A Key Role for the Urokinase Plasminogen Activator (uPA) in Invasive Group A Streptococcal Infection

English version České info

Recruitment of the serine protease plasmin is central to the pathogenesis of many bacterial species, including Group A streptococcus (GAS), a leading cause of morbidity and mortality globally. A key process in invasive GAS disease is the ability to accumulate plasmin at the cell surface, however the role of host activators of plasminogen in this process is poorly understood. Here, we demonstrate for the first time that the urokinase-type plasminogen activator (uPA) contributes to plasmin recruitment and subsequent invasive disease initiation in vivo. In the absence of a source of host plasminogen activators, streptokinase (Ska) was required to facilitate cell surface plasmin acquisition by GAS. However, in the absence of Ska, host activators were sufficient to promote cell surface plasmin acquisition by GAS strain 5448 during incubation with plasminogen or human plasma. Furthermore, GAS were able mediate a significant increase in the activation of zymogen pro-uPA in human plasma. In order to assess the contribution of uPA to invasive GAS disease, a previously undescribed transgenic mouse model of infection was employed. Both C57/black 6J, and AlbPLG1 mice expressing the human plasminogen transgene, were significantly more susceptible to invasive GAS disease than uPA−/− mice. The observed decrease in virulence in uPA−/−mice was found to correlate directly with a decrease in bacterial dissemination and reduced cell surface plasmin accumulation by GAS. These findings have significant implications for our understanding of GAS pathogenesis, and research aimed at therapeutic targeting of plasminogen activation in invasive bacterial infections.

Vyšlo v časopise: A Key Role for the Urokinase Plasminogen Activator (uPA) in Invasive Group A Streptococcal Infection. PLoS Pathog 9(7): e32767. doi:10.1371/journal.ppat.1003469
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003469

Souhrn

Zdroje

1. Sanderson-SmithM, De OliveiraDP, RansonM, McArthurJD (2012) Bacterial plasminogen receptors: Mediators of a multifaceted relationship. Journal of Biomedicine and Biotechnology 2012 doi: 10.1155/2012/272148

2. McArthurJD, CookSM, VenturiniC, WalkerMJ (2012) The role of streptokinase as a virulence determinant of Streptococcus pyogenes–potential for therapeutic targeting. Curr Drug Targets 13: 297–307.

3. SunH, XuY, SitkiewiczI, MaY, WangX, et al. (2012) Inhibitor of streptokinase gene expression improves survival after group A streptococcus infection in mice. Proc Natl Acad Sci U S A 109: 3469–3474.

4. SunH (2011) Exploration of the host haemostatic system by group A streptococcus: implications in searching for novel antimicrobial therapies. J Thromb Haemost 9 Suppl 1: 189–194.

5. HollandsA, GonzalezD, LeireE, DonaldC, GalloRL, et al. (2012) A bacterial pathogen co-opts host plasmin to resist killing by cathelicidin antimicrobial peptides. J Biol Chem 287: 40891–7.

6. CarapetisJR, SteerAC, MulhollandEK, WeberM (2005) The global burden of group A streptococcal diseases. Lancet Infect Dis 5: 685–694.

7. Sanderson-SmithML, DinklaK, ColeJN, CorkAJ, MaamaryPG, et al. (2008) M protein-mediated plasminogen binding is essential for the virulence of an invasive Streptococcus pyogenes isolate. Faseb J 22: 2715–2722.

8. ColeJN, McArthurJD, McKayFC, Sanderson-SmithML, CorkAJ, et al. (2006) Trigger for group A streptococcal M1T1 invasive disease. Faseb J 20: 1745–1747.

9. SunH, RingdahlU, HomeisterJW, FayWP, EnglebergNC, et al. (2004) Plasminogen is a critical host pathogenicity factor for group A streptococcal infection. Science 305: 1283–1286.

10. KhilJ, ImM, HeathA, RingdahlU, MundadaL, et al. (2003) Plasminogen enhances virulence of group A streptococci by streptokinase-dependent and streptokinase-independent mechanisms. J Infect Dis 188: 497–505.

11. WalkerMJ, HollandsA, Sanderson-SmithML, ColeJN, KirkJK, et al. (2007) DNase Sda1 provides selection pressure for a switch to invasive group A streptococcal infection. Nat Med 13: 981–985.

12. PlowEF, HerrenT, RedlitzA, MilesLA, Hoover-PlowJL (1995) The cell biology of the plasminogen system. Faseb J 9: 939–945.

13. WimanB, CollenD (1978) On the kinetics of the reaction between human antiplasmin and plasmin. Eur J Biochem 84: 573–578.

14. MarcumJA, KlineDL (1983) Species specificity of streptokinase. Comp Biochem Physiol B 75: 389–394.

15. KobayashiH, SchmittM, GoretzkiL, ChucholowskiN, CalveteJ, et al. (1991) Cathepsin B efficiently activates the soluble and the tumor cell receptor-bound form of the proenzyme urokinase-type plasminogen activator (Pro-uPA). J Biol Chem 266: 5147–5152.

16. OrgelD, SchroderW, Hecker-KiaA, WeithmannKU, KolkenbrockH, et al. (1998) The cleavage of pro-urokinase type plasminogen activator by stromelysin-1. Clin Chem Lab Med 36: 697–702.

17. CroucherDR, SaundersDN, LobovS, RansonM (2008) Revisiting the biological roles of PAI2 (SERPINB2) in cancer. Nat Rev Cancer 8: 535–545.

18. EllisV, ScullyMF, KakkarVV (1989) Plasminogen activation initiated by single-chain urokinase-type plasminogen activator. Potentiation by U937 monocytes. J Biol Chem 264: 2185–2188.

19. RomerJ, LundLR, EriksenJ, RalfkiaerE, ZehebR, et al. (1991) Differential expression of urokinase-type plasminogen activator and its type-1 inhibitor during healing of mouse skin wounds. J Invest Dermatol 97: 803–811.

20. BeyrichC, LofflerJ, KobsarA, SpeerCP, KneitzS, et al. (2011) Infection of human coronary artery endothelial cells by group B streptococcus contributes to dysregulation of apoptosis, hemostasis, and innate immune responses. Mediators Inflamm 2011: 971502.

21. WinklerF, KastenbauerS, KoedelU, PfisterHW (2002) Role of the urokinase plasminogen activator system in patients with bacterial meningitis. Neurology 59: 1350–1355.

22. AzizRK, KotbM (2008) Rise and persistence of global M1T1 clone of Streptococcus pyogenes. Emerg Infect Dis 14: 1511–1517.

23. EllisV, ScullyMF, KakkarVV (1987) Plasminogen activation by single-chain urokinase in functional isolation. A kinetic study. J Biol Chem 262: 14998–15003.

24. HusainSS (1991) Single-chain urokinase-type plasminogen activator does not possess measurable intrinsic amidolytic or plasminogen activator activities. Biochemistry 30: 5797–5805.

25. StillfriedGE, SaundersDN, RansonM (2007) Plasminogen binding and activation at the breast cancer cell surface: the integral role of urokinase activity. Breast Cancer Res 9: R14.

26. LottenbergR, BroderCC, BoyleMD (1987) Identification of a specific receptor for plasmin on a group A streptococcus. Infect Immun 55: 1914–1918.

27. BuggeTH, FlickMJ, DantonMJ, DaughertyCC, RomerJ, et al. (1996) Urokinase-type plasminogen activator is effective in fibrin clearance in the absence of its receptor or tissue-type plasminogen activator. Proc Natl Acad Sci U S A 93: 5899–5904.

28. CarmelietP, SchoonjansL, KieckensL, ReamB, DegenJ, et al. (1994) Physiological consequences of loss of plasminogen activator gene function in mice. Nature 368: 419–424.

29. JogiA, RonoB, LundIK, NielsenBS, PlougM, et al. (2010) Neutralisation of uPA with a monoclonal antibody reduces plasmin formation and delays skin wound healing in tPA-deficient mice. PLoS One 5: e12746.

30. Grondahl-HansenJ, AgerlinN, Munkholm-LarsenP, BachF, NielsenLS, et al. (1988) Sensitive and specific enzyme-linked immunosorbent assay for urokinase-type plasminogen activator and its application to plasma from patients with breast cancer. J Lab Clin Med 111: 42–51.

31. PlesnerT, PlougM, EllisV, RonneE, Hoyer-HansenG, et al. (1994) The receptor for urokinase-type plasminogen activator and urokinase is translocated from two distinct intracellular compartments to the plasma membrane on stimulation of human neutrophils. Blood 83: 808–815.

32. RijkenDC, LijnenHR (2009) New insights into the molecular mechanisms of the fibrinolytic system. J Thromb Haemost 7: 4–13.

33. BaldiA, PecoriniC, RebucciR, SacconeF, CheliF, et al. (2012) Effect of Escherichia coli lipopolysaccharide on u-PA activity and u-PA and u-PAR RNA expression in a bovine mammary epithelial cell line. Res Vet Sci 93: 758–762.

34. AshbaughCD, WesselsMR (2001) Absence of a cysteine protease effect on bacterial virulence in two murine models of human invasive group A streptococcal infection. Infect Immun 69: 6683–6688.

35. ZimmermanM, QuigleyJP, AsheB, DornC, GoldfarbR, et al. (1978) Direct fluorescent assay of urokinase and plasminogen activators of normal and malignant cells: kinetics and inhibitor profiles. Proc Natl Acad Sci U S A 75: 750–753.