1887

Abstract

Pathogenic bacteria of the genus Leptospira are the causative agent of leptospirosis, an emergent infectious disease that affects humans and animals worldwide. Severe forms of the disease in humans include jaundice, multiple organ failure and intense haemorrhage. Up to now, mechanisms associated with the haemorrhage foci are poorly understood. We report in this work that, despite the low levels of antithrombin III in convalescent human serum samples, virulent, culture-attenuated and saprophyte strains of Leptospira are unable to bind and/or degrade this thrombin inhibitor, suggesting an indirect mechanism of pathogenesis. Lower levels of prothrombin were found in serum samples at the onset and convalescent phase of the disease when compared to normal human sera. The concomitant decreased levels of antithrombin III and prothrombin suggest a process of stimulated coagulation, which is corroborated by the increase of prothrombin fragment F1+2 in the serum samples. Data obtained with hamsters experimentally infected with virulent Leptospira interrogans serovars Kennewicki and Canicola strongly point out that haemorrhage is correlated with decreased levels of thrombin inhibitors and prothrombin. Activated coagulation might lead to an overconsumption of coagulation factors ultimately leading to bleeding and organ failure.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.000318
2016-08-01
2019-10-21
Loading full text...

Full text loading...

/deliver/fulltext/micro/162/8/1407.html?itemId=/content/journal/micro/10.1099/mic.0.000318&mimeType=html&fmt=ahah

References

  1. Aird W. C. . ( 2005;). Coagulation. . Crit Care Med 33: S485–487. [CrossRef] [PubMed]
    [Google Scholar]
  2. Bauer K. A. , ten Cate H. , Barzegar S. , Spriggs D. R. , Sherman M. L. , Rosenberg R. D. . ( 1989;). Tumor necrosis factor infusions have a procoagulant effect on the hemostatic mechanism of humans. . Blood 74: 165–172.[PubMed]
    [Google Scholar]
  3. Bharti A. R. , Nally J. E. , Ricaldi J. N. , Matthias M. A. , Diaz M. M. , Lovett M. A. , Levett P. N. , Gilman R. H. , Willig M. R. et al. ( 2003;). Leptospirosis: a zoonotic disease of global importance. . Lancet Infect Dis 3: 757–771. [CrossRef] [PubMed]
    [Google Scholar]
  4. Carvalho E. , Barbosa A. S. , Gómez R. M. , Cianciarullo A. M. , Hauk P. , Abreu P. A. , Fiorini L. C. , Oliveira M. L. , Romero E. C. et al. ( 2009;). Leptospiral TlyC is an extracellular matrix-binding protein and does not present hemolysin activity. . FEBS Lett 583: 1381–1385. [CrossRef] [PubMed]
    [Google Scholar]
  5. Chierakul W. , Tientadakul P. , Suputtamongkol Y. , Wuthiekanun V. , Phimda K. , Limpaiboon R. , Opartkiattikul N. , White N. J. , Peacock S. J. et al. ( 2008;). Activation of the coagulation cascade in patients with leptospirosis. . Clin Infect Dis 46: 254–260. [CrossRef] [PubMed]
    [Google Scholar]
  6. Cinco M. , Vecile E. , Murgia R. , Dobrina P. , Dobrina A. . ( 1996;). Leptospira interrogans and Leptospira peptidoglycans induce the release of tumor necrosis factor α from human monocytes. . FEMS Microbiol Lett 138: 211–214. [CrossRef] [PubMed]
    [Google Scholar]
  7. Cinel I. , Opal S. M. . ( 2009;). Molecular biology of inflammation and sepsis: a primer. . Crit Care Med 37: 291–304. [CrossRef] [PubMed]
    [Google Scholar]
  8. da Silva J. J. , Netto B. A. , Lilembaum W. , Alvim M. E. , de Oliveira A. V. . ( 1995;). The hemorrhagic syndrome of leptospirosis: an experimental study in guinea pigs. . Rev Soc Bras Med Trop 28: 169–177. [CrossRef] [PubMed]
    [Google Scholar]
  9. Diament D. , Brunialti M. K. , Romero E. C. , Kallas E. G. , Salomao R. . ( 2002;). Peripheral blood mononuclear cell activation induced by Leptospira interrogans glycolipoprotein. . Infect Immun 70: 1677–1683. [CrossRef] [PubMed]
    [Google Scholar]
  10. Dickneite G. . ( 2008;). A comparison of the pharmacokinetics of antithrombin derived from human plasma and from transgenic goats and the prevention of sepsis in an animal model. . Biopharm Drug Dispos 29: 356–365. [CrossRef] [PubMed]
    [Google Scholar]
  11. Doolittle R. F. . ( 1984;). Fibrinogen and fibrin. . Annu Rev Biochem 53: 195–229. [CrossRef] [PubMed]
    [Google Scholar]
  12. Esen S. , Sunbul M. , Leblebicioglu H. , Eroglu C. , Turan D. . ( 2004;). Impact of clinical and laboratory findings on prognosis in leptospirosis. . Swiss Med Wkly 134: 347–352.[PubMed]
    [Google Scholar]
  13. Esmon C. T. , Fukudome K. , Mather T. , Bode W. , Regan L. M. , Stearns-Kurosawa D. J. , Kurosawa S. . ( 1999;). Inflammation, sepsis, and coagulation. . Haematologica 84: 254–259.[PubMed]
    [Google Scholar]
  14. Faine S. , Adler B. , Bolin C. , Perolat P. . (editors) ( 1999;). Leptospira and Leptospirosis, 2nd edn. Melbourne:: MediSci;.
    [Google Scholar]
  15. Fernandes L. G. , de Morais Z. M. , Vasconcellos S. A. , Nascimento A. L. . ( 2015;). Leptospira interrogans reduces fibrin clot formation by modulating human thrombin activity via exosite I. . Pathog Dis 73: ftv001. [CrossRef] [PubMed]
    [Google Scholar]
  16. Fernandes L. G. , Vieira M. L. , Kirchgatter K. , Alves I. J. , de Morais Z. M. , Vasconcellos S. A. , Romero E. C. , Nascimento A. L. . ( 2012;). OmpL1 is an extracellular matrix- and plasminogen-interacting protein of Leptospira spp. . Infect Immun 80: 3679–3692. [CrossRef] [PubMed]
    [Google Scholar]
  17. Higgins R. , Cousineau G. . ( 1977;). The pathogenesis of leptospirosis I. Hemorrhages in experimental leptospirosis in guinea pigs. . Can J Comp Med 41: 174–181.[PubMed]
    [Google Scholar]
  18. Ko A. I. , Galvão Reis M. , Ribeiro Dourado C. M. , Johnson W. D. , Riley L. W. . Salvador Leptospirosis Study Group ( 1999;). Urban epidemic of severe leptospirosis in Brazil. . Lancet 354: 820–825. [CrossRef] [PubMed]
    [Google Scholar]
  19. Levett P. N. . ( 2001;). Leptospirosis. . Clin Microbiol Rev 14: 296–326. [CrossRef] [PubMed]
    [Google Scholar]
  20. Levi M. . ( 2010;). The coagulant response in sepsis and inflammation. . Hamostaseologie 30: 10-12–10-14.[PubMed]
    [Google Scholar]
  21. Levi M. . ( 2014;). Diagnosis and treatment of disseminated intravascular coagulation. . Int J Lab Hematol 36: 228–236. [CrossRef] [PubMed]
    [Google Scholar]
  22. Levi M. , van der Poll T. . ( 2008;). The role of natural anticoagulants in the pathogenesis and management of systemic activation of coagulation and inflammation in critically ill patients. . Semin Thromb Hemost 34: 459–468. [CrossRef] [PubMed]
    [Google Scholar]
  23. Levi M. , de Jonge E. , van der Poll T. . ( 2003;). Sepsis and disseminated intravascular coagulation. . J Thromb Thrombolysis 16: 43–47. [CrossRef] [PubMed]
    [Google Scholar]
  24. Levi M. , Schouten M. , van der Poll T. . ( 2008;). Sepsis, coagulation, and antithrombin: old lessons and new insights. . Semin Thromb Hemost 34: 742–746. [CrossRef] [PubMed]
    [Google Scholar]
  25. Levi M. , de Jonge E. , van der Poll T. , ten Cate H. . ( 1999;). Disseminated intravascular coagulation. . Thromb Haemost 82: 695–705. [CrossRef] [PubMed]
    [Google Scholar]
  26. Levi M. , van der Poll T. , ten Cate H. , van Deventer S. J. . ( 1997;). The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. . Eur J Clin Invest 27: 3–9. [CrossRef] [PubMed]
    [Google Scholar]
  27. Lo Y. Y. , Hsu S. H. , Ko Y. C. , Hung C. C. , Chang M. Y. , Hsu H. H. , Pan M. J. , Chen Y. W. , Lee C. H. et al. ( 2013;). Essential calcium-binding cluster of Leptospira LipL32 protein for inflammatory responses through the Toll-like receptor 2 pathway. . J Biol Chem 288: 12335–12344. [CrossRef] [PubMed]
    [Google Scholar]
  28. Maciel E. A. , de Carvalho A. L. , Nascimento S. F. , de Matos R. B. , Gouveia E. L. , Reis M. G. , Ko A. I. . ( 2008;). Household transmission of Leptospira infection in urban slum communities. . PLoS Negl Trop Dis 2: e154. [CrossRef] [PubMed]
    [Google Scholar]
  29. Mak P. , Enghild J. J. , Dubin A. . ( 1996;). Hamster antithrombin III: purification, characterization and acute phase response. . Comp Biochem Physiol B Biochem Mol Biol 115: 135–141. [CrossRef] [PubMed]
    [Google Scholar]
  30. Marotto P. C. , Nascimento C. M. , Eluf-Neto J. , Marotto M. S. , Andrade L. , Sztajnbok J. , Seguro A. C. . ( 1999;). Acute lung injury in leptospirosis: clinical and laboratory features, outcome, and factors associated with mortality. . Clin Infect Dis 29: 1561–1563. [CrossRef] [PubMed]
    [Google Scholar]
  31. Matsui M. , Rouleau V. , Bruyère-Ostells L. , Goarant C. . ( 2011;). Gene expression profiles of immune mediators and histopathological findings in animal models of leptospirosis: comparison between susceptible hamsters and resistant mice. . Infect Immun 79: 4480–4492. [CrossRef] [PubMed]
    [Google Scholar]
  32. Miragliotta G. , Fumarola D. . ( 1983;). In vitro effect of Leptospira icterohaemorrhagiae on human mononuclear leukocytes procoagulant activity: comparison of virulent with nonvirulent strain. . Can J Comp Med 47: 70–72.[PubMed]
    [Google Scholar]
  33. Nicodemo A. C. , Duarte M. I. , Alves V. A. , Takakura C. F. , Santos R. T. , Nicodemo E. L. . ( 1997;). Lung lesions in human leptospirosis: microscopic, immunohistochemical, and ultrastructural features related to thrombocytopenia. . Am J Trop Med Hyg 56: 181–187.[PubMed]
    [Google Scholar]
  34. Oliveira R. , Domingos R. F. , Siqueira G. H. , Fernandes L. G. , Souza N. M. , Vieira M. L. , de Morais Z. M. , Vasconcellos S. A. , Nascimento A. L. . ( 2013;). Adhesins of Leptospira interrogans mediate the interaction to fibrinogen and inhibit fibrin clot formation in vitro . . PLoS Negl Trop Dis 7: e2396. [CrossRef] [PubMed]
    [Google Scholar]
  35. Østerud B. , Bjørklid E. . ( 2001;). The tissue factor pathway in disseminated intravascular coagulation. . Semin Thromb Hemost 27: 605–617. [CrossRef] [PubMed]
    [Google Scholar]
  36. Plank R. , Dean D. . ( 2000;). Overview of the epidemiology, microbiology, and pathogenesis of Leptospira spp. in humans. . Microbes Infect 2: 1265–1276. [CrossRef] [PubMed]
    [Google Scholar]
  37. Reis E. A. , Hagan J. E. , Ribeiro G. S. , Teixeira-Carvalho A. , Martins-Filho O. A. , Montgomery R. R. , Shaw A. C. , Ko A. I. , Reis M. G. . ( 2013;). Cytokine response signatures in disease progression and development of severe clinical outcomes for leptospirosis. . PLoS Negl Trop Dis 7: e2457. [CrossRef] [PubMed]
    [Google Scholar]
  38. Segura E. R. , Ganoza C. A. , Campos K. , Ricaldi J. N. , Torres S. , Silva H. , Céspedes M. J. , Matthias M. A. , Swancutt M. A. et al. ( 2005;). Clinical spectrum of pulmonary involvement in leptospirosis in a region of endemicity, with quantification of leptospiral burden. . Clin Infect Dis 40: 343–351. [CrossRef] [PubMed]
    [Google Scholar]
  39. Tajiki M. H. , Salomao R. . ( 1996;). Association of plasma levels of tumor necrosis factor with severity of disease and mortality among patients with leptospirosis. . Clin Infect Dis 23: 1177–1178. [CrossRef]
    [Google Scholar]
  40. Teixeira A. F. , de Morais Z. M. , Kirchgatter K. , Romero E. C. , Vasconcellos S. A. , Nascimento A. L. . ( 2015;). Features of two new proteins with OmpA-like domains identified in the genome sequences of Leptospira interrogans . . PLoS One 10: e0122762. [CrossRef] [PubMed]
    [Google Scholar]
  41. Tsujimoto H. , Ono S. , Efron P. A. , Scumpia P. O. , Moldawer L. L. , Mochizuki H. . ( 2008;). Role of Toll-like receptors in the development of sepsis. . Shock 29: 315–321. [CrossRef] [PubMed]
    [Google Scholar]
  42. Turner L. H. . ( 1970;). Leptospirosis. 3. Maintenance, isolation and demonstration of leptospires. . Trans R Soc Trop Med Hyg 64: 623–646.[PubMed] [CrossRef]
    [Google Scholar]
  43. van der Poll T. , Büller H. R. , ten Cate H. , Wortel C. H. , Bauer K. A. , van Deventer S. J. , Hack C. E. , Sauerwein H. P. , Rosenberg R. D. et al. ( 1990;). Activation of coagulation after administration of tumor necrosis factor to normal subjects. . N Engl J Med 322: 1622–1627. [CrossRef] [PubMed]
    [Google Scholar]
  44. van Gorp E. C. , Suharti C. , ten Cate H. , Dolmans W. M. , van der Meer J. W. , ten Cate J. W. , Brandjes D. P. . ( 1999;). Review: infectious diseases and coagulation disorders. . J Infect Dis 180: 176–186. [CrossRef] [PubMed]
    [Google Scholar]
  45. Vieira M. L. , Naudin C. , Mörgelin M. , Romero E. C. , Nascimento A. L. , Herwald H. . ( 2016;). Modulation of Hemostatic and Inflammatory Responses by Leptospira Spp. . PLoS Negl Trop Dis 10: e0004713. [CrossRef] [PubMed]
    [Google Scholar]
  46. Vieira M. L. , Vasconcellos S. A. , Gonçales A. P. , de Morais Z. M. , Nascimento A. L. . ( 2009;). Plasminogen acquisition and activation at the surface of Leptospira species lead to fibronectin degradation. . Infect Immun 77: 4092–4101. [CrossRef] [PubMed]
    [Google Scholar]
  47. Volz M. S. , Moos V. , Allers K. , Luge E. , Mayer-Scholl A. , Nöckler K. , Loddenkemper C. , Jansen A. , Schneider T. . ( 2015;). Specific CD4+ T-cell reactivity and cytokine release in different clinical presentations of leptospirosis. . Clin Vaccine Immunol 22: 1276–1284. [CrossRef] [PubMed]
    [Google Scholar]
  48. Wagenaar J. F. , Goris M. G. , Partiningrum D. L. , Isbandrio B. , Hartskeerl R. A. , Brandjes D. P. , Meijers J. C. , Gasem M. H. , van Gorp E. C. . ( 2010;). Coagulation disorders in patients with severe leptospirosis are associated with severe bleeding and mortality. . Trop Med Int Health 15: 152–159. [CrossRef] [PubMed]
    [Google Scholar]
  49. Wagenaar J. F. , Goris M. G. , Sakundarno M. S. , Gasem M. H. , Mairuhu A. T. , de Kruif M. D. , ten Cate H. , Hartskeerl R. , Brandjes D. P. et al. ( 2007;). What role do coagulation disorders play in the pathogenesis of leptospirosis?. Trop Med Int Health 12: 111–122. [CrossRef] [PubMed]
    [Google Scholar]
  50. Wang H. , Wu Y. , Ojcius D. M. , Yang X. F. , Zhang C. , Ding S. , Lin X. , Yan J. . ( 2012;). Leptospiral hemolysins induce proinflammatory cytokines through Toll-like receptor 2- and 4-mediated JNK and NF-κB signaling pathways. . PLoS One 7: e42266. [CrossRef] [PubMed]
    [Google Scholar]
  51. Weisel J. W. . ( 2005;). Fibrinogen and fibrin. . Adv Protein Chem 70: 247–299. [CrossRef] [PubMed]
    [Google Scholar]
  52. Werts C. , Tapping R. I. , Mathison J. C. , Chuang T. H. , Kravchenko V. , Saint Girons I. , Haake D. A. , Godowski P. J. , Hayashi F. et al. ( 2001;). Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism. . Nat Immunol 2: 346–352. [CrossRef] [PubMed]
    [Google Scholar]
  53. Wheeler A. P. , Bernard G. R. . ( 1999;). Treating patients with severe sepsis. . N Engl J Med 340: 207–214. [CrossRef] [PubMed]
    [Google Scholar]
  54. Yang C.-W. , Hung C.-C. , Wu M.-S. , Tian Y.-C. , Chang C.-T. , Pan M.-J. , Vandewalle A. . ( 2006a;). Toll-like receptor 2 mediates early inflammation by leptospiral outer membrane proteins in proximal tubule cells. . Kidney Int 69: 815–822. [CrossRef]
    [Google Scholar]
  55. Yang H. L. , Jiang X. C. , Zhang X. Y. , Li W. J. , Hu B. Y. , Zhao G. P. , Guo X. K. . ( 2006b;). Thrombocytopenia in the experimental leptospirosis of guinea pig is not related to disseminated intravascular coagulation. . BMC Infect Dis 6: 19.[CrossRef]
    [Google Scholar]
  56. Zhang Y. X. , Geng Y. , Yang J. W. , Guo X. K. , Zhao G. P. . ( 2008;). Cytotoxic activity and probable apoptotic effect of Sph2, a sphigomyelinase hemolysin from Leptospira interrogans strain Lai. . BMB Rep 41: 119–125. [CrossRef] [PubMed]
    [Google Scholar]
  57. Zhao H. , Bao L. . ( 2012;). [Research on the expression of hemolysin genes of Leptospira in vivo by GeneChip]. . Sichuan Da Xue Xue Bao Yi Xue Ban 43: 520–524.[PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.000318
Loading
/content/journal/micro/10.1099/mic.0.000318
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error