#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Protective Vaccination against Papillomavirus-Induced Skin Tumors under Immunocompetent and Immunosuppressive Conditions: A Preclinical Study Using a Natural Outbred Animal Model


Certain cutaneous human papillomaviruses (HPVs), which are ubiquitous and acquired early during childhood, can cause a variety of skin tumors and are likely involved in the development of non-melanoma skin cancer, especially in immunosuppressed patients. Hence, the burden of these clinical manifestations demands for a prophylactic approach. To evaluate whether protective efficacy of a vaccine is potentially translatable to patients, we used the rodent Mastomys coucha that is naturally infected with Mastomys natalensis papillomavirus (MnPV). This skin type papillomavirus induces not only benign skin tumours, such as papillomas and keratoacanthomas, but also squamous cell carcinomas, thereby allowing a straightforward read-out for successful vaccination in a small immunocompetent laboratory animal. Here, we examined the efficacy of a virus-like particle (VLP)-based vaccine on either previously or newly established infections. VLPs raise a strong and long-lasting neutralizing antibody response that confers protection even under systemic long-term cyclosporine A treatment. Remarkably, the vaccine completely prevents the appearance of benign as well as malignant skin tumors. Protection involves the maintenance of a low viral load in the skin by an antibody-dependent prevention of virus spread. Our results provide first evidence that VLPs elicit an effective immune response in the skin under immunocompetent and immunosuppressed conditions in an outbred animal model, irrespective of the infection status at the time of vaccination. These findings provide the basis for the clinical development of potent vaccination strategies against cutaneous HPV infections and HPV-induced tumors, especially in patients awaiting organ transplantation.


Vyšlo v časopise: Protective Vaccination against Papillomavirus-Induced Skin Tumors under Immunocompetent and Immunosuppressive Conditions: A Preclinical Study Using a Natural Outbred Animal Model. PLoS Pathog 10(2): e32767. doi:10.1371/journal.ppat.1003924
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003924

Souhrn

Certain cutaneous human papillomaviruses (HPVs), which are ubiquitous and acquired early during childhood, can cause a variety of skin tumors and are likely involved in the development of non-melanoma skin cancer, especially in immunosuppressed patients. Hence, the burden of these clinical manifestations demands for a prophylactic approach. To evaluate whether protective efficacy of a vaccine is potentially translatable to patients, we used the rodent Mastomys coucha that is naturally infected with Mastomys natalensis papillomavirus (MnPV). This skin type papillomavirus induces not only benign skin tumours, such as papillomas and keratoacanthomas, but also squamous cell carcinomas, thereby allowing a straightforward read-out for successful vaccination in a small immunocompetent laboratory animal. Here, we examined the efficacy of a virus-like particle (VLP)-based vaccine on either previously or newly established infections. VLPs raise a strong and long-lasting neutralizing antibody response that confers protection even under systemic long-term cyclosporine A treatment. Remarkably, the vaccine completely prevents the appearance of benign as well as malignant skin tumors. Protection involves the maintenance of a low viral load in the skin by an antibody-dependent prevention of virus spread. Our results provide first evidence that VLPs elicit an effective immune response in the skin under immunocompetent and immunosuppressed conditions in an outbred animal model, irrespective of the infection status at the time of vaccination. These findings provide the basis for the clinical development of potent vaccination strategies against cutaneous HPV infections and HPV-induced tumors, especially in patients awaiting organ transplantation.


Zdroje

1. zur HausenH (2002) Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2: 342–350.

2. SchillerJT, BuckCB (2011) Cutaneous squamous cell carcinoma: a smoking gun but still no suspects. J Invest Dermatol 131: 1595–1596.

3. AkgülB, CookeJC, StoreyA (2006) HPV-associated skin disease. J Pathol 208: 165–175.

4. UnderbrinkMP, HowieHL, BedardKM, KoopJI, GallowayDA (2008) E6 proteins from multiple human betapapillomavirus types degrade Bak and protect keratinocytes from apoptosis after UVB irradiation. J Virol 82: 10408–10417.

5. MuschikD, Braspenning-WeschI, StockflethE, RöslF, HofmannTG, et al. (2011) Cutaneous HPV23 E6 prevents p53 phosphorylation through interaction with HIPK2. PLoS One 6: e27655.

6. ViarisioD, Mueller-DeckerK, KlozU, AengeneyndtB, Kopp-SchneiderA, et al. (2011) E6 and E7 from Beta Hpv38 Cooperate with Ultraviolet Light in the Development of Actinic Keratosis-Like Lesions and Squamous Cell Carcinoma in Mice. PLoS Pathog 7: e1002125.

7. SchaperID, MarcuzziGP, WeissenbornSJ, KasperHU, DriesV, et al. (2005) Development of skin tumors in mice transgenic for early genes of human papillomavirus type 8. Cancer Res 65: 1394–1400.

8. PfisterH (2003) Chapter 8: Human papillomavirus and skin cancer. J Natl Cancer Inst Monogr 31: 52–56.

9. NindlI, RöslF (2008) Molecular concepts of virus infections causing skin cancer in organ transplant recipients. Am J Transplant 8: 2199–2204.

10. JablonskaS, OrthG, ObalekS, CroissantO (1985) Cutaneous warts. Clinical, histologic, and virologic correlations. Clin Dermatol 3: 71–82.

11. Bouwes BavinckJN, FeltkampM, StruijkL, ter ScheggetJ (2001) Human papillomavirus infection and skin cancer risk in organ transplant recipients. J Investig Dermatol Symp Proc 6: 207–211.

12. SchillerJT, LowyDR (2012) Understanding and learning from the success of prophylactic human papillomavirus vaccines. Nat Rev Microbiol 10: 681–692.

13. SzarewskiA, PoppeWA, SkinnerSR, WheelerCM, PaavonenJ, et al. (2012) Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15–25 years with and without serological evidence of previous exposure to HPV-16/18. Int J Cancer 131: 106–116.

14. KruppaTF, IglauerF, IhnenE, MillerK, KunstyrI (1990) Mastomys natalensis or Mastomys coucha. Correct species designation in animal experiments. Trop Med Parasitol 41: 219–220.

15. MüllerH, GissmannL (1978) Mastomys natalensis papilloma virus (MnPV), the causative agent of epithelial proliferations: characterization of the virus particle. J Gen Virol 41: 315–323.

16. NafzJ, SchäferK, ChenSF, BravoIG, IbbersonM, et al. (2008) A novel rodent papillomavirus isolated from anogenital lesions in its natural host. Virology 374: 186–197.

17. AmtmannE, VolmM, WayssK (1984) Tumour induction in the rodent Mastomys natalensis by activation of endogenous papilloma virus genomes. Nature 308: 291–292.

18. WayssK, Reyes-MayesD, VolmM (1981) Chemical carcinogenesis by the two-stage protocol in the skin of Mastomys natalensis (Muridae) using topical initiation with 7, 12-dimethylbenz(a)anthracene and topical promotion with 12-0-tetradecanoylphorbol-13-acetate. Virchows Archiv B Cell Pathology 38: 13–21.

19. HelfrichI, ChenM, SchmidtR, FurstenbergerG, Kopp-SchneiderA, et al. (2004) Increased incidence of squamous cell carcinomas in Mastomys natalensis papillomavirus E6 transgenic mice during two-stage skin carcinogenesis. J Virol 78: 4797–4805.

20. GiriI, DanosO, YanivM (1985) Genomic structure of the cottontail rabbit (Shope) papillomavirus. Proc Natl Acad Sci U S A 82: 1580–1584.

21. de VilliersEM, FauquetC, BrokerTR, BernardHU, zur HausenH (2004) Classification of papillomaviruses. Virology 324: 17–27.

22. TanCH, TachezyR, Van RanstM, ChanSY, BernardHU, et al. (1994) The Mastomys natalensis papillomavirus: nucleotide sequence, genome organization, and phylogenetic relationship of a rodent papillomavirus involved in tumorigenesis of cutaneous epithelia. Virology 198: 534–541.

23. SchäferK, NeumannJ, WaterboerT, RöslF (2011) Serological markers for papillomavirus infection and skin tumour development in the rodent model Mastomys coucha. J Gen Virol 92: 383–394.

24. AntonssonA, KaranfilovskaS, LindqvistPG, HanssonBG (2003) General acquisition of human papillomavirus infections of skin occurs in early infancy. J Clin Microbiol 41: 2509–2514.

25. MichaelKM, WaterboerT, SehrP, RotherA, ReidelU, et al. (2008) Seroprevalence of 34 human papillomavirus types in the German general population. PLoS Pathog 4: e1000091.

26. CampoMS (2002) Animal models of papillomavirus pathogenesis. Virus Res 89: 249–261.

27. ChristensenND (2005) Cottontail rabbit papillomavirus (CRPV) model system to test antiviral and immunotherapeutic strategies. Antivir Chem Chemother 16: 355–362.

28. NafzJ, KöhlerA, OhnesorgeM, NindlI, StockflethE, et al. (2007) Persistence of Mastomys natalensis papillomavirus in multiple organs identifies novel targets for infection. J Gen Virol 88: 2670–2678.

29. ShultzCL, BadowskiM, HarrisDT (2013) The Immune Response in Inbred and Outbred Strains of Mice before and after Bone Marrow Transplantation. Cell & Tissue Transplantation & Therapy 5: 9–18.

30. GambhiraR, KaranamB, JaguS, RobertsJN, BuckCB, et al. (2007) A protective and broadly cross-neutralizing epitope of human papillomavirus L2. J Virol 81: 13927–13931.

31. Sztein J, Kastenmayer R, Perdue K (2011) Pathogen-Free Mouse Rederivation by IVF, Natural Mating and Hysterectomy. Advanced Protocols for Animal Transgenesis: Springer. pp. 615–642.

32. ChackerianB (2007) Virus-like particles: flexible platforms for vaccine development. Expert Rev Vaccines 6: 381–390.

33. TannousBA (2009) Gaussia luciferase reporter assay for monitoring biological processes in culture and in vivo. Nat Protoc 4: 582–591.

34. RubioI, SeitzH, CanaliE, SehrP, BolchiA, et al. (2011) The N-terminal region of the human papillomavirus L2 protein contains overlapping binding sites for neutralizing, cross-neutralizing and non-neutralizing antibodies. Virology 409: 348–359.

35. de GruijlFR, KoehlGE, VoskampP, StrikA, RebelHG, et al. (2010) Early and late effects of the immunosuppressants rapamycin and mycophenolate mofetil on UV carcinogenesis. Int J Cancer 127: 796–804.

36. KoehlGE, GaumannA, ZuelkeC, HoehnA, HofstaedterF, et al. (2006) Development of de novo cancer in p53 knock-out mice is dependent on the type of long-term immunosuppression used. Transplantation 82: 741–748.

37. JauhariH, WadhawanS, Yashpal, KumarA (1999) Cyclosporine trough levels in renal graft recipients. J Indian Med Assoc 97: 476–477.

38. Gafter-GviliA, SredniB, GalR, GafterU, KalechmanY (2003) Cyclosporin A-induced hair growth in mice is associated with inhibition of calcineurin-dependent activation of NFAT in follicular keratinocytes. Am J Physiol Cell Physiol 284: C1593–1603.

39. AmtmannE, WayssK (1987) The Mastomys natalensis papillomavirus. The Papovaviridae 2: 187–198.

40. RudolphRL, MullerH, ReinacherM, ThielW (1981) Morphology of experimentally induced so-called keratoacanthomas and squamous cell carcinomas in 2 inbred-lines of Mastomys natalensis. J Comp Pathol 91: 123–134.

41. GissmannL (2009) HPV vaccines: preclinical development. Arch Med Res 40: 466–470.

42. DayPM, KinesRC, ThompsonCD, JaguS, RodenRB, et al. (2010) In vivo mechanisms of vaccine-induced protection against HPV infection. Cell Host Microbe 8: 260–270.

43. KupperTS, FuhlbriggeRC (2004) Immune surveillance in the skin: mechanisms and clinical consequences. Nat Rev Immunol 4: 211–222.

44. SchlechtNF, TrevisanA, Duarte-FrancoE, RohanTE, FerenczyA, et al. (2003) Viral load as a predictor of the risk of cervical intraepithelial neoplasia. Int J Cancer 103: 519–524.

45. CarcopinoX, HenryM, ManciniJ, GiusianoS, BoubliL, et al. (2012) Significance of HPV 16 and 18 viral load quantitation in women referred for colposcopy. J Med Virol 84: 306–313.

46. LowyDR, SchillerJT (2006) Prophylactic human papillomavirus vaccines. J Clin Invest 116: 1167–1173.

47. LiZ, PalaniyandiS, ZengR, TuoW, RoopenianDC, et al. (2011) Transfer of IgG in the female genital tract by MHC class I-related neonatal Fc receptor (FcRn) confers protective immunity to vaginal infection. Proc Natl Acad Sci U S A 108: 4388–4393.

48. RobertsJN, BuckCB, ThompsonCD, KinesR, BernardoM, et al. (2007) Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan. Nat Med 13: 857–861.

49. GeherinSA, FintushelSR, LeeMH, WilsonRP, PatelRT, et al. (2012) The skin, a novel niche for recirculating B cells. J Immunol 188: 6027–6035.

50. El-RachkidyRG, YoungHS, GriffithsCE, CampRD (2008) Humoral autoimmune responses to the squamous cell carcinoma antigen protein family in psoriasis. J Invest Dermatol 128: 2219–2224.

51. MajewskiS, JablonskaS (2003) Possible involvement of epidermodysplasia verruciformis human papillomaviruses in the immunopathogenesis of psoriasis: a proposed hypothesis. Exp Dermatol 12: 721–728.

52. AveryRK, LjungmanP (2001) Prophylactic measures in the solid-organ recipient before transplantation. Clin Infect Dis 33 Suppl 1: S15–21.

53. DuchiniA, GossJA, KarpenS, PockrosPJ (2003) Vaccinations for adult solid-organ transplant recipients: current recommendations and protocols. Clin Microbiol Rev 16: 357–364.

54. ChristensenND, CladelNM, ReedCA, HanR (2000) Rabbit oral papillomavirus complete genome sequence and immunity following genital infection. Virology 269: 451–461.

55. RentenaarRJ, van DiepenFN, MeijerRT, SurachnoS, WilminkJM, et al. (2002) Immune responsiveness in renal transplant recipients: mycophenolic acid severely depresses humoral immunity in vivo. Kidney Int 62: 319–328.

56. VoskampP, BodmannCA, KoehlGE, TensenCP, BavinckJN, et al. (2013) No Acceleration of UV-Induced Skin Carcinogenesis from Evenly Spread Dietary Intake of Cyclosporine in Contrast to Oral Bolus Dosages. Transplantation 96: 871–876.

57. Bouwes BavinckJN, NealeRE, AbeniD, EuvrardS, GreenAC, et al. (2010) Multicenter study of the association between betapapillomavirus infection and cutaneous squamous cell carcinoma. Cancer Res 70: 9777–9786.

58. DentonMD, MageeCC, SayeghMH (1999) Immunosuppressive strategies in transplantation. Lancet 353: 1083–1091.

59. WeissenbornSJ, WielandU, JunkM, PfisterH (2010) Quantification of beta-human papillomavirus DNA by real-time PCR. Nat Protoc 5: 1–13.

60. JennemannR, SandhoffR, WangS, KissE, GretzN, et al. (2005) Cell-specific deletion of glucosylceramide synthase in brain leads to severe neural defects after birth. Proc Natl Acad Sci U S A 102: 12459–12464.

61. SengerT, SchädlichL, GissmannL, MüllerM (2009) Enhanced papillomavirus-like particle production in insect cells. Virology 388: 344–353.

62. BuckCB, ThompsonCD (2007) Production of papillomavirus-based gene transfer vectors. Curr Protoc Cell Biol Chapter 26 Unit 26 21.

63. SehrP, RubioI, SeitzH, PutzkerK, Ribeiro-MullerL, et al. (2013) High-Throughput Pseudovirion-Based Neutralization Assay for Analysis of Natural and Vaccine-Induced Antibodies against Human Papillomaviruses. PLoS One 8: e75677.

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2014 Číslo 2
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#