cAMP-Signalling Regulates Gametocyte-Infected Erythrocyte Deformability Required for Malaria Parasite Transmission

English version České info

Malaria transmission is ensured by deformable mature gametocyte-infected erythrocytes being taken up when a mosquito bites. Non-deformable immature gametocyte stages are sequestered in the bone marrow, as their lack of deformability would lead to their splenic clearance. In the present study, we apply nano-filtration technology to mimic splenic retention and demonstrate that deformability of transmissible mature stage V gametocytes is regulated by parasite cyclic AMP-dependent kinase signalling. Importantly, when we used drugs to raise cAMP levels we render transmissible mature gametocytes as stiff as non-transmissible gametocytes. In contrast, when we inhibit the cAMP-dependent kinase we render immature gametocytes more deformable. Thus, by two different approaches we confirm that the drop in cAMP levels in mature gametocytes leads to an increase in their deformability and hence more likely to circulate through the spleen. Our molecular observations have the potential to be translated into therapies for blocking malaria transmission by demonstrating that raising cAMP levels with sildenafil also known as “Viagra” renders mature gametocytes rigid. These findings provide the proof of principle that deformability of circulating gametocytes is targetable by pharmacological agents and as such, it provides a novel approach to prevent the spread of parasites. PDE inhibitors therefore represent novel drug leads potentially capable of blocking transmission and improving the worldwide fight to eliminate malaria from the human population.

Vyšlo v časopise: cAMP-Signalling Regulates Gametocyte-Infected Erythrocyte Deformability Required for Malaria Parasite Transmission. PLoS Pathog 11(5): e32767. doi:10.1371/journal.ppat.1004815
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004815

Souhrn

Zdroje

1. Sinden RE, Carter R, Drakeley C, Leroy D (2012) The biology of sexual development of Plasmodium: the design and implementation of transmission-blocking strategies. Malar J 11: 70. doi: 10.1186/1475-2875-11-70 22424474

2. Hawking F, Wilson ME, Gammage K (1971) Evidence for cyclic development and short-lived maturity in the gametocytes of Plasmodium falciparum. Trans R Soc Trop Med Hyg 65: 549–559. 5003557

3. Smalley ME, Abdalla S, Brown J (1981) The distribution of Plasmodium falciparum in the peripheral blood and bone marrow of Gambian children. Trans R Soc Trop Med Hyg 75: 103–105. 7022784

4. Farfour E, Charlotte F, Settegrana C, Miyara M, Buffet P (2012) The extravascular compartment of the bone marrow: a niche for Plasmodium falciparum gametocyte maturation? Malar J 11: 285. doi: 10.1186/1475-2875-11-285 22905863

5. Aguilar R, Magallon-Tejada A, Achtman AH, Moraleda C, Joice R, et al. (2014) Molecular evidence for the localization of Plasmodium falciparum immature gametocytes in bone marrow. Blood 123: 959–966. doi: 10.1182/blood-2013-08-520767 24335496

6. Joice R, Nilsson SK, Montgomery J, Dankwa S, Egan E, et al. (2014) Plasmodium falciparum transmission stages accumulate in the human bone marrow. Sci Transl Med 6: 244re245.

7. Silvestrini F, Tiburcio M, Bertuccini L, Alano P (2012) Differential adhesive properties of sequestered asexual and sexual stages of Plasmodium falciparum on human endothelial cells are tissue independent. PLoS One 7: e31567. doi: 10.1371/journal.pone.0031567 22363675

8. Tiburcio M, Silvestrini F, Bertuccini L, Sander A, Turner L, et al. (2012) Early gametocytes of the malaria parasite Plasmodium falciparum specifically remodel the adhesive properties of infected erythrocyte surface. Cell Microbiol.

9. Tiburcio M, Niang M, Deplaine G, Perrot S, Bischoff E, et al. (2012) A switch in infected erythrocyte deformability at the maturation and blood circulation of Plasmodium falciparum transmission stages. Blood 119: e172–180. doi: 10.1182/blood-2012-03-414557 22517905

10. Bousema T, Drakeley C (2011) Epidemiology and infectivity of Plasmodium falciparum and Plasmodium vivax gametocytes in relation to malaria control and elimination. Clin Microbiol Rev 24: 377–410. doi: 10.1128/CMR.00051-10 21482730

11. Aingaran M, Zhang R, Law SK, Peng Z, Undisz A, et al. (2012) Host cell deformability is linked to transmission in the human malaria parasite Plasmodium falciparum. Cell Microbiol.

12. Dearnley MK, Yeoman JA, Hanssen E, Kenny S, Turnbull L, et al. (2012) Origin, composition, organization and function of the inner membrane complex of Plasmodium falciparum gametocytes. J Cell Sci 125: 2053–2063. doi: 10.1242/jcs.099002 22328505

13. Dixon MW, Dearnley MK, Hanssen E, Gilberger T, Tilley L (2012) Shape-shifting gametocytes: how and why does P. falciparum go banana-shaped? Trends Parasitol 28: 471–478. doi: 10.1016/j.pt.2012.07.007 22939181

14. Hliscs M, Millet C, Dixon MW, Siden-Kiamos I, McMillan P, et al. (2014) Organisation and function of an actin cytoskeleton in Plasmodium falciparum gametocytes. Cell Microbiol.

15. Sinden RE (1982) Gametocytogenesis of Plasmodium falciparum in vitro: an electron microscopic study. Parasitology 84: 1–11. 7099715

16. Mohandas N, Gallagher PG (2008) Red cell membrane: past, present, and future. Blood 112: 3939–3948. doi: 10.1182/blood-2008-07-161166 18988878

17. Pantaleo A, De Franceschi L, Ferru E, Vono R, Turrini F (2010) Current knowledge about the functional roles of phosphorylative changes of membrane proteins in normal and diseased red cells. J Proteomics 73: 445–455. doi: 10.1016/j.jprot.2009.08.011 19758581

18. Ling E, Danilov YN, Cohen CM (1988) Modulation of red cell band 4.1 function by cAMP-dependent kinase and protein kinase C phosphorylation. J Biol Chem 263: 2209–2216. 3339007

19. Chen L, Brown JW, Mok YF, Hatters DM, McKnight CJ (2013) The allosteric mechanism induced by protein kinase A (PKA) phosphorylation of dematin (band 4.9). J Biol Chem 288: 8313–8320. doi: 10.1074/jbc.M112.438861 23355471

20. Koshino I, Mohandas N, Takakuwa Y (2012) Identification of a novel role for dematin in regulating red cell membrane function by modulating spectrin-actin interaction. J Biol Chem 287: 35244–35250. doi: 10.1074/jbc.M111.305441 22927433

21. Syin C, Parzy D, Traincard F, Boccaccio I, Joshi MB, et al. (2001) The H89 cAMP-dependent protein kinase inhibitor blocks Plasmodium falciparum development in infected erythrocytes. Eur J Biochem 268: 4842–4849. 11559352

22. Ono T, Cabrita-Santos L, Leitao R, Bettiol E, Purcell LA, et al. (2008) Adenylyl cyclase alpha and cAMP signaling mediate Plasmodium sporozoite apical regulated exocytosis and hepatocyte infection. PLoS Pathog 4: e1000008. doi: 10.1371/journal.ppat.1000008 18389080

23. Harrison T, Samuel BU, Akompong T, Hamm H, Mohandas N, et al. (2003) Erythrocyte G protein-coupled receptor signaling in malarial infection. Science 301: 1734–1736. 14500986

24. Leykauf K, Treeck M, Gilson PR, Nebl T, Braulke T, et al. (2010) Protein kinase a dependent phosphorylation of apical membrane antigen 1 plays an important role in erythrocyte invasion by the malaria parasite. PLoS Pathog 6: e1000941. doi: 10.1371/journal.ppat.1000941 20532217

25. Merckx A, Nivez MP, Bouyer G, Alano P, Langsley G, et al. (2008) Plasmodium falciparum regulatory subunit of cAMP-dependent PKA and anion channel conductance. PLoS Pathog 4: e19. doi: 10.1371/journal.ppat.0040019 18248092

26. Muhia DK, Swales CA, Eckstein-Ludwig U, Saran S, Polley SD, et al. (2003) Multiple splice variants encode a novel adenylyl cyclase of possible plastid origin expressed in the sexual stage of the malaria parasite Plasmodium falciparum. J Biol Chem 278: 22014–22022. 12668669

27. Read LK, Mikkelsen RB (1991) Comparison of adenylate cyclase and cAMP-dependent protein kinase in gametocytogenic and nongametocytogenic clones of Plasmodium falciparum. J Parasitol 77: 346–352. 2040946

28. Deplaine G, Safeukui I, Jeddi F, Lacoste F, Brousse V, et al. (2011) The sensing of poorly deformable red blood cells by the human spleen can be mimicked in vitro. Blood 117: e88–95. doi: 10.1182/blood-2010-10-312801 21163923

29. Lavazec C, Deplaine G, Safeukui I, Perrot S, Milon G, et al. (2013) Microsphiltration: a microsphere matrix to explore erythrocyte deformability. Methods Mol Biol 923: 291–297. 22990786

30. Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, et al. (2007) The selectivity of protein kinase inhibitors: a further update. Biochem J 408: 297–315. 17850214

31. Davies SP, Reddy H, Caivano M, Cohen P (2000) Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 351: 95–105. 10998351

32. Sudo A, Kato K, Kobayashi K, Tohya Y, Akashi H (2008) Susceptibility of Plasmodium falciparum cyclic AMP-dependent protein kinase and its mammalian homologue to the inhibitors. Mol Biochem Parasitol 160: 138–142. doi: 10.1016/j.molbiopara.2008.03.011 18501980

33. Taylor HM, McRobert L, Grainger M, Sicard A, Dluzewski AR, et al. (2010) The malaria parasite cyclic GMP-dependent protein kinase plays a central role in blood-stage schizogony. Eukaryot Cell 9: 37–45. doi: 10.1128/EC.00186-09 19915077

34. Kim SP, Ha JM, Yun SJ, Kim EK, Chung SW, et al. (2010) Transcriptional activation of peroxisome proliferator-activated receptor-gamma requires activation of both protein kinase A and Akt during adipocyte differentiation. Biochem Biophys Res Commun 399: 55–59. doi: 10.1016/j.bbrc.2010.07.038 20638365

35. Dawn A, Singh S, More KR, Siddiqui FA, Pachikara N, et al. (2014) The Central Role of cAMP in Regulating Plasmodium falciparum Merozoite Invasion of Human Erythrocytes. PLoS Pathog 10: e1004520. doi: 10.1371/journal.ppat.1004520 25522250

36. Yokoyama D, Saito-Ito A, Asao N, Tanabe K, Yamamoto M, et al. (1998) Modulation of the growth of Plasmodium falciparum in vitro by protein serine/threonine phosphatase inhibitors. Biochem Biophys Res Commun 247: 18–23. 9636646

37. Goto N, Harayama H (2009) Calyculin A-sensitive protein phosphatases are involved in maintenance of progressive movement in mouse spermatozoa in vitro by suppression of autophosphorylation of protein kinase A. J Reprod Dev 55: 327–334. 19293561

38. Baker DA (2011) Cyclic nucleotide signalling in malaria parasites. Cell Microbiol 13: 331–339. doi: 10.1111/j.1462-5822.2010.01561.x 21176056

39. Wentzinger L, Bopp S, Tenor H, Klar J, Brun R, et al. (2008) Cyclic nucleotide-specific phosphodiesterases of Plasmodium falciparum: PfPDEalpha, a non-essential cGMP-specific PDE that is an integral membrane protein. Int J Parasitol 38: 1625–1637. doi: 10.1016/j.ijpara.2008.05.016 18590734

40. Lopez-Barragan MJ, Lemieux J, Quinones M, Williamson KC, Molina-Cruz A, et al. (2011) Directional gene expression and antisense transcripts in sexual and asexual stages of Plasmodium falciparum. BMC Genomics 12: 587. doi: 10.1186/1471-2164-12-587 22129310

41. Silvestrini F, Lasonder E, Olivieri A, Camarda G, van Schaijk B, et al. (2010) Protein export marks the early phase of gametocytogenesis of the human malaria parasite Plasmodium falciparum. Mol Cell Proteomics 9: 1437–1448. doi: 10.1074/mcp.M900479-MCP200 20332084

42. Taylor CJ, McRobert L, Baker DA (2008) Disruption of a Plasmodium falciparum cyclic nucleotide phosphodiesterase gene causes aberrant gametogenesis. Mol Microbiol 69: 110–118. doi: 10.1111/j.1365-2958.2008.06267.x 18452584

43. Knebel SM, Elrick MM, Bowles EA, Zdanovec AK, Stephenson AH, et al. (2013) Synergistic effects of prostacyclin analogs and phosphodiesterase inhibitors on cyclic adenosine 3',5' monophosphate accumulation and adenosine 3'5' triphosphate release from human erythrocytes. Exp Biol Med (Maywood) 238: 1069–1074. doi: 10.1177/1535370213498981 23986226

44. Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, et al. (1996) Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 8: 47–52. 8858389

45. Smith WB 2nd, McCaslin IR, Gokce A, Mandava SH, Trost L, et al. (2013) PDE5 inhibitors: considerations for preference and long-term adherence. Int J Clin Pract 67: 768–780. doi: 10.1111/ijcp.12074 23869678

46. Lasonder E, Green JL, Camarda G, Talabani H, Holder AA, et al. (2012) The Plasmodium falciparum schizont phosphoproteome reveals extensive phosphatidylinositol and cAMP-protein kinase A signaling. J Proteome Res 11: 5323–5337. doi: 10.1021/pr300557m 23025827

47. Sanyal S, Egee S, Bouyer G, Perrot S, Safeukui I, et al. (2012) Plasmodium falciparum STEVOR proteins impact erythrocyte mechanical properties. Blood 119: e1–8. doi: 10.1182/blood-2011-08-370734 22106347

48. Bianco AE, Crewther PE, Coppel RL, Stahl HD, Kemp DJ, et al. (1988) Patterns of antigen expression in asexual blood stages and gametocytes of Plasmodium falciparum. Am J Trop Med Hyg 38: 258–267. 3281492

49. Coppel RL, Lustigman S, Murray L, Anders RF (1988) MESA is a Plasmodium falciparum phosphoprotein associated with the erythrocyte membrane skeleton. Mol Biochem Parasitol 31: 223–231. 3065643

50. Heiber A, Kruse F, Pick C, Gruring C, Flemming S, et al. (2013) Identification of new PNEPs indicates a substantial non-PEXEL exportome and underpins common features in Plasmodium falciparum protein export. PLoS Pathog 9: e1003546. doi: 10.1371/journal.ppat.1003546 23950716

51. Moon RW, Taylor CJ, Bex C, Schepers R, Goulding D, et al. (2009) A cyclic GMP signalling module that regulates gliding motility in a malaria parasite. PLoS Pathog 5: e1000599. doi: 10.1371/journal.ppat.1000599 19779564

52. Seebeck T, Sterk GJ, Ke H (2011) Phosphodiesterase inhibitors as a new generation of antiprotozoan drugs: exploiting the benefit of enzymes that are highly conserved between host and parasite. Future Med Chem 3: 1289–1306. doi: 10.4155/fmc.11.77 21859303

53. Lavazec C, Sanyal S, Templeton TJ (2007) Expression switching in the stevor and Pfmc-2TM superfamilies in Plasmodium falciparum. Mol Microbiol 64: 1621–1634. 17555442

54. Trager W, Jensen JB (1976) Human malaria parasites in continuous culture. Science 193: 673–675. 781840

55. Fivelman QL, McRobert L, Sharp S, Taylor CJ, Saeed M, et al. (2007) Improved synchronous production of Plasmodium falciparum gametocytes in vitro. Mol Biochem Parasitol 154: 119–123. 17521751

56. D'Alessandro S, Silvestrini F, Dechering K, Corbett Y, Parapini S, et al. (2013) A Plasmodium falciparum screening assay for anti-gametocyte drugs based on parasite lactate dehydrogenase detection. J Antimicrob Chemother 68: 2048–2058. doi: 10.1093/jac/dkt165 23645588

57. McRobert L, Taylor CJ, Deng W, Fivelman QL, Cummings RM, et al. (2008) Gametogenesis in malaria parasites is mediated by the cGMP-dependent protein kinase. PLoS Biol 6: e139. doi: 10.1371/journal.pbio.0060139 18532880

58. Kunz S, Kloeckner T, Essen LO, Seebeck T, Boshart M (2004) TbPDE1, a novel class I phosphodiesterase of Trypanosoma brucei. Eur J Biochem 271: 637–647. 14728691

59. Tang KM, Jang EK, Haslam RJ (1994) Photoaffinity labelling of cyclic GMP-inhibited phosphodiesterase (PDE III) in human and rat platelets and rat tissues: effects of phosphodiesterase inhibitors. Eur J Pharmacol 268: 105–114. 7925608