α-Macroglobulin Can Crosslink Multiple Erythrocyte Membrane Protein 1 (PfEMP1) Molecules and May Facilitate Adhesion of Parasitized Erythrocytes

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Erythrocytes infected by parasites causing severe P. falciparum malaria often form rosettes by binding a number of uninfected erythrocytes. Several of the parasite proteins involved are known, whereas the identity of the corresponding host receptor(s) on the surrounding erythrocytes is not. Although formation of rosettes often depends on non-immune IgM also binding to the infected erythrocytes, that does not by itself lead to formation of rosettes. Here, we report that the serum protein α2-macroglobulin (α2M) is able to induce rosetting in several in vitro and ex vivo parasite isolates. In contrast to IgM, α2M supports rosetting on its own, while presence of IgM markedly lowers the concentration of α2M required. These findings are explainable by the ability of α2M to crosslink at least four individual PfEMP1 molecules, indicating that the role of α2M in rosetting is to align multiple parasite adhesion proteins, thereby increasing their combined avidity for carbohydrate receptors on surrounding erythrocytes. Our study suggests a new mechanism whereby P. falciparum exploits soluble host proteins to avoid immune destruction, by using them to facilitate adhesion of infected erythrocytes to low-affinity carbohydrate receptors, and points to new strategies to interfere with a major pathogenic mechanism of this devastating parasite.

Vyšlo v časopise: α-Macroglobulin Can Crosslink Multiple Erythrocyte Membrane Protein 1 (PfEMP1) Molecules and May Facilitate Adhesion of Parasitized Erythrocytes. PLoS Pathog 11(7): e32767. doi:10.1371/journal.ppat.1005022
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005022

Souhrn

Zdroje

1. World Health Organization (2013) World Malaria Report 2013.

2. Murray CJ, Rosenfeld LC, Lim SS, Andrews KG, Foreman KJ, Haring D, Fullman N, Naghavi M, Lozano R, Lopez AD (2012) Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet 379: 413–431. doi: 10.1016/S0140-6736(12)60034-8 22305225

3. Barnwell JW, Asch AS, Nachman RL, Yamaya M, Aikawa M, Ingravallo P (1989) A human 88-kD membrane glycoprotein (CD36) functions in vitro as a receptor for a cytoadherence ligand on Plasmodium falciparum-infected erythrocytes. J Clin Invest 84: 765–772. 2474574

4. Berendt AR, Simmons DL, Tansey J, Newbold CI, Marsh K (1989) Intercellular adhesion molecule-1 is an endothelial cell adhesion receptor for Plasmodium falciparum. Nature 341: 57–59. 2475784

5. Treutiger CJ, Heddini A, Fernandez V, Muller WA, Wahlgren M (1997) PECAM-1/CD31, an endothelial receptor for binding Plasmodium falciparum-infected erythrocytes. Nat Med 3: 1405–1408. 9396614

6. Turner L, Lavstsen T, Berger SS, Wang CW, Petersen JE, Avril M, Brazier AJ, Freeth J, Jespersen JS, Nielsen MA, Magistrado P, Lusingu J, Smith JD, Higgins MK, Theander TG (2013) Severe malaria is associated with parasite binding to endothelial protein C receptor. Nature 498: 502–505. doi: 10.1038/nature12216 23739325

7. Turner GDH, Morrison H, Jones M, Davis TME, Looareesuwan S, Buley ID, Gatter KC, Newbold CI, Pukrittayakamee S, Nagachinta B, White NJ, Berendt AR (1994) An immunohistochemical study of the pathology of fatal malaria: evidence for widespread endothelial activation and a potential role for intercellular adhesion molecule-1 in cerebral sequestration. Am J Pathol 145: 1057–1069. 7526692

8. Udomsangpetch R, Wåhlin B, Carlson J, Berzins K, Torii M, Aikawa M, Perlmann P, Wahlgren M (1989) Plasmodium falciparum-infected erythrocytes form spontaneous erythrocyte rosettes. J Exp Med 169: 1835–1840. 2654325

9. Adams Y, Kuhnrae P, Higgins MK, Ghumra A, Rowe JA (2014) Rosetting Plasmodium falciparum-infected erythrocytes bind to human brain microvascular endothelial cells in vitro, demonstrating a dual adhesion phenotype mediated by distinct P. falciparum erythrocyte membrane protein 1 domains. Infect Immun 82: 949–959. doi: 10.1128/IAI.01233-13 24343658

10. Carlson J, Helmby H, Hill AV, Brewster D, Greenwood BM, Wahlgren M (1990) Human cerebral malaria: association with erythrocyte rosetting and lack of anti-rosetting antibodies. Lancet 336: 1457–1460. 1979090

11. Treutiger CJ, Hedlund I, Helmby H, Carlson J, Jepson A, Twumasi P, Kwiatkowski D, Greenwood BM, Wahlgren M (1992) Rosette formation in Plasmodium falciparum isolates and anti-rosette activity of sera from Gambians with cerebral or uncomplicated malaria. Am J Trop Med Hyg 46: 503–510. 1599043

12. Rowe A, Obeiro J, Newbold CI, Marsh K (1995) Plasmodium falciparum rosetting is associated with malaria severity in Kenya. Infect Immun 63: 2323–2326. 7768616

13. Moxon CA, Wassmer SC, Milner DA Jr., Chisala NV, Taylor TE, Seydel KB, Molyneux ME, Faragher B, Esmon CT, Downey C, Toh CH, Craig AG, Heyderman RS (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

14. Mercereau-Puijalon O, Guillotte M, Vigan-Womas I (2008) Rosetting in Plasmodium falciparum: A cytoadherence phenotype with multiple actors. Transfus Clin Biol 15: 62–71. doi: 10.1016/j.tracli.2008.04.003 18514562

15. Scholander C, Carlson J, Kremsner PG, Wahlgren M (1998) Extensive immunoglobulin binding of Plasmodium falciparum-infected erythrocytes in a group of children with moderate anemia. Infect Immun 66: 361–363. 9423881

16. Somner EA, Black J, Pasvol G (2000) Multiple human serum components act as bridging molecules in rosette formation by Plasmodium falciparum-infected erythrocytes. Blood 95: 674–682. 10627479

17. Stevenson L, Huda P, Jeppesen A, Laursen E, Rowe JA, Craig A, Streicher W, Barfod L, Hviid L (2015) Investigating the function of Fc-specific binding of IgM to Plasmodium falciparum erythrocyte membrane protein 1 mediating erythrocyte rosetting. Cell Microbiol 17: 819–831. doi: 10.1111/cmi.12403 25482886

18. Ghumra A, Semblat J-P, McIntosh RS, Raza A, Rasmussen IB, Braathen R, Johansen F-E, Sandlie I, Mongini PK, Rowe JA, Pleass RJ (2008) Identification of residues in the Cμ4 domain of polymeric IgM essential for interaction with Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). J Immunol 181: 1988–2000. 18641336

19. Rowe JA, Moulds JM, Newbold CI, Miller LH (1997) P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1. Nature 388: 292–295. 9230440

20. Chen Q, Barragan A, Fernandez V, Sundstrom A, Schlichtherle M, Sahlen A, Carlson J, Datta S, Wahlgren M (1998) Identification of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) as the rosetting ligand of the malaria parasite P. falciparum. J Exp Med 187: 15–23. 9419207

21. Vigan-Womas I, Guillotte M, Le Scanf C, Igonet S, Petres S, Juillerat A, Badaut C, Nato F, Schneider A, Lavergne A, Contamin H, Tall A, Baril L, Bentley GA, Mercereau-Puijalon O (2008) An in vivo/in vitro model of rosetting and autoagglutination mediated by Plasmodium falciparum VarO, a group A var gene encoding a frequent serotype. Infect Immun 76: 5565–5580. doi: 10.1128/IAI.00901-08 18809668

22. Barragan A, Fernandez V, Chen Q, von Euler A, Wahlgren M, Spillmann D (2000) The duffy-binding-like domain 1 of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a heparan sulfate ligand that requires 12 mers for binding. Blood 95: 3594–3599. 10828049

23. Barragan A, Kremsner PG, Wahlgren M, Carlson J (2000) Blood group A antigen is a co-receptor in Plasmodium falciparum rosetting. Infect Immun 68: 2971–2975. 10768996

24. Vogt AM, Winter G, Wahlgren M, Spillmann D (2004) Heparan sulphate identified on human erythrocytes: a Plasmodium falciparum receptor. Biochem J 381: 593–597. 15209561

25. Jensen ATR, Magistrado PA, Sharp S, Joergensen L, Lavstsen T, Chiucchiuini A, Salanti A, Vestergaard LS, Lusingu JP, Hermsen R, Sauerwein R, Christensen J, Nielsen MA, Hviid L, Sutherland C, Staalsoe T, Theander TG (2004) Plasmodium falciparum associated with severe childhood malaria preferentially expresses PfEMP1 encoded by Group A var genes. J Exp Med 199: 1179–1190. 15123742

26. Bengtsson A, Joergensen L, Rask TS, Olsen RW, Andersen MA, Turner L, Theander TG, Hviid L, Higgins MK, Craig A, Brown A, Jensen AT (2013) A novel domain cassette identifies Plasmodium falciparum PfEMP1 proteins binding ICAM-1 and is a target of cross-reactive, adhesion-inhibitory antibodies. J Immunol 190: 240–249. doi: 10.4049/jimmunol.1202578 23209327

27. Marrero A, Duquerroy S, Trapani S, Goulas T, Guevara T, Andersen GR, Navaza J, Sottrup-Jensen L, Gomis-Ruth FX (2012) The crystal structure of human α2-macroglobulin reveals a unique molecular cage. Angew Chem Int Ed Engl 51: 3340–3344. doi: 10.1002/anie.201108015 22290936

28. Tunstall AM, Merriman JM, Milne I, James K (1975) Normal and pathological serum levels of α2-macroglobulins in men and mice. J Clin Pathol 28: 133–139. 47865

29. Rehman AA, Ahsan H, Khan FH (2013) Alpha-2-macroglobulin: a physiological guardian. J Cell Physiol 228: 1665–1675. doi: 10.1002/jcp.24266 23086799

30. Baruch DI, Pasloske BL, Singh HB, Bi X, Ma XC, Feldman M, Taraschi TF, Howard RJ (1995) Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell 82: 77–87. 7541722

31. Joergensen L, Bengtsson DC, Bengtsson A, Ronander E, Berger SS, Turner L, Dalgaard MB, Cham GK, Victor ME, Lavstsen T, Theander TG, Arnot DE, Jensen AT (2010) Surface co-expression of two different PfEMP1 antigens on single Plasmodium falciparum-infected erythrocytes facilitates binding to ICAM1 and PECAM1. PLoS Pathog 6: e1001083. doi: 10.1371/journal.ppat.1001083 20824088

32. Imber MJ, Pizzo SV (1981) Clearance and binding of two electrophoretic "fast" forms of human α2-macroglobulin. J Biol Chem 256: 8134–8139. 6167573

33. Kristensen T, Moestrup SK, Gliemann J, Bendtsen L, Sand O, Sottrup-Jensen L (1990) Evidence that the newly cloned low-density-lipoprotein receptor related protein (LRP) is the α2-macroglobulin receptor. FEBS Lett 276: 151–155. 1702392

34. Sottrup-Jensen L (1989) Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation. J Biol Chem 264: 11539–11542. 2473064

35. Stark C, Breitkreutz BJ, Reguly T, Boucher L, Breitkreutz A, Tyers M (2006) BioGRID: a general repository for interaction datasets. Nucleic Acids Res 34: D535–D539. 16381927

36. Vigan-Womas I, Guillotte M, Juillerat A, Hessel A, Raynal B, England P, Cohen JH, Bertrand O, Peyrard T, Bentley GA, Lewit-Bentley A, Mercereau-Puijalon O (2012) Structural basis for the ABO blood-group dependence of Plasmodium falciparum rosetting. PLoS Pathog 8: e1002781. doi: 10.1371/journal.ppat.1002781 22807674

37. Rask TS, Hansen DA, Theander TG, Pedersen AG, Lavstsen T (2010) Plasmodium falciparum erythrocyte membrane protein 1 diversity in seven genomes—divide and conquer. PLoS Comput Biol 6: e1000933. doi: 10.1371/journal.pcbi.1000933 20862303

38. Scholander C, Treutiger CJ, Hultenby K, Wahlgren M (1996) Novel fibrillar structure confers adhesive property to malaria- infected erythrocytes. Nat Med 2: 204–208. 8574966

39. Clough B, Atilola FA, Black J, Pasvol G (1998) Plasmodium falciparum: the importance of IgM in the rosetting of parasite-infected erythrocytes. Exp Parasitol 89: 129–132. 9603499

40. Chhatwal GS, Muller HP, Blobel H (1983) Characterization of binding of human alpha 2-macroglobulin to group G streptococci. Infect Immun 41: 959–964. 6193068

41. Muller HP, Rantamaki LK (1995) Binding of native alpha 2-macroglobulin to human group G streptococci. Infect Immun 63: 2833–2839. 7542633

42. Rasmussen M, Muller HP, Bjorck L (1999) Protein GRAB of streptococcus pyogenes regulates proteolysis at the bacterial surface by binding alpha2-macroglobulin. J Biol Chem 274: 15336–15344. 10336419

43. Kun JF, Schmidt-Ott RJ, Lehman LG, Lell B, Luckner D, Greve B, Matousek P, Kremsner PG (1998) Merozoite surface antigen 1 and 2 genotypes and rosetting of Plasmodium falciparum in severe and mild malaria in Lambaréné, Gabon. Trans R Soc Trop Med Hyg 92: 110–114. 9692171

44. Warrell DA, Molyneux ME, Beales PF (1990) Severe and complicated malaria. Second edition. Trans R Soc Trop Med Hyg 84 (suppl. 2): 1–65. 2219249

45. Gjelstrup LC, Kaspersen JD, Behrens MA, Pedersen JS, Thiel S, Kingshott P, Oliveira CL, Thielens NM, Vorup-Jensen T (2012) The role of nanometer-scaled ligand patterns in polyvalent binding by large mannan-binding lectin oligomers. J Immunol 188: 1292–1306. doi: 10.4049/jimmunol.1103012 22219330

46. Tolia NH, Enemark EJ, Sim BK, Joshua-Tor L (2005) Structural basis for the EBA-175 erythrocyte invasion pathway of the malaria parasite Plasmodium falciparum. Cell 122: 183–193. 16051144

47. Batchelor JD, Zahm JA, Tolia NH (2011) Dimerization of Plasmodium vivax DBP is induced upon receptor binding and drives recognition of DARC. Nat Struct Mol Biol 18: 908–914. doi: 10.1038/nsmb.2088 21743458

48. Levashina EA, Moita LF, Blandin S, Vriend G, Lagueux M, Kafatos FC (2001) Conserved role of a complement-like protein in phagocytosis revealed by dsRNA knockout in cultured cells of the mosquito, Anopheles gambiae. Cell 104: 709–718. 11257225

49. Szulman AE (1960) The histological distribution of blood group substances A and B in man. J Exp Med 111: 785–800. 13774694

50. Ampomah P, Stevenson L, Ofori MF, Barfod L, Hviid L (2014) B-cell responses to pregnancy-restricted and -unrestricted Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) antigens in Ghanaian women naturally exposed to malaria parasites. Infect Immun 82: 1860–1871. doi: 10.1128/IAI.01514-13 24566620

51. Khunrae P, Dahlbäck M, Nielsen MA, Andersen G, Ditlev SB, Resende M, Pinto VV, Theander TG, Higgins MK, Salanti A (2010) Full-length recombinant Plasmodium falciparum VAR2CSA binds specifically to CSPG and induces potent parasite adhesion-blocking antibodies. J Mol Biol 397: 826–834. doi: 10.1016/j.jmb.2010.01.040 20109466

52. Brown A, Turner L, Christoffersen S, Andrews KA, Szestak T, Zhao Y, Larsen S, Craig AG, Higgins MK (2013) Molecular architecture of a complex between an adhesion protein from the malaria parasite and intracellular adhesion molecule 1. J Biol Chem 288: 5992–6003. doi: 10.1074/jbc.M112.416347 23297413

53. Claessens A, Adams Y, Ghumra A, Lindergard G, Buchan CC, Andisi C, Bull PC, Mok S, Gupta AP, Wang CW, Turner L, Arman M, Raza A, Bozdech Z, Rowe JA (2012) A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells. Proc Natl Acad Sci U S A 109: E1772–E1781. doi: 10.1073/pnas.1120461109 22619330

54. Sottrup-Jensen L, Petersen TE, Magnusson S (1980) A thiol-ester in α2-macroglobulin cleaved during proteinase complex formation. FEBS Lett 121: 275–279. 6161841

55. Andersen GR, Jacobsen L, Thirup S, Nyborg J, Sottrup-Jensen L (1991) Crystallization and preliminary X-ray analysis of methylamine-treated α2-macroglobulin and 3 α2-macroglobulin-proteinase complexes. FEBS Lett 292: 267–270. 1720400

56. Higon M, Cowan G, Nausch N, Cavanagh D, Oleaga A, Toledo R, Stothard JR, Antunez O, Marcilla A, Burchmore R, Mutapi F (2011) Screening trematodes for novel intervention targets: a proteomic and immunological comparison of Schistosoma haematobium, Schistosoma bovis and Echinostoma caproni. Parasitology 138: 1607–1619. doi: 10.1017/S0031182011000412 21729355

57. Wilm M, Shevchenko A, Houthaeve T, Breit S, Schweigerer L, Fotsis T, Mann M (1996) Femtomole sequencing of proteins from polyacrylamide gels by nano-electrospray mass spectrometry. Nature 379: 466–469. 8559255

58. Bhasin VK, Trager W (1984) Gametocyte-forming and non-gametocyte-forming clones of Plasmodium falciparum. Am J Trop Med Hyg 33: 534–537. 6383092

59. Handunnetti SM, Gilladoga AD, van Schravendijk M- R, Nakamura K-I, Aikawa M, Howard RJ (1992) Purification and in vitro selection of rosette-positive (R+) and rosette-negative (R-) phenotypes of knob-positive Plasmodium falciparum parasites. Am J Trop Med Hyg 46: 371–381. 1575284

60. Staalsoe T, Nielsen MA, Vestergaard LS, Jensen ATR, Theander TG, Hviid L (2003) In vitro selection of Plasmodium falciparum 3D7 for expression of variant surface antigens associated with severe malaria in African children. Parasite Immunol 25: 421–427. 14651589

61. Robson KJ, Walliker D, Creasey A, McBride J, Beale G, Wilson RJM (1992) Cross-contamination of Plasmodium cultures. Parasitol Today 8: 38–39.

62. Roberts DJ, Craig AG, Berendt AR, Pinches R, Nash G, Marsh K, Newbold CI (1992) Rapid switching to multiple antigenic and adhesive phenotypes in malaria. Nature 357: 689–692. 1614515

63. Carlson J, Ekre HP, Helmby H, Gysin J, Greenwood BM, Wahlgren M (1992) Disruption of Plasmodium falciparum erythrocyte rosettes by standard heparin and heparin devoid of anticoagulant activity. Am J Trop Med Hyg 46: 595–602. 1599054

64. Moll K., Ljungström I., Perlmann H., Scherf A., and Wahlgren M. (2008) Methods in malaria research. Manassas, VA: MR4/ATCC.

65. Barfod L, Dalgaard MB, Pleman ST, Ofori MF, Pleass RJ, Hviid L (2011) Evasion of immunity to Plasmodium falciparum malaria by IgM masking of protective IgG epitopes in infected erythrocyte surface-exposed PfEMP1. Proc Natl Acad Sci U S A 108: 12485–12490. doi: 10.1073/pnas.1103708108 21746929

66. Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9: 671–675. 22930834