A Unique Virulence Gene Occupies a Principal Position in Immune Evasion by the Malaria Parasite

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Many eukaryotic pathogens avoid the immune system of their hosts by switching expression between genes encoding their exposed surface antigens. This process, called antigenic variation, is key to the ability of these organisms to cause long-term, chronic infections and represents a major virulence determinant for many infectious diseases. The human malaria parasite Plasmodium falciparum achieves this by varying expression between members of the multi-copy var gene family. While significant progress has been made in recent years to identify factors that determine whether an individual var gene is active or silent, how switching between members of the family is coordinated remains a mystery. Previous work has shown that switching is not random, but rather is coordinated to result in rising and falling populations of parasites expressing single surface antigens. Here we provide evidence that one specific, highly conserved var gene occupies a unique position within the switching network, fulfilling a prediction made by mathematical models derived from population switching patterns. These data provide the first insights into the regulatory network underlying antigenic variation by malaria parasites.

Vyšlo v časopise: A Unique Virulence Gene Occupies a Principal Position in Immune Evasion by the Malaria Parasite. PLoS Genet 11(5): e32767. doi:10.1371/journal.pgen.1005234
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005234

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Zdroje

1. Haber JE (2012) Mating-type genes and MAT switching in Saccharomyces cerevisiae. Genetics 191: 33–64. doi: 10.1534/genetics.111.134577 22555442

2. Corcoran AE (2005) Immunoglobulin locus silencing and allelic exclusion. Semin Immunol 17: 141–154. 15737575

3. Rodriguez I (2013) Singular expression of olfactory receptor genes. Cell 155: 274–277. S0092-8674(13)01206-3 [pii]. doi: 10.1016/j.cell.2013.09.032 24120129

4. Chang SC, Tucker T, Thorogood NP, Brown CJ (2006) Mechanisms of X-chromosome inactivation. Front Biosci 11: 852–866. 16146776

5. Deitsch KW, Lukehart SA, Stringer JR (2009) Common strategies for antigenic variation by bacterial, fungal and protozoan pathogens. Nat Rev Microbiol 7: 493–503. doi: 10.1038/nrmicro2145 19503065

6. Prucca CG, Lujan HD (2009) Antigenic variation in Giardia lamblia. Cell Microbiol 11: 1706–1715. CMI1367 [pii]. doi: 10.1111/j.1462-5822.2009.01367.x 19709056

7. Saraiya AA, Li W, Wu J, Chang CH, Wang CC (2014) The microRNAs in an ancient protist repress the variant-specific surface protein expression by targeting the entire coding sequence. PLoS Pathog 10: e1003791. doi: 10.1371/journal.ppat.1003791 24586143

8. al Khedery B, Allred DR (2006) Antigenic variation in Babesia bovis occurs through segmental gene conversion of the ves multigene family, within a bidirectional locus of active transcription. Mol Microbiol 59: 402–414. 16390438

9. Horn D (2014) Antigenic variation in African trypanosomes. Mol Biochem Parasitol. S0166-6851(14)00059-0 [pii]

10. Scherf A, Lopez-Rubio JJ, Riviere L (2008) Antigenic variation in Plasmodium falciparum. Annu Rev Microbiol 62: 445–470. doi: 10.1146/annurev.micro.61.080706.093134 18785843

11. Miller LH, Good MF, Milon G (1994) Malaria Pathogenesis. Science 264: 1878–1883. 8009217

12. 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

13. Smith JD, Chitnis CE, Craig AG, Roberts DJ, Hudson-Taylor DE, Peterson DS, Pinches R, Newbold CI, Miller LH (1995) Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell 82: 101–110. 7606775

14. Su X, Heatwole VM, Wertheimer SP, Guinet F, Herrfeldt JV, Peterson DS, Ravetch JV, Wellems TE (1995) A large and diverse gene family (var) encodes 200–350 kD proteins implicated in the antigenic variation and cytoadherence of Plasmodium falciparum-infected erythrocytes. Cell 82: 89–100. 7606788

15. 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. nature12216 [pii]. doi: 10.1038/nature12216 23739325

16. Baruch DI, Gormley JA, Ma C, Howard RJ, Pasloske BL (1996) Plasmodium falciparum erythrocyte membrane protein 1 is a parasitized erythrocyte receptor for adherence to CD36, thrombospondin, and intercellular adhesion molecule 1. Proceedings of the National Academy of Sciences USA 93: 3497–3502. 8622965

17. Fried M, Duffy PE (1996) Plasmodium falciparum-infected erythrocytes adhere to chondroitin sulfate A in the human placenta. Science 272: 1502–1504. 8633247

18. Scherf A, Hernandez-Rivas R, Buffet P, Bottius E, Benatar C, Pouvelle B, Gysin J, Lanzer M (1998) Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum. EMBO J 17: 5418–5426. 9736619

19. Tonkin CJ, Carret CK, Duraisingh MT, Voss TS, Ralph SA, Hommel M, Duffy MF, Silva LM, Scherf A, Ivens A, Speed TP, Beeson JG, Cowman AF (2009) Sir2 paralogues cooperate to regulate virulence genes and antigenic variation in Plasmodium falciparum. PLoS Biol 7: e84. doi: 10.1371/journal.pbio.1000084 19402747

20. Duraisingh MT, Voss TS, Marty AJ, Duffy MF, Good RT, Thompson JK, Freitas-Junior LH, Scherf A, Crabb BS, Cowman AF (2005) Heterochromatin silencing and locus repositioning linked to regulation of virulence genes in Plasmodium faiciparum. Cell 121: 13–24. 15820675

21. Freitas-Junior LH, Hernandez-Rivas R, Ralph SA, Montiel-Condado D, Ruvalcaba-Salazar OK, Rojas-Meza AP, Mancio-Silva L, Leal-Silvestre RJ, Gontijo AM, Shorte S, Scherf A (2005) Telomeric heterochromatin propagation and histone acetylation control mutually exclusive expression of antigenic variation genes in malaria parasites. Cell 121: 25–36. 15820676

22. Flueck C, Bartfai R, Volz J, Niederwieser I, Salcedo-Amaya AM, Alako BT, Ehlgen F, Ralph SA, Cowman AF, Bozdech Z, Stunnenberg HG, Voss TS (2009) Plasmodium falciparum heterochromatin protein 1 marks genomic loci linked to phenotypic variation of exported virulence factors. PLoS Pathog 5: e1000569. doi: 10.1371/journal.ppat.1000569 19730695

23. Chookajorn T, Dzikowski R, Frank M, Li F, Jiwani AZ, Hartl DL, Deitsch KW (2007) Epigenetic memory at malaria virulence genes. Proc Natl Acad Sci U S A 104: 899–902. 17209011

24. Lopez-Rubio JJ, Gontijo AM, Nunes MC, Issar N, Hernandez RR, Scherf A (2007) 5' flanking region of var genes nucleate histone modification patterns linked to phenotypic inheritance of virulence traits in malaria parasites. Mol Microbiol 66: 1296–1305. 18028313

25. Lopez-Rubio JJ, Mancio-Silva L, Scherf A (2009) Genome-wide analysis of heterochromatin associates clonally variant gene regulation with perinuclear repressive centers in malaria parasites. Cell Host Microbe 5: 179–190. doi: 10.1016/j.chom.2008.12.012 19218088

26. Jiang L, Mu J, Zhang Q, Ni T, Srinivasan P, Rayavara K, Yang W, Turner L, Lavstsen T, Theander TG, Peng W, Wei G, Jing Q, Wakabayashi Y, Bansal A, Luo Y, Ribeiro JM, Scherf A, Aravind L, Zhu J, Zhao K, Miller LH (2013) PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum. Nature 499: 223–227. doi: 10.1038/nature12361 23823717

27. Ukaegbu UE, Kishore SP, Kwiatkowski DL, Pandarinath C, Dahan-Pasternak N, Dzikowski R, Deitsch KW (2014) Recruitment of PfSET2 by RNA polymerase II to variant antigen encoding loci contributes to antigenic variation in P. falciparum. PLoS Pathog 10: e1003854. doi: 10.1371/journal.ppat.1003854 24391504

28. Frank M, Dzikowski R, Amulic B, Deitsch K (2007) Variable switching rates of malaria virulence genes are associated with chromosomal position. Mol Microbiol 64: 1486–1498. 17555435

29. Recker M, Buckee CO, Serazin A, Kyes S, Pinches R, Christodoulou Z, Springer AL, Gupta S, Newbold CI (2011) Antigenic variation in Plasmodium falciparum malaria involves a highly structured switching pattern. PLoS Pathog 7: e1001306. doi: 10.1371/journal.ppat.1001306 21408201

30. Noble R, Christodoulou Z, Kyes S, Pinches R, Newbold CI, Recker M (2013) The antigenic switching network of Plasmodium falciparum and its implications for the immuno-epidemiology of malaria. Elife (Cambridge) 2: e01074. 01074 [pii]. doi: 10.7554/eLife.01074 24062941

31. Mok BW, Ribacke U, Rasti N, Kironde F, Chen Q, Nilsson P, Wahlgren M (2008) Default Pathway of var2csa switching and translational repression in Plasmodium falciparum. PLoS ONE 3: e1982. doi: 10.1371/journal.pone.0001982 18431472

32. Salanti A, Dahlback M, Turner L, Nielsen MA, Barfod L, Magistrado P, Jensen AT, Lavstsen T, Ofori MF, Marsh K, Hviid L, Theander TG (2004) Evidence for the involvement of VAR2CSA in pregnancy-associated malaria. J Exp Med 200: 1197–1203. 15520249

33. Trimnell AR, Kraemer SM, Mukherjee S, Phippard DJ, Janes JH, Flamoe E, Su XZ, Awadalla P, Smith JD (2006) Global genetic diversity and evolution of var genes associated with placental and severe childhood malaria. Mol Biochem Parasitol 148: 169–180. 16697476

34. Amulic B, Salanti A, Lavstsen T, Nielsen MA, Deitsch KW (2009) An upstream open reading frame controls translation of var2csa, a gene implicated in placental malaria. PLoS Pathog 5: e1000256. doi: 10.1371/journal.ppat.1000256 19119419

35. Bancells C, Deitsch KW (2013) A molecular switch in the efficiency of translation reinitiation controls expression of var2csa, a gene implicated in pregnancy-associated malaria. Mol Microbiol.

36. Lavstsen T, Magistrado P, Hermsen CC, Salanti A, Jensen AT, Sauerwein R, Hviid L, Theander TG, Staalsoe T (2005) Expression of Plasmodium falciparum erythrocyte membrane protein 1 in experimentally infected humans. Malar J 4: 21. 15857512

37. Duffy MF, Caragounis A, Noviyanti R, Kyriacou HM, Choong EK, Boysen K, Healer J, Rowe JA, Molyneux ME, Brown GV, Rogerson SJ (2006) Transcribed var genes associated with placental malaria in Malawian women. Infect Immun 74: 4875–4883. 16861676

38. Rask TS, Hansen DA, Theander TG, Gorm PA, Lavstsen T (2010) Plasmodium falciparum erythrocyte membrane protein 1 diversity in seven genomes—divide and conquer. PLoS Comput Biol 6.

39. Barry AE, Leliwa-Sytek A, Tavul L, Imrie H, Migot-Nabias F, Brown SM, McVean GA, Day KP (2007) Population Genomics of the Immune Evasion (var) Genes of Plasmodium falciparum. PLoS Pathog 3: e34. 17367208

40. Lavstsen T, Salanti A, Jensen ATR, Arnot DE, Theander TG (2003) Sub-grouping of Plasmodium falciparum 3D7 var genes based on sequence analysis of coding and non-coding regions. Malaria Journal 2: 27. 14565852

41. Kraemer SM, Smith JD (2003) Evidence for the importance of genetic structuring to the structural and functional specialization of the Plasmodium falciparum var gene family. Molecular Microbiology 50: 1527–1538. 14651636

42. Epp C, Raskolnikov D, Deitsch KW (2008) A regulatable transgene expression system for cultured Plasmodium falciparum parasites. Malar J 7: 86. doi: 10.1186/1475-2875-7-86 18492282

43. Salanti A, Staalsoe T, Lavstsen T, Jensen ATR, Sowa MPK, Arnot DE, Hviid L, Theander TG (2003) Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria. Molecular Microbiology 49: 179–191. 12823820

44. Horrocks P, Pinches R, Christodoulou Z, Kyes SA, Newbold CI (2004) Variable var transition rates underlie antigenic variation in malaria. Proc Natl Acad Sci U S A 101: 11129–11134. 15256597

45. Greiner D, Bonaldi T, Eskeland R, Roemer E, Imhof A (2005) Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9. Nat Chem Biol 1: 143–145. nchembio721 [pii]. 16408017

46. Cui L, Fan Q, Cui L, Miao J (2008) Histone lysine methyltransferases and demethylases in Plasmodium falciparum. Int J Parasitol 38: 1083–1097. doi: 10.1016/j.ijpara.2008.01.002 18299133

47. Sander AF, Salanti A, Lavstsen T, Nielsen MA, Magistrado P, Lusingu J, Ndam NT, Arnot DE (2009) Multiple var2csa-type PfEMP1 genes located at different chromosomal loci occur in many Plasmodium falciparum isolates. PLoS ONE 4: e6667. doi: 10.1371/journal.pone.0006667 19690615

48. Kraemer SM, Kyes SA, Aggarwal G, Springer AL, Nelson SO, Christodoulou Z, Smith LM, Wang W, Levin E, Newbold CI, Myler PJ, Smith JD (2007) Patterns of gene recombination shape var gene repertoires in Plasmodium falciparum: comparisons of geographically diverse isolates. BMC Genomics 8: 45. 17286864

49. Brolin KJ, Ribacke U, Nilsson S, Ankarklev J, Moll K, Wahlgren M, Chen Q (2009) Simultaneous transcription of duplicated var2csa gene copies in individual Plasmodium falciparum parasites. Genome Biol 10: R117. gb-2009-10-10-r117 [pii]. doi: 10.1186/gb-2009-10-10-r117 19849836

50. Duffy MF, Byrne TJ, Carret C, Ivens A, Brown GV (2009) Ectopic recombination of a malaria var gene during mitosis associated with an altered var switch rate. J Mol Biol 389: 453–469. S0022-2836(09)00476-8 [pii]. doi: 10.1016/j.jmb.2009.04.032 19389407

51. Dzikowski R, Frank M, Deitsch K (2006) Mutually Exclusive Expression of Virulence Genes by Malaria Parasites Is Regulated Independently of Antigen Production. PLoS Pathog 2: e22. 16518466

52. Bartfai R, Hoeijmakers WA, Salcedo-Amaya AM, Smits AH, Janssen-Megens E, Kaan A, Treeck M, Gilberger TW, Francoijs KJ, Stunnenberg HG (2010) H2A.Z demarcates intergenic regions of the plasmodium falciparum epigenome that are dynamically marked by H3K9ac and H3K4me3. PLoS Pathog 6: e1001223. doi: 10.1371/journal.ppat.1001223 21187892

53. Pacheco MA, Cranfield M, Cameron K, Escalante AA (2013) Malarial parasite diversity in chimpanzees: the value of comparative approaches to ascertain the evolution of Plasmodium falciparum antigens. Malar J 12: 328. 1475-2875-12-328 [pii]. doi: 10.1186/1475-2875-12-328 24044371

54. Wakimoto BT (1998) Beyond the nucleosome: epigenetic aspects of position-effect variegation in Drosophila. Cell 93: 321–324. 9590165

55. Schnell R, Rine J (1986) A position effect on the expression of a tRNA gene mediated by the SIR genes in Saccharomyces cerevisiae. Mol Cell Biol 6: 494–501. 3023851

56. Kyes SA, Christodoulou Z, Raza A, Horrocks P, Pinches R, Rowe JA, Newbold CI (2003) A well-conserved Plasmodium falciparum var gene shows an unusual stage-specific transcript pattern. Molecular Microbiology 48: 1339–1348. 12787360

57. Winter G, Chen QJ, Flick K, Kremsner P, Fernandez V, Wahlgren M (2003) The 3D7var5.2 (var(COMMON)) type var gene family is commonly expressed in non-placental Plasmodium falciparum malaria. Molecular and Biochemical Parasitology 127: 179–191. 12672527

58. Wang CW, Lavstsen T, Bengtsson DC, Magistrado PA, Berger SS, Marquard AM, Alifrangis M, Lusingu JP, Theander TG, Turner L (2012) Evidence for in vitro and in vivo expression of the conserved VAR3 (type 3) plasmodium falciparum erythrocyte membrane protein 1. Malar J 11: 129. 1475-2875-11-129 [pii]. doi: 10.1186/1475-2875-11-129 22533832

59. Zhang Y, Jiang N, Chang Z, Wang H, Lu H, Wahlgren M, Chen Q (2014) The var3 genes of Plasmodium falciparum 3D7 strain are differentially expressed in infected erythrocytes. Parasite 21: 19. parasite140022 [pii]. doi: 10.1051/parasite/2014019 24759654

60. Deitsch KW, Driskill CL, Wellems TE (2001) Transformation of malaria parasites by the spontaneous uptake and expression of DNA from human erythrocytes. Nucleic Acids Research 29: 850–853. 11160909

61. Shechter D, Dormann HL, Allis CD, Hake SB (2007) Extraction, purification and analysis of histones. Nat Protoc 2: 1445–1457. 17545981

62. Heinberg A, Siu E, Stern C, Lawrence EA, Ferdig MT, Deitsch KW, Kirkman LA (2013) Direct evidence for the adaptive role of copy number variation on antifolate susceptibility in Plasmodium falciparum. Mol Microbiol 88: 702–712. doi: 10.1111/mmi.12162 23347134

63. Braun-Breton C, Rosenberry TL, Da Silva LP (1988) Induction of the proteolytic activity of a membrane protein in Plasmodium falciparum by phosphatidyl inositol-specific phospholipase C. Nature 332: 457–459. 3281025

64. Smilkstein M, Sriwilaijaroen N, Kelly JX, Wilairat P, Riscoe M (2004) Simple and inexpensive fluorescence-based technique for high-throughput antimalarial drug screening. Antimicrob Agents Chemother 48: 1803–1806. 15105138