#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Mycolactone-Dependent Depletion of Endothelial Cell Thrombomodulin Is Strongly Associated with Fibrin Deposition in Buruli Ulcer Lesions


Buruli ulcer (BU) is a neglected tropical disease that is most common in West Africa and parts of Australia, but has been reported from over 30 countries worldwide. The symptoms are painless ulcers of the skin caused by a bacterial infection. The bacteria, Mycobacterium ulcerans, produce a macrolide toxin called mycolactone. In this manuscript, we have studied the effects of mycolactone on endothelial cells, specialised cells that line blood vessels and form capillaries. One of the most important functions of these cells is to prevent blood from clotting inside the vessels. We show that mycolactone reduces the ability of cultured endothelial cells to anticoagulate blood, by blocking the expression of a protein called thrombomodulin. We went on to examine samples of BU patient skin and found that thrombomodulin is also reduced here, and that in contrast to normal skin large amounts of fibrin (one of the main constituents of blood clots) were present. This means that it may be useful to consider whether anticoagulants might improve the response to antibiotics and thereby improve treatment outcomes for BU patients.


Vyšlo v časopise: Mycolactone-Dependent Depletion of Endothelial Cell Thrombomodulin Is Strongly Associated with Fibrin Deposition in Buruli Ulcer Lesions. PLoS Pathog 11(7): e32767. doi:10.1371/journal.ppat.1005011
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005011

Souhrn

Buruli ulcer (BU) is a neglected tropical disease that is most common in West Africa and parts of Australia, but has been reported from over 30 countries worldwide. The symptoms are painless ulcers of the skin caused by a bacterial infection. The bacteria, Mycobacterium ulcerans, produce a macrolide toxin called mycolactone. In this manuscript, we have studied the effects of mycolactone on endothelial cells, specialised cells that line blood vessels and form capillaries. One of the most important functions of these cells is to prevent blood from clotting inside the vessels. We show that mycolactone reduces the ability of cultured endothelial cells to anticoagulate blood, by blocking the expression of a protein called thrombomodulin. We went on to examine samples of BU patient skin and found that thrombomodulin is also reduced here, and that in contrast to normal skin large amounts of fibrin (one of the main constituents of blood clots) were present. This means that it may be useful to consider whether anticoagulants might improve the response to antibiotics and thereby improve treatment outcomes for BU patients.


Zdroje

1. Chany AC, Tresse C, Casarotto V, Blanchard N (2013) History, biology and chemistry of Mycobacterium ulcerans infections (Buruli ulcer disease). Nat Prod Rep 30: 1527–1567. doi: 10.1039/c3np70068b 24178858

2. Walsh DS, Portaels F, Meyers WM (2011) Buruli ulcer: Advances in understanding Mycobacterium ulcerans infection. Dermatol Clin 29: 1–8. doi: 10.1016/j.det.2010.09.006 21095521

3. Merritt RW, Walker ED, Small PL, Wallace JR, Johnson PD, et al. (2010) Ecology and transmission of Buruli ulcer disease: a systematic review. PLoS Negl Trop Dis 4: e911. doi: 10.1371/journal.pntd.0000911 21179505

4. Roche B, Benbow ME, Merritt R, Kimbirauskas R, McIntosh M, et al. (2013) Identifying the Achilles' heel of multi-host pathogens: The concept of keystone "host" species illustrated by transmission. Environ Res Lett 8: 045009. 24554969

5. Converse PJ, Nuermberger EL, Almeida DV, Grosset JH (2011) Treating Mycobacterium ulcerans disease (Buruli ulcer): from surgery to antibiotics, is the pill mightier than the knife? Future Microbiol 6: 1185–1198. doi: 10.2217/fmb.11.101 22004037

6. Simpson C, O'Brien DP, McDonald A, Callan P (2013) Mycobacterium ulcerans infection: evolution in clinical management. ANZ J Surg 83: 523–526. doi: 10.1111/j.1445-2197.2012.06230.x 22989109

7. Ruf MT, Chauty A, Adeye A, Ardant MF, Koussemou H, 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. doi: 10.1371/journal.pntd.0001252 21829740

8. Nienhuis WA, Stienstra Y, Abass KM, Tuah W, Thompson WA, et al. (2012) Paradoxical responses after start of antimicrobial treatment in Mycobacterium ulcerans infection. Clin Infect Dis 54: 519–526. doi: 10.1093/cid/cir856 22156855

9. Yeboah-Manu D, Kpeli GS, Ruf MT, Asan-Ampah K, Quenin-Fosu K, et al. (2013) Secondary bacterial infections of buruli ulcer lesions before and after chemotherapy with streptomycin and rifampicin. PLoS Negl Trop Dis 7: e2191. doi: 10.1371/journal.pntd.0002191 23658847

10. 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. doi: 10.1517/14712590802631854 19236249

11. Ruf MT, Schutte D, Chauffour A, Jarlier V, Ji B, 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. doi: 10.1128/AAC.05543-11 22143518

12. 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. doi: 10.1016/S1473-3099(09)70234-8 19850228

13. George KM, Chatterjee D, Gunawardana G, Welty D, Hayman J, et al. (1999) Mycolactone: a polyketide toxin from Mycobacterium ulcerans required for virulence. Science 283: 854–857. 9933171

14. Sarfo FS, Le Chevalier F, Aka N, Phillips RO, Amoako Y, et al. (2011) Mycolactone diffuses into the peripheral blood of Buruli ulcer patients—implications for diagnosis and disease monitoring. PLoS Negl Trop Dis 5: e1237. doi: 10.1371/journal.pntd.0001237 21811642

15. Sarfo FS, Phillips RO, Zhang J, Abass MK, Abotsi J, et al. (2014) Kinetics of mycolactone in human subcutaneous tissue during antibiotic therapy for Mycobacterium ulcerans disease. BMC Infect Dis 14: 202. doi: 10.1186/1471-2334-14-202 24731247

16. Bozzo C, Tiberio R, Graziola F, Pertusi G, Valente G, et al. (2010) A Mycobacterium ulcerans toxin, mycolactone, induces apoptosis in primary human keratinocytes and in HaCaT cells. Microbes Infect 12: 1258–1263. doi: 10.1016/j.micinf.2010.08.005 20800104

17. 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. 10639458

18. Hall BS, Hill K, McKenna M, Ogbechi J, High S, et al. (2014) The Pathogenic Mechanism of the Mycobacterium ulcerans Virulence Factor, Mycolactone, Depends on Blockade of Protein Translocation into the ER. PLoS Pathog 10: e1004061. doi: 10.1371/journal.ppat.1004061 24699819

19. Pahlevan AA, Wright DJ, Andrews C, George KM, Small PL, 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. 10490994

20. Coutanceau E, Decalf J, Martino A, Babon A, Winter N, et al. (2007) Selective suppression of dendritic cell functions by Mycobacterium ulcerans toxin mycolactone. J Exp Med 204: 1395–1403. 17517970

21. Coutanceau E, Marsollier L, Brosch R, Perret E, Goossens P, 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. 16008585

22. Torrado E, Adusumilli S, Fraga AG, Small PL, Castro AG, et al. (2007) Mycolactone-mediated inhibition of tumor necrosis factor production by macrophages infected with Mycobacterium ulcerans has implications for the control of infection. Infect Immun 75: 3979–3988. 17517872

23. 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. doi: 10.4049/jimmunol.0802294 19201873

24. Connor DH, M. WC, Fletcher Lunn H (1966) Buruli ulceration. A clinicopathologic study of 38 Ugandans with Mycobacterium ulcerans ulceration. Arch Path 81: 183–189.

25. Zavattaro E, Boccafoschi F, Borgogna C, Conca A, Johnson RC, et al. (2012) Apoptosis in Buruli ulcer: a clinicopathological study of 45 cases. Histopathology 61: 224–236. doi: 10.1111/j.1365-2559.2012.04206.x 22439755

26. van Hinsbergh VW (2012) Endothelium—role in regulation of coagulation and inflammation. Semin Immunopathol 34: 93–106. doi: 10.1007/s00281-011-0285-5 21845431

27. Simmonds RE, Lane DA (1998) Regulation of Coagulation. In: Loscalzo J, Schafer AI, editors. Thrombosis and Haemorrhage. 2nd Ed ed. Baltimore: Williamsn & Wilkins. pp. 45–76.

28. Esmon CT (2012) Protein C anticoagulant system—anti-inflammatory effects. Semin Immunopathol 34: 127–132. doi: 10.1007/s00281-011-0284-6 21822632

29. Ye X, Fukudome K, Tsuneyoshi N, Satoh T, Tokunaga O, et al. (1999) The endothelial cell protein C receptor (EPCR) functions as a primary receptor for protein C activation on endothelial cells in arteries, veins, and capillaries. Biochem Biophys Res Commun 259: 671–677. 10364477

30. Archipoff G, Beretz A, Freyssinet JM, Klein-Soyer C, Brisson C, et al. (1991) Heterogeneous regulation of constitutive thrombomodulin or inducible tissue-factor activities on the surface of human saphenous-vein endothelial cells in culture following stimulation by interleukin-1, tumour necrosis factor, thrombin or phorbol ester. Biochem J 273 (Pt 3): 679–684.

31. Nawroth PP, Handley DA, Esmon CT, Stern DM (1986) Interleukin 1 induces endothelial cell procoagulant while suppressing cell-surface anticoagulant activity. Proc Natl Acad Sci U S A 83: 3460–3464. 3486418

32. Guenin-Mace L, Veyron-Churlet R, Thoulouze MI, Romet-Lemonne G, Hong H, et al. (2013) Mycolactone activation of Wiskott-Aldrich syndrome proteins underpins Buruli ulcer formation. J Clin Invest 123: 1501–1512. doi: 10.1172/JCI66576 23549080

33. Boehme MW, Galle P, Stremmel W (2002) Kinetics of thrombomodulin release and endothelial cell injury by neutrophil-derived proteases and oxygen radicals. Immunology 107: 340–349. 12423310

34. Fukudome K, Ye X, Tsuneyoshi N, Tokunaga O, Sugawara K, et al. (1998) Activation mechanism of anticoagulant protein C in large blood vessels involving the endothelial cell protein C receptor. J Exp Med 187: 1029–1035. 9529319

35. Kunz G, Ohlin AK, Adami A, Zoller B, Svensson P, et al. (2002) Naturally occurring mutations in the thrombomodulin gene leading to impaired expression and function. Blood 99: 3646–3653. 11986219

36. Stearns-Kurosawa DJ, Kurosawa S, Mollica JS, Ferrell GL, Esmon CT (1996) The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci U S A 93: 10212–10216. 8816778

37. d'Adhemar CJ, Spillane CD, Gallagher MF, Bates M, Costello KM, et al. (2014) The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer. PLoS One 9: e100816. doi: 10.1371/journal.pone.0100816 24977712

38. Peterson JJ, Rayburn HB, Lager DJ, Raife TJ, Kealey GP, et al. (1999) Expression of thrombomodulin and consequences of thrombomodulin deficiency during healing of cutaneous wounds. Am J Pathol 155: 1569–1575. 10550314

39. Hui KY, Haber E, Matsueda GR (1983) Monoclonal antibodies to a synthetic fibrin-like peptide bind to human fibrin but not fibrinogen. Science 222: 1129–1132. 6648524

40. Ruf MT, Sopoh GE, Brun LV, Dossou AD, Barogui YT, et al. (2011) Histopathological changes and clinical responses of Buruli ulcer plaque lesions during chemotherapy: a role for surgical removal of necrotic tissue? PLoS Negl Trop Dis 5: e1334. doi: 10.1371/journal.pntd.0001334 21980547

41. Le TL, Yap AS, Stow JL (1999) Recycling of E-cadherin: a potential mechanism for regulating cadherin dynamics. J Cell Biol 146: 219–232. 10402472

42. Adusumilli S, Mve-Obiang A, Sparer T, Meyers W, Hayman J, et al. (2005) Mycobacterium ulcerans toxic macrolide, mycolactone modulates the host immune response and cellular location of M. ulcerans in vitro and in vivo. Cell Microbiol 7: 1295–1304. 16098217

43. Andreoli A, Ruf MT, Sopoh GE, Schmid P, Pluschke G (2014) Immunohistochemical monitoring of wound healing in antibiotic treated Buruli ulcer patients. PLoS Negl Trop Dis 8: e2809. doi: 10.1371/journal.pntd.0002809 24762629

44. Maruyama I, Majerus PW (1985) The turnover of thrombin-thrombomodulin complex in cultured human umbilical vein endothelial cells and A549 lung cancer cells. Endocytosis and degradation of thrombin. J Biol Chem 260: 15432–15438. 2999116

45. Chu M, Bird CH, Teasdale M, Bird PI (1998) Turnover of thrombomodulin at the cell surface occurs at a similar rate to receptors that are not actively internalized. Thromb Haemost 80: 119–127. 9684797

46. Healy AM, Rayburn HB, Rosenberg RD, Weiler H (1995) Absence of the blood-clotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system. Proc Natl Acad Sci U S A 92: 850–854. 7846065

47. Isermann B, Hendrickson SB, Zogg M, Wing M, Cummiskey M, et al. (2001) Endothelium-specific loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis. J Clin Invest 108: 537–546. 11518727

48. Navarro S, Medina P, Bonet E, Corral J, Martinez-Sales V, et al. (2013) Association of the thrombomodulin gene c.1418C>T polymorphism with thrombomodulin levels and with venous thrombosis risk. Arterioscler Thromb Vasc Biol 33: 1435–1440. doi: 10.1161/ATVBAHA.113.301360 23520161

49. Moxon CA, Wassmer SC, Milner DA Jr., Chisala NV, Taylor TE, et al. (2013) Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children. Blood 122: 842–851. doi: 10.1182/blood-2013-03-490219 23741007

50. Esmon CT (2001) The normal role of Activated Protein C in maintaining homeostasis and its relevance to critical illness. Crit Care 5: S7–12. 11379986

51. Mosnier LO, Zlokovic BV, Griffin JH (2007) The cytoprotective protein C pathway. Blood 109: 3161–3172. 17110453

52. Esmon CT (2006) Inflammation and the activated protein C anticoagulant pathway. Semin Thromb Hemost 32 Suppl 1: 49–60. 16673266

53. Huang HC, Shi GY, Jiang SJ, Shi CS, Wu CM, et al. (2003) Thrombomodulin-mediated cell adhesion: involvement of its lectin-like domain. J Biol Chem 278: 46750–46759. 12951323

54. Mehta D, Malik AB (2006) Signaling mechanisms regulating endothelial permeability. Physiol Rev 86: 279–367. 16371600

55. Raife TJ, Lager DJ, Madison KC, Piette WW, Howard EJ, et al. (1994) Thrombomodulin expression by human keratinocytes. Induction of cofactor activity during epidermal differentiation. J Clin Invest 93: 1846–1851. 8163684

56. Cheng TL, Wu YT, Lai CH, Kao YC, Kuo CH, et al. (2013) Thrombomodulin regulates keratinocyte differentiation and promotes wound healing. J Invest Dermatol 133: 1638–1645. doi: 10.1038/jid.2013.8 23321922

57. Hsu YY, Shi GY, Kuo CH, Liu SL, Wu CM, et al. (2012) Thrombomodulin is an ezrin-interacting protein that controls epithelial morphology and promotes collective cell migration. FASEB J 26: 3440–3452. doi: 10.1096/fj.12-204917 22593542

58. Kanga JM, Dion-Laine M, Kacou DE, Menan EI (2001) Contribution of heparin therapy in the medical treatment of Buruli ulcer apropos of 1 case. Bull Soc Pathol Exot 94: 32–35. 11346980

59. Phillips RO, Sarfo FS, Abass MK, Abotsi J, Wilson T, et al. (2014) Clinical and bacteriological efficacy of rifampin-streptomycin combination for two weeks followed by rifampin and clarithromycin for six weeks for treatment of Mycobacterium ulcerans disease. Antimicrob Agents Chemother 58: 1161–1166. doi: 10.1128/AAC.02165-13 24323473

60. Song F, Fidanze S, Benowitz AB, Kishi Y (2002) Total synthesis of the mycolactones. Org Lett 4: 647–650. 11843613

61. Ahnstrom J, Andersson HM, Canis K, Norstrom E, Yu Y, et al. (2011) Activated protein C cofactor function of protein S: a novel role for a gamma-carboxyglutamic acid residue. Blood 117: 6685–6693. doi: 10.1182/blood-2010-11-317099 21508412

62. Vaiyapuri S, Hutchinson EG, Ali MS, Dannoura A, Stanley RG, et al. (2012) Rhinocetin, a venom-derived integrin-specific antagonist inhibits collagen-induced platelet and endothelial cell functions. J Biol Chem 287: 26235–26244. doi: 10.1074/jbc.M112.381483 22689571

63. Vaiyapuri S, Jones CI, Sasikumar P, Moraes LA, Munger SJ, et al. (2012) Gap junctions and connexin hemichannels underpin hemostasis and thrombosis. Circulation 125: 2479–2491. doi: 10.1161/CIRCULATIONAHA.112.101246 22528526

64. Ruf MT, Pluschke G (2014) Histopathological Staining Techniques. In: Portaels F, editor. Laboratory diagnosis of Buruli ulcer: A manual for healthcare providers. Geneva: World Health Organization. pp. 76–93.

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2015 Číslo 7
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#