mutants of herpes simplex virus type 1 lacking glycoproteins gG, gE, gI or the putative gJ. J Gen Virol 75(Pt 6): 1245–1258.

50. SilvermanJL, HeldweinEE (2013) Mutations in the Cytoplasmic Tail of Herpes Simplex Virus 1 gH Reduce the Fusogenicity of gB in Transfected Cells. J Virol 87: 10139–10147.

51. HarmanA, BrowneH, MinsonT (2002) The transmembrane domain and cytoplasmic tail of herpes simplex virus type 1 glycoprotein H play a role in membrane fusion. J Virol 76: 10708–10716.

52. JonesNA, GeraghtyRJ (2004) Fusion activity of lipid-anchored envelope glycoproteins of herpes simplex virus type 1. Virology 324: 213–228.

53. JacksonJO, LinE, SpearPG, LongneckerR (2010) Insertion mutations in herpes simplex virus 1 glycoprotein H reduce cell surface expression, slow the rate of cell fusion, or abrogate functions in cell fusion and viral entry. J Virol 84: 2038–2046.

54. HumphriesAC, DoddingMP, BarryDJ, CollinsonLM, DurkinCH, et al. (2012) Clathrin potentiates vaccinia-induced actin polymerization to facilitate viral spread. Cell Host Microbe 12: 346–359.

55. ChouW, NgoT, GershonPD (2012) An overview of the vaccinia virus infectome: a survey of the proteins of the poxvirus-infected cell. J Virol 86: 1487–1499.

56. DuusKM, HatfieldC, GroseC (1995) Cell surface expression and fusion by the varicella-zoster virus gH:gL glycoprotein complex: analysis by laser scanning confocal microscopy. Virology 210: 429–440.

57. DomsRW, BlumenthalR, MossB (1990) Fusion of intra- and extracellular forms of vaccinia virus with the cell membrane. J Virol 64: 4884–4892.

58. BryskMM, RajaramanS (1992) Cohesion and desquamation of epidermal stratum corneum. Prog Histochem Cytochem 25: 1–53.

59. KyteJ, DoolittleRF (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157: 105–132.

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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