Skip to main content

Pathogenesis of skin ulcers: lessons from the Mycobacterium ulcerans and Leishmania spp. pathogens

Abstract

Skin ulcers are most commonly due to circulatory or metabolic disorders and are a major public health concern. In developed countries, chronic wounds affect more than 1 % of the population and their incidence is expected to follow those observed for diabetes and obesity. In tropical and subtropical countries, an additional issue is the occurrence of ulcers of infectious origins with diverse etiologies. While the severity of cutaneous Leishmaniasis correlates with protective immune responses, Buruli ulcers caused by Mycobacterium ulcerans develop in the absence of major inflammation. Based on these two examples, this review aims to demonstrate how studies on microorganism-provoked wounds can provide insight into the molecular mechanisms controlling skin integrity. We highlight the potential interest of a mouse model of non-inflammatory skin ulceration caused by intradermal injection of mycolactone, an original lipid toxin with ulcerative and immunosuppressive properties produced by M. ulcerans.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. Hu FB (2011) Globalization of diabetes: the role of diet, lifestyle, and genes. Diabetes Care 34:1249–1257

    PubMed Central  PubMed  Article  Google Scholar 

  2. Frank C, Bayoumi I, Westendorp C (2005) Approach to infected skin ulcers. Can Fam Physician 51:1352–1359

    PubMed Central  PubMed  Google Scholar 

  3. Lawall H (2012) Treatment of chronic wounds. Vasa 41:396–409

    CAS  PubMed  Article  Google Scholar 

  4. Wild S, Roglic G, Green A, Sicree R, King H (2004) Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27:1047–1053

    PubMed  Article  Google Scholar 

  5. Powell FC, Schroeter AL, Su WP, Perry HO (1985) Pyoderma gangrenosum: a review of 86 patients. Q J Med 55:173–186

    CAS  PubMed  Google Scholar 

  6. Firnhaber JM (2012) Diagnosis and treatment of basal cell and squamous cell carcinoma. Am Fam Physician 86:161–168

    PubMed  Google Scholar 

  7. Cornwall JV, Dore CJ, Lewis JD (1986) Leg ulcers: epidemiology and aetiology. Br J Surg 73:693–696

    CAS  PubMed  Article  Google Scholar 

  8. Salcido R, Popescu A, Ahn C (2007) Animal models in pressure ulcer research. J Spinal Cord Med 30:107–117

    PubMed Central  PubMed  Google Scholar 

  9. Wong VW, Sorkin M, Glotzbach JP, Longaker MT, Gurtner GC (2011) Surgical approaches to create murine models of human wound healing. J Biomed Biotechnol 2011:969618

    PubMed Central  PubMed  Google Scholar 

  10. Bergan JJ et al (2006) Chronic venous disease. N Engl J Med 355:488–498

    CAS  PubMed  Article  Google Scholar 

  11. Mast BA, Schultz GS (1996) Interactions of cytokines, growth factors, and proteases in acute and chronic wounds. Wound Repair Regen 4:411–420

    CAS  PubMed  Article  Google Scholar 

  12. James TJ, Hughes MA, Cherry GW, Taylor RP (2003) Evidence of oxidative stress in chronic venous ulcers. Wound Repair Regen 11:172–176

    PubMed  Article  Google Scholar 

  13. Moseley R et al (2004) Comparison of oxidative stress biomarker profiles between acute and chronic wound environments. Wound Repair Regen 12:419–429

    PubMed  Article  Google Scholar 

  14. Wenk J et al (2001) Selective pick-up of increased iron by deferoxamine-coupled cellulose abrogates the iron-driven induction of matrix-degrading metalloproteinase 1 and lipid peroxidation in human dermal fibroblasts in vitro: a new dressing concept. J Invest Dermatol 116:833–839

    CAS  PubMed  Article  Google Scholar 

  15. Dalton SJ, Mitchell DC, Whiting CV, Tarlton JF (2005) Abnormal extracellular matrix metabolism in chronically ischemic skin: a mechanism for dermal failure in leg ulcers. J Invest Dermatol 125:373–379

    CAS  PubMed  Google Scholar 

  16. Dalton SJ, Whiting CV, Bailey JR, Mitchell DC, Tarlton JF (2007) Mechanisms of chronic skin ulceration linking lactate, transforming growth factor-beta, vascular endothelial growth factor, collagen remodeling, collagen stability, and defective angiogenesis. J Invest Dermatol 127:958–968

    CAS  PubMed  Article  Google Scholar 

  17. Falanga V, Zhou L, Yufit T (2002) Low oxygen tension stimulates collagen synthesis and COL1A1 transcription through the action of TGF-beta1. J Cell Physiol 191:42–50

    CAS  PubMed  Article  Google Scholar 

  18. Salo T, Lyons JG, Rahemtulla F, Birkedal-Hansen H, Larjava H (1991) Transforming growth factor-beta 1 up-regulates type IV collagenase expression in cultured human keratinocytes. J Biol Chem 266:11436–11441

    CAS  PubMed  Google Scholar 

  19. Detmar M et al (1997) Hypoxia regulates the expression of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) and its receptors in human skin. J Invest Dermatol 108:263–268

    CAS  PubMed  Article  Google Scholar 

  20. Berse B et al (1999) Hypoxia augments cytokine (transforming growth factor-beta (TGF-beta) and IL-1)-induced vascular endothelial growth factor secretion by human synovial fibroblasts. Clin Exp Immunol 115:176–182

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  21. Johnson PD et al (2005) Buruli ulcer (M. ulcerans infection): new insights, new hope for disease control. PLoS Med 2:e108

    PubMed Central  PubMed  Article  Google Scholar 

  22. Silva MT, Portaels F, Pedrosa J (2009) Pathogenetic mechanisms of the intracellular parasite Mycobacterium ulcerans leading to Buruli ulcer. Lancet Infect Dis 9:699–710

    PubMed  Article  Google Scholar 

  23. van der Werf TS, Stinear T, Stienstra Y, van der Graaf WT, Small PL (2003) Mycolactones and Mycobacterium ulcerans disease. Lancet 362:1062–1064

    PubMed  Article  Google Scholar 

  24. Wansbrough-Jones M, Phillips R (2006) Buruli ulcer: emerging from obscurity. Lancet 367:1849–1858

    PubMed  Article  Google Scholar 

  25. Amofah G et al (2002) Buruli ulcer in Ghana: results of a national case search. Emerg Infect Dis 8:167–170

    PubMed Central  PubMed  Article  Google Scholar 

  26. Khan SJ, Muneeb S (2005) Cutaneous leishmaniasis in Pakistan. Dermatol Online J 11:4

    PubMed  Google Scholar 

  27. Ross BC et al (1997) Detection of Mycobacterium ulcerans in environmental samples during an outbreak of ulcerative disease. Appl Environ Microbiol 63:4135–4138

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Debacker M, Zinsou C, Aguiar J, Meyers WM, Portaels F (2003) First case of Mycobacterium ulcerans disease (Buruli ulcer) following a human bite. Clin Infect Dis 36:e67–e68

    PubMed  Article  Google Scholar 

  29. Merritt RW et al (2010) Ecology and transmission of Buruli ulcer disease: a systematic review. PLoS Negl Trop Dis 4:e911

    PubMed Central  PubMed  Article  Google Scholar 

  30. Guarner J et al (2003) Histopathologic features of Mycobacterium ulcerans infection. Emerg Infect Dis 9:651–656

    PubMed Central  PubMed  Article  Google Scholar 

  31. Hayman J (1991) Mycobacterium ulcerans infection. Lancet 337:124

    CAS  PubMed  Article  Google Scholar 

  32. Hayman J, McQueen A (1985) The pathology of Mycobacterium ulcerans infection. Pathology 17:594–600

    CAS  PubMed  Article  Google Scholar 

  33. Yeboah-Manu D et al (2006) Systemic suppression of interferon-gamma responses in Buruli ulcer patients resolves after surgical excision of the lesions caused by the extracellular pathogen Mycobacterium ulcerans. J Leukoc Biol 79:1150–1156

    CAS  PubMed  Google Scholar 

  34. Phillips, R., et al (2009) Immunosuppressive signature of cutaneous Mycobacterium ulcerans infection in the peripheral blood of patients with Buruli ulcer disease. J Infect Dis 200:1675–1684

    Google Scholar 

  35. George KM et al (1999) Mycolactone: a polyketide toxin from Mycobacterium ulcerans required for virulence. Science 283:854–857

    CAS  PubMed  Article  Google Scholar 

  36. Hong H, Demangel C, Pidot SJ, Leadlay PF, Stinear T (2008) Mycolactones: immunosuppressive and cytotoxic polyketides produced by aquatic mycobacteria. Nat Prod Rep 25:447–454

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  37. Coutanceau E et al (2007) Selective suppression of dendritic cell functions by Mycobacterium ulcerans toxin mycolactone. J Exp Med 204:1395–1403

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  38. Coutanceau E et al (2005) Modulation of the host immune response by a transient intracellular stage of Mycobacterium ulcerans: the contribution of endogenous mycolactone toxin. Cell Microbiol 7:1187–1196

    CAS  PubMed  Article  Google Scholar 

  39. Demangel C, Stinear TP, Cole ST (2009) Buruli ulcer: reductive evolution enhances pathogenicity of Mycobacterium ulcerans. Nat Rev Microbiol 7:50–60

    CAS  PubMed  Article  Google Scholar 

  40. Guenin-Mace L et al (2011) Mycolactone impairs T cell homing by suppressing microRNA control of l-selectin expression. Proc Natl Acad Sci USA 108:12833–12838

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  41. Pahlevan AA et al (1999) The inhibitory action of Mycobacterium ulcerans soluble factor on monocyte/T cell cytokine production and NF-kappa B function. J Immunol 163:3928–3935

    CAS  PubMed  Google Scholar 

  42. Simmonds RE, Lali FV, Smallie T, Small PL, Foxwell BM (2009) Mycolactone inhibits monocyte cytokine production by a posttranscriptional mechanism. J Immunol 182:2194–2202

    CAS  PubMed  Article  Google Scholar 

  43. Ruf MT et al (2011) Secondary Buruli ulcer skin lesions emerging several months after completion of chemotherapy: paradoxical reaction or evidence for immune protection? PLoS Negl Trop Dis 5:e1252

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  44. Ruf MT et al (2012) Chemotherapy-associated changes of histopathological features of Mycobacterium ulcerans lesions in a Buruli ulcer mouse model. Antimicrob Agents Chemother 56:687–696

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  45. Schutte D, Pluschke G (2009) Immunosuppression and treatment-associated inflammatory response in patients with Mycobacterium ulcerans infection (Buruli ulcer). Expert Opin Biol Ther 9:187–200

    PubMed  Article  Google Scholar 

  46. Schutte D et al (2007) Development of highly organized lymphoid structures in Buruli ulcer lesions after treatment with rifampicin and streptomycin. PLoS Negl Trop Dis 1:e2

    PubMed Central  PubMed  Article  Google Scholar 

  47. Schutte D, Umboock A, Pluschke G (2009) Phagocytosis of Mycobacterium ulcerans in the course of rifampicin and streptomycin chemotherapy in Buruli ulcer lesions. Br J Dermatol 160:273–283

    CAS  PubMed  Article  Google Scholar 

  48. Guenin-Mace L et al (2013) Mycolactone activation of Wiskott–Aldrich syndrome proteins underpins Buruli ulcer formation. J Clin Invest 123:1501–1512

    Google Scholar 

  49. Snapper SB et al (2001) N-WASP deficiency reveals distinct pathways for cell surface projections and microbial actin-based motility. Nat Cell Biol 3:897–904

    CAS  PubMed  Article  Google Scholar 

  50. Machesky LM et al (1999) Scar, a WASp-related protein, activates nucleation of actin filaments by the Arp2/3 complex. Proc Natl Acad Sci USA 96:3739–3744

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  51. Rohatgi R et al (1999) The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly. Cell 97:221–231

    CAS  PubMed  Article  Google Scholar 

  52. Thrasher AJ, Burns SO (2010) WASP: a key immunological multitasker. Nat Rev Immunol 10:182–192

    CAS  PubMed  Article  Google Scholar 

  53. Kovacs EM et al (2011) N-WASP regulates the epithelial junctional actin cytoskeleton through a non-canonical post-nucleation pathway. Nat Cell Biol 13:934–943

    CAS  PubMed  Article  Google Scholar 

  54. Lefever T et al (2010) N-WASP is a novel regulator of hair-follicle cycling that controls antiproliferative TGF{beta} pathways. J Cell Sci 123:128–140

    CAS  PubMed  Article  Google Scholar 

  55. Lyubimova A et al (2010) Neural Wiskott–Aldrich syndrome protein modulates Wnt signaling and is required for hair follicle cycling in mice. J Clin Invest 120:446–456

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  56. Etienne-Manneville S (2008) Polarity proteins in migration and invasion. Oncogene 27:6970–6980

    CAS  PubMed  Article  Google Scholar 

  57. Peterson JR et al (2004) Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation. Nat Struct Mol Biol 11:747–755

    CAS  PubMed  Article  Google Scholar 

  58. Ridley DS, Ridley MJ (1983) The evolution of the lesion in cutaneous leishmaniasis. J Pathol 141:83–96

    CAS  PubMed  Article  Google Scholar 

  59. Grevelink SA, Lerner EA (1996) Leishmaniasis. J Am Acad Dermatol 34:257–272

    CAS  PubMed  Article  Google Scholar 

  60. Sharma U, Singh S (2009) Immunobiology of leishmaniasis. Indian J Exp Biol 47:412–423

    CAS  PubMed  Google Scholar 

  61. Kolde G, Luger T, Sorg C, Sunderkotter C (1996) Successful treatment of cutaneous leishmaniasis using systemic interferon-gamma. Dermatology 192:56–60

    CAS  PubMed  Article  Google Scholar 

  62. Saab J et al (2012) Cutaneous leishmaniasis mimicking inflammatory and neoplastic processes: a clinical, histopathological and molecular study of 57 cases. J Cutan Pathol 39:251–262

    PubMed  Article  Google Scholar 

  63. Tasew G et al (2010) Systemic FasL and TRAIL neutralisation reduce leishmaniasis induced skin ulceration. PLoS Negl Trop Dis 4:e844

    PubMed Central  PubMed  Article  Google Scholar 

  64. Rethi B, Eidsmo L (2012) FasL and TRAIL signaling in the skin during cutaneous leishmaniasis—implications for tissue immunopathology and infectious control. Front Immunol 3:163

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  65. Oliveira F et al (2011) Lesion size correlates with Leishmania antigen-stimulated TNF-levels in human cutaneous leishmaniasis. Am J Trop Med Hyg 85:70–73

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  66. Snyder DS, Small PL (2003) Uptake and cellular actions of mycolactone, a virulence determinant for Mycobacterium ulcerans. Microb Pathog 34:91–101

    CAS  PubMed  Article  Google Scholar 

  67. George KM, Pascopella L, Welty DM, Small PL (2000) A Mycobacterium ulcerans toxin, mycolactone, causes apoptosis in guinea pig ulcers and tissue culture cells. Infect Immun 68:877–883

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  68. Huygen K (2003) Prospects for vaccine development against Buruli disease. Expert Rev Vaccines 2:561–569

    PubMed  Article  Google Scholar 

  69. Ji BH, Chauffour A, Robert J, Lefrancois S, Jarlier V (2007) Orally administered combined regimens for treatment of Mycobacterium ulcerans infection in mice. Antimicrob Agents Ch 51:3737–3739

    CAS  Article  Google Scholar 

  70. Rajput C et al (2013) Neural Wiskott–Aldrich syndrome protein (N-WASP)-mediated p120-catenin interaction with Arp2-Actin complex stabilizes endothelial adherens junctions. J Biol Chem 288:4241–4250

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  71. Nienhuis WA et al (2012) Paradoxical responses after start of antimicrobial treatment in Mycobacterium ulcerans infection. Clin Infect Dis 54:519–526

    PubMed  Article  Google Scholar 

  72. Friedman ND, McDonald AH, Robson ME, O’Brien DP (2012) Corticosteroid use for paradoxical reactions during antibiotic treatment for Mycobacterium ulcerans. PLoS Negl Trop Dis 6:e1767

    PubMed Central  PubMed  Article  Google Scholar 

  73. Trevillyan JM, Johnson PD (2013) Steroids control paradoxical worsening of Mycobacterium ulcerans infection following initiation of antibiotic therapy. Med J Aust 198:443–444

    PubMed  Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Caroline Demangel.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Guenin-Macé, L., Oldenburg, R., Chrétien, F. et al. Pathogenesis of skin ulcers: lessons from the Mycobacterium ulcerans and Leishmania spp. pathogens. Cell. Mol. Life Sci. 71, 2443–2450 (2014). https://doi.org/10.1007/s00018-014-1561-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-014-1561-z

Keywords

  • Skin
  • Infection
  • Cutaneous Leishmaniasis
  • Leishmania spp.
  • Buruli ulcer
  • Mycobacterium ulcerans
  • Mycolactone