Secreted Herpes Simplex Virus-2 Glycoprotein G Modifies NGF-TrkA Signaling to Attract Free Nerve Endings to the Site of Infection


Herpes simplex virus type 1 and 2 (HSV-1 and HSV-2, respectively) establish latency in peripheral sensory ganglia, where they remain for the lifetime of the infected individual. Understanding the mechanisms that allow these viruses to colonize the nervous system will permit devising antiviral strategies. We show that HSV-2 glycoprotein G (SgG2) binds to and increases the function of nerve growth factor (NGF), a neurotrophin expressed in the skin and mucosa essential for axonal growth and neuronal survival. This constitutes the first description, to our knowledge, of a human pathogen with the ability to augment neurotrophic factor function. The enhancement in NGF activity results in an increase in axonal growth of neurons expressing the receptor for NGF. These results were obtained in vitro, ex vivo and in the infected mouse, suggesting that this effect may permit a more efficient infection of NGF dependent free nerve endings by HSV-2. Absence of a similar function for HSV-1 gG may indicate a preference for the infection of particular subsets of neurons by these viruses. These results shed light on the modulation of neurotrophic factors by relevant human pathogens and on the mechanisms of colonization of the nervous system by HSV.


Vyšlo v časopise: Secreted Herpes Simplex Virus-2 Glycoprotein G Modifies NGF-TrkA Signaling to Attract Free Nerve Endings to the Site of Infection. PLoS Pathog 11(1): e32767. doi:10.1371/journal.ppat.1004571
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.ppat.1004571

Souhrn

Herpes simplex virus type 1 and 2 (HSV-1 and HSV-2, respectively) establish latency in peripheral sensory ganglia, where they remain for the lifetime of the infected individual. Understanding the mechanisms that allow these viruses to colonize the nervous system will permit devising antiviral strategies. We show that HSV-2 glycoprotein G (SgG2) binds to and increases the function of nerve growth factor (NGF), a neurotrophin expressed in the skin and mucosa essential for axonal growth and neuronal survival. This constitutes the first description, to our knowledge, of a human pathogen with the ability to augment neurotrophic factor function. The enhancement in NGF activity results in an increase in axonal growth of neurons expressing the receptor for NGF. These results were obtained in vitro, ex vivo and in the infected mouse, suggesting that this effect may permit a more efficient infection of NGF dependent free nerve endings by HSV-2. Absence of a similar function for HSV-1 gG may indicate a preference for the infection of particular subsets of neurons by these viruses. These results shed light on the modulation of neurotrophic factors by relevant human pathogens and on the mechanisms of colonization of the nervous system by HSV.


Zdroje

1. Roizman B, Knipe DM, Whitley RJ (2007) Fields Virology, Fifth Edition. Lippincott Williams & Wilkins. 2: 2501–2601. doi: 10.1148/radiol.14144045 25531481

2. Tessier-Lavigne M, Goodman CS (1996) The molecular biology of axon guidance. Science 274: 1123–1133. 8895455

3. Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4: 299–309. 12671646

4. Lu B, Pang PT, Woo NH (2005) The yin and yang of neurotrophin action. Nat Rev Neurosci 6: 603–614. 16062169

5. Airaksinen MS, Saarma M (2002) The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 3: 383–394. 11988777

6. Montano JA, Perez-Pinera P, Garcia-Suarez O, Cobo J, Vega JA (2010) Development and neuronal dependence of cutaneous sensory nerve formations: Lessons from neurotrophins. Microsc Res Tech 73: 513–529. doi: 10.1002/jemt.20790 19839059

7. Truzzi F, Marconi A, Pincelli C (2011) Neurotrophins in healthy and diseased skin. Dermatoendocrinol 3: 32–36. doi: 10.4161/derm.3.1.14661 21519407

8. Mense S (2008) The Senses: A Comprehensive Reference. Academic Press, New York. 5: Pages 11–41. doi: 10.1186/1742-4755-5-11 19148995

9. McGeoch DJ, Moss HW, McNab D, Frame MC (1987) DNA sequence and genetic content of the HindIII l region in the short unique component of the herpes simplex virus type 2 genome: identification of the gene encoding glycoprotein G, and evolutionary comparisons. J Gen Virol 68 (Pt 1): 19–38.

10. Balachandran N, Hutt-Fletcher LM (1985) Synthesis and processing of glycoprotein gG of herpes simplex virus type 2. J Virol 54: 825–832. 2987534

11. Richman DD, Buckmaster A, Bell S, Hodgman C, Minson AC (1986) Identification of a new glycoprotein of herpes simplex virus type 1 and genetic mapping of the gene that codes for it. J Virol 57: 647–655. 3003396

12. Viejo-Borbolla A, Martinez-Martin N, Nel HJ, Rueda P, Martin R, et al. (2012) Enhancement of chemokine function as an immunomodulatory strategy employed by human herpesviruses. PLoS Pathog 8: e1002497. doi: 10.1371/journal.ppat.1002497 22319442

13. Indo Y (2010) Nerve growth factor, pain, itch and inflammation: lessons from congenital insensitivity to pain with anhidrosis. Expert Rev Neurother 10: 1707–1724. doi: 10.1586/ern.10.154 20977328

14. Parry CM, Simas JP, Smith VP, Stewart CA, Minson AC, et al. (2000) A broad spectrum secreted chemokine binding protein encoded by a herpesvirus. J Exp Med 191: 573–578. 10662803

15. Barbacid M (1995) Neurotrophic factors and their receptors. Curr Opin Cell Biol 7: 148–155. 7612265

16. Dillon TE, Saldanha J, Giger R, Verhaagen J, Rochlin MW (2004) Sema3A regulates the timing of target contact by cranial sensory axons. J Comp Neurol 470: 13–24. 14755522

17. Seiradake E, Harlos K, Sutton G, Aricescu AR, Jones EY (2010) An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly. Nat Struct Mol Biol 17: 398–402. doi: 10.1038/nsmb.1782 20228801

18. Harrington AW, St Hillaire C, Zweifel LS, Glebova NO, Philippidou P, et al. (2011) Recruitment of actin modifiers to TrkA endosomes governs retrograde NGF signaling and survival. Cell 146: 421–434. doi: 10.1016/j.cell.2011.07.008 21816277

19. Gomez-Mouton C, Abad JL, Mira E, Lacalle RA, Gallardo E, et al. (2001) Segregation of leading-edge and uropod components into specific lipid rafts during T cell polarization. Proc Natl Acad Sci U S A 98: 9642–9647. 11493690

20. Huang CS, Zhou J, Feng AK, Lynch CC, Klumperman J, et al. (1999) Nerve growth factor signaling in caveolae-like domains at the plasma membrane. J Biol Chem 274: 36707–36714. 10593976

21. Ueda A, Shima S, Miyashita T, Ito S, Ueda M, et al. (2010) Anti-GM1 antibodies affect the integrity of lipid rafts. Mol Cell Neurosci 45: 355–362. doi: 10.1016/j.mcn.2010.07.008 20659560

22. Geetha T, Jiang J, Wooten MW (2005) Lysine 63 polyubiquitination of the nerve growth factor receptor TrkA directs internalization and signaling. Mol Cell 20: 301–312. 16246731

23. Zweifel LS, Kuruvilla R, Ginty DD (2005) Functions and mechanisms of retrograde neurotrophin signalling. Nat Rev Neurosci 6: 615–625. 16062170

24. Bamburg JR (1999) Proteins of the ADF/cofilin family: essential regulators of actin dynamics. Annu Rev Cell Dev Biol 15: 185–230. 10611961

25. Zylka MJ, Rice FL, Anderson DJ (2005) Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45: 17–25. 15629699

26. Molliver DC, Wright DE, Leitner ML, Parsadanian AS, Doster K, et al. (1997) IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life. Neuron 19: 849–861. 9354331

27. Luo W, Wickramasinghe SR, Savitt JM, Griffin JW, Dawson TM, et al. (2007) A hierarchical NGF signaling cascade controls Ret-dependent and Ret-independent events during development of nonpeptidergic DRG neurons. Neuron 54: 739–754. 17553423

28. Ozaktay AC, Cavanaugh JM, Asik I, DeLeo JA, Weinstein JN (2002) Dorsal root sensitivity to interleukin-1 beta, interleukin-6 and tumor necrosis factor in rats. Eur Spine J 11: 467–475. 12384756

29. Puttur FK, Fernandez MA, White R, Roediger B, Cunningham AL, et al. (2010) Herpes simplex virus infects skin gamma delta T cells before Langerhans cells and impedes migration of infected Langerhans cells by inducing apoptosis and blocking E-cadherin downregulation. J Immunol 185: 477–487. doi: 10.4049/jimmunol.0904106 20519652

30. Bradley H, Markowitz LE, Gibson T, McQuillan GM (2014) Seroprevalence of herpes simplex virus types 1 and 2—United States, 1999–2010. J Infect Dis 209: 325–333. doi: 10.1093/infdis/jit458 24136792

31. Bernstein DI, Bellamy AR, Hook EW 3rd, Levin MJ, Wald A, et al. (2013) Epidemiology, clinical presentation, and antibody response to primary infection with herpes simplex virus type 1 and type 2 in young women. Clin Infect Dis 56: 344–351. doi: 10.1093/cid/cis891 23087395

32. Sauerbrei A, Schmitt S, Scheper T, Brandstadt A, Saschenbrecker S, et al. (2011) Seroprevalence of herpes simplex virus type 1 and type 2 in Thuringia, Germany, 1999 to 2006. Euro Surveill 16. 22085620

33. Roberts CM, Pfister JR, Spear SJ (2003) Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students. Sex Transm Dis 30: 797–800. 14520181

34. Engelberg R, Carrell D, Krantz E, Corey L, Wald A (2003) Natural history of genital herpes simplex virus type 1 infection. Sex Transm Dis 30: 174–177. 12567178

35. Li S, Carpenter D, Hsiang C, Wechsler SL, Jones C (2010) Herpes simplex virus type 1 latency-associated transcript inhibits apoptosis and promotes neurite sprouting in neuroblastoma cells following serum starvation by maintaining protein kinase B (AKT) levels. J Gen Virol 91: 858–866. doi: 10.1099/vir.0.015719-0 19955563

36. Hamza MA, Higgins DM, Feldman LT, Ruyechan WT (2007) The latency-associated transcript of herpes simplex virus type 1 promotes survival and stimulates axonal regeneration in sympathetic and trigeminal neurons. J Neurovirol 13: 56–66. 17454449

37. Taylor AM, Peleshok JC, Ribeiro-da-Silva A (2009) Distribution of P2X(3)-immunoreactive fibers in hairy and glabrous skin of the rat. J Comp Neurol 514: 555–566. doi: 10.1002/cne.22048 19363794

38. Robinson DR, Gebhart GF (2008) Inside information: the unique features of visceral sensation. Mol Interv 8: 242–253. doi: 10.1124/mi.8.5.9 19015388

39. Bertke AS, Swanson SM, Chen J, Imai Y, Kinchington PR, et al. (2011) A5-positive primary sensory neurons are nonpermissive for productive infection with herpes simplex virus 1 in vitro. J Virol 85: 6669–6677. doi: 10.1128/JVI.00204-11 21507969

40. Bertke AS, Apakupakul K, Ma A, Imai Y, Gussow AM, et al. (2012) LAT region factors mediating differential neuronal tropism of HSV-1 and HSV-2 do not act in trans. PLoS One 7: e53281. doi: 10.1371/journal.pone.0053281 23300908

41. Carvalho TL, Hodson NP, Blank MA, Watson PF, Mulderry PK, et al. (1986) Occurrence, distribution and origin of peptide-containing nerves of guinea-pig and rat male genitalia and the effects of denervation on sperm characteristics. J Anat 149: 121–141. 3693101

42. Inyama CO, Wharton J, Su HC, Polak JM (1986) CGRP-immunoreactive nerves in the genitalia of the female rat originate from dorsal root ganglia T11-L3 and L6-S1: a combined immunocytochemical and retrograde tracing study. Neurosci Lett 69: 13–18. 3528934

43. Hiltunen JO, Laurikainen A, Klinge E, Saarma M (2005) Neurotrophin-3 is a target-derived neurotrophic factor for penile erection-inducing neurons. Neuroscience 133: 51–58. 15893630

44. Stanberry LR, Bourne N, Bravo FJ, Bernstein DI (1992) Capsaicin-sensitive peptidergic neurons are involved in the zosteriform spread of herpes simplex virus infection. J Med Virol 38: 142–146. 1334128

45. Balan P, Davis-Poynter N, Bell S, Atkinson H, Browne H, 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.

46. Meignier B, Longnecker R, Mavromara-Nazos P, Sears AE, Roizman B (1988) Virulence of and establishment of latency by genetically engineered deletion mutants of herpes simplex virus 1. Virology 162: 251–254. 2827384

47. Weber PC, Levine M, Glorioso JC (1987) Rapid identification of nonessential genes of herpes simplex virus type 1 by Tn5 mutagenesis. Science 236: 576–579. 3033824

48. Paratcha G, Ibanez CF (2002) Lipid rafts and the control of neurotrophic factor signaling in the nervous system: variations on a theme. Curr Opin Neurobiol 12: 542–549. 12367633

49. Tansey MG, Baloh RH, Milbrandt J, Johnson EM Jr. (2000) GFRalpha-mediated localization of RET to lipid rafts is required for effective downstream signaling, differentiation, and neuronal survival. Neuron 25: 611–623. 10774729

50. Cabrera JR, Sanchez-Pulido L, Rojas AM, Valencia A, Manes S, et al. (2006) Gas1 is related to the glial cell-derived neurotrophic factor family receptors alpha and regulates Ret signaling. J Biol Chem 281: 14330–14339. 16551639

51. Kuruvilla R, Zweifel LS, Glebova NO, Lonze BE, Valdez G, et al. (2004) A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of TrkA trafficking and retrograde signaling. Cell 118: 243–255. 15260993

52. Reichardt LF, Mobley WC (2004) Going the distance, or not, with neurotrophin signals. Cell 118: 141–143. 15260984

53. Dent EW, Gupton SL, Gertler FB (2011) The growth cone cytoskeleton in axon outgrowth and guidance. Cold Spring Harb Perspect Biol 3. doi: 10.1101/cshperspect.a011510 22134888

54. Baggiolini M (1998) Chemokines and leukocyte traffic. Nature 392: 565–568. 9560152

55. Abaitua F, Zia FR, Hollinshead M, O’Hare P (2013) Polarized cell migration during cell-to-cell transmission of herpes simplex virus in human skin keratinocytes. J Virol 87: 7921–7932. doi: 10.1128/JVI.01172-13 23658449

56. Li M, Ransohoff RM (2008) Multiple roles of chemokine CXCL12 in the central nervous system: a migration from immunology to neurobiology. Prog Neurobiol 84: 116–131. doi: 10.1016/j.pneurobio.2007.11.003 18177992

57. Chalasani SH, Sabelko KA, Sunshine MJ, Littman DR, Raper JA (2003) A chemokine, SDF-1, reduces the effectiveness of multiple axonal repellents and is required for normal axon pathfinding. J Neurosci 23: 1360–1371. 12598624

58. Su B, Pan S, He X, Li P, Liang Y (2012) Sprouting of nervous fibers and upregulation of C-X-C chemokine receptor type 4 expression in hippocampal formation of rats with enhanced spatial learning and memory. Anat Rec (Hoboken) 295: 121–126. doi: 10.1002/ar.21518 22140095

59. Pezet S, McMahon SB (2006) Neurotrophins: mediators and modulators of pain. Annu Rev Neurosci 29: 507–538. 16776595

60. Guo T, Mandai K, Condie BG, Wickramasinghe SR, Capecchi MR, et al. (2011) An evolving NGF-Hoxd1 signaling pathway mediates development of divergent neural circuits in vertebrates. Nat Neurosci 14: 31–36. doi: 10.1038/nn.2710 21151121

61. Goodness TP, Albers KM, Davis FE, Davis BM (1997) Overexpression of nerve growth factor in skin increases sensory neuron size and modulates Trk receptor expression. Eur J Neurosci 9: 1574–1585. 9283812

62. Chiu IM, von Hehn CA, Woolf CJ (2012) Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat Neurosci 15: 1063–1067. doi: 10.1038/nn.3144 22837035

63. Viejo-Borbolla A, Munoz A, Tabares E, Alcami A (2010) Glycoprotein G from pseudorabies virus binds to chemokines with high affinity and inhibits their function. J Gen Virol 91: 23–31. doi: 10.1099/vir.0.011940-0 19776237

64. Hazen VM, Phan K, Yamauchi K, Butler SJ (2010) Assaying the ability of diffusible signaling molecules to reorient embryonic spinal commissural axons. J Vis Exp. doi: 10.3791/1853 20212425

65. Encinas M, Rozen EJ, Dolcet X, Jain S, Comella JX, et al. (2008) Analysis of Ret knockin mice reveals a critical role for IKKs, but not PI 3-K, in neurotrophic factor-induced survival of sympathetic neurons. Cell Death Differ 15: 1510–1521. doi: 10.1038/cdd.2008.76 18497757

66. Li Q, Lau A, Morris TJ, Guo L, Fordyce CB, et al. (2004) A syntaxin 1, Galpha(o), and N-type calcium channel complex at a presynaptic nerve terminal: analysis by quantitative immunocolocalization. J Neurosci 24: 4070–4081. 15102922

67. Lisziewicz J, Trocio J, Whitman L, Varga G, Xu J, et al. (2005) DermaVir: a novel topical vaccine for HIV/AIDS. J Invest Dermatol 124: 160–169. 15654970

68. Verdu E, Navarro X (1997) Comparison of immunohistochemical and functional reinnervation of skin and muscle after peripheral nerve injury. Exp Neurol 146: 187–198. 9225752

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