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Sammanfattning på svenska

Chlamydia trachomatis är en obligat intracellulär bakterie som orsakar kla-mydiainfektioner, lymphogranuloma venereum (LGV) och trakom. Klamy-dia är en av de vanligaste sexuellt överförbara infektionerna världen över och kan leda till infertilitet.

I de fyra första studierna som ingår i den här avhandlingen har vi använt ett högupplösande multilokus sekvenstypningssystem (MLST) för att under-söka klamydiabakteriens epidemiologi och vi visar att MLST ger mycket högre upplösning än konventionell ompA genotypning. I den femte studien förenklade vi metodiken genom att utveckla en multilokus typnings (MLT) mikroarray baserat på MLST systemet.

Mer detaljerat så MLST-typades konsekutiva prover insamlade i Örebro 2006 och jämfördes med prover insamlade 1999-2000, vilket visade att den nya C. trachomatis varianten (nvCT) har klonal spridning och började san-nolikt spridas i större omfattning först på senare år.

MLST-typning av LGV-prover från män som har sex med män (MSM) visade att utbrottet i Europa faktiskt var just ett monoklonalt utbrott, medan LGV tvärtom kan ha varit endemisk i USA under en längre tid.

I den tredje studien undersöktes om patienters kliniska symptom gick att korrelera till MLST-genotypen. Men vi fann ingen signifikant korrelation, vilket ytterligare understödjer den växande insikten att mer fokus måste läg-gas på patientens genetik om man vill förstå varför somliga drabbas av svåra komplikationer, medan andra klarar sig utan.

MLST-typning av prover från ett område med hög klamydiaprevalens i Nordnorge avslöjade intressanta epidemiologiska detaljer angående ovanliga genetiska varianter, nvCT och MSM, men vi fann ingen signifikant skillnad i klamydiastammarnas genetiska diversitet jämfört med andra områden i Nor-ge.

I den femte studien utvecklade vi en MLT array som ger hög upplösning samtidigt som den är snabb och kostnadseffektiv, vilket gör den till ett in-tressant alternativ vid typning av C. trachomatis.

Sammanfattningsvis så har både MLST systemet och MLT arrayen visat sig vara användbara verktyg som nu borde användas i ytterligare studier för att öka vår kunskap om klamydiabakteriens epidemiologi.

Acknowledgements

Above all, I thank Björn Herrmann for the opportunity to do this PhD. I greatly appreciate his enthusiasm and continuous support. I thank Markus Klint for helping me when I was new in the lab and for always answering my questions. I thank Björn Olsen for support when dealing with the university bureaucracy. I also thank co-authors and collaborators, all my colleagues, past as present, as well as everyone else at Mikrobiologen. Thank you for being nice and friendly!

Finally, I thank my pet rats for keeping me company after work: Snork-fröken, Filifjonkan, Isfrun, Lilla Knyttet, Mymlan, Snusmumriken, Svartkat-ten and Mårddjuret. Thank you!

References

1. Mariotti SP, Pascolini D, Rose-Nussbaumer J. Trachoma: Global magnitude of a preventable cause of blindness. Br J Ophthalmol. 2009; 93: 563-568.

2. Centers for Disease Control and Prevention, 2010 Chlamydia statistics.

http://www.cdc.gov/std/chlamydia/stats.htm

3. The Swedish Institute for Communicable Disease Control (SMI), 2011 Statistik för klamydiainfektion.

http://www.smittskyddsinstitutet.se/statistik/klamydiainfektion/

4. Haggerty CL, Gottlieb SL, Taylor BD, Low N, Xu F, Ness RB. Risk of seque-lae after Chlamydia trachomatis genital infection in women. J Infect Dis. 2010;

201 Suppl 2: S134-155.

5. Cunningham KA, Beagley KW. Male genital tract chlamydial infection: Impli-cations for pathology and infertility. Biol Reprod. 2008; 79: 180-189.

6. Thygeson P. The treatment of trachoma with sulfanilamide: A report of 28 cases. Trans Am Ophthalmol Soc. 1939; 37: 395-403.

7. Halberstaedter L, von Prowazek S. Uber zelleinschlusse parasitarer natur beim trachom. Arb Gesumdhamt Berlin. 1907; 26: 44-47.

8. Moulder JW. The relation of the psittacosis group (Chlamydiae) to bacteria and viruses. Annu Rev Microbiol. 1966; 20: 107-130.

9. Christerson L, Blomqvist M, Grannas K, et al. A novel Chlamydiaceae-like bacterium found in faecal specimens from sea birds from the Bering Sea. Envi-ron Microbiol Rep. 2010; 2: 605-610.

10. Everett KD, Bush RM, Andersen AA. Emended description of the order Chla-mydiales, proposal of Parachlamydiaceae fam. nov. and Simkaniaceae fam.

nov., each containing one monotypic genus, revised taxonomy of the family Chlamydiaceae, including a new genus and five new species, and standards for the identification of organisms. Int J Syst Bacteriol. 1999; 49 Pt 2: 415-440.

11. Herrmann B, Pettersson B, Everett KD, Mikkelsen NE, Kirsebom LA. Charac-terization of the rnpB gene and RNase P RNA in the order Chlamydiales. Int J Syst Evol Microbiol. 2000; 50 Pt 1: 149-158.

12. Bush RM, Everett KD. Molecular evolution of the Chlamydiaceae. Int J Syst Evol Microbiol. 2001; 51: 203-220.

13. Stephens RS, Myers G, Eppinger M, Bavoil PM. Divergence without differ-ence: Phylogenetics and taxonomy of Chlamydia resolved. FEMS Immunol Med Microbiol. 2009; 55: 115-119.

14. Mpiga P, Ravaoarinoro M. Chlamydia trachomatis persistence: An update.

Microbiol Res. 2006; 161: 9-19.

15. Wyrick PB. Intracellular survival by Chlamydia. Cell Microbiol. 2000; 2: 275-282.

16. Dautry-Varsat A, Balana ME, Wyplosz B. Chlamydia--host cell interactions:

Recent advances on bacterial entry and intracellular development. Traffic. 2004;

5: 561-570.

17. Morrison RP. New insights into a persistent problem -- chlamydial infections. J Clin Invest. 2003; 111: 1647-1649.

18. Hu VH, Harding-Esch EM, Burton MJ, Bailey RL, Kadimpeul J, Mabey DC.

Epidemiology and control of trachoma: Systematic review. Trop Med Int Health. 2010; 15: 673-691.

19. Mabey DC, Solomon AW, Foster A. Trachoma. Lancet. 2003; 362: 223-229.

20. Fehlner-Gardiner C, Roshick C, Carlson JH, et al. Molecular basis defining human Chlamydia trachomatis tissue tropism. A possible role for tryptophan synthase. J Biol Chem. 2002; 277: 26893-26903.

21. World Health Organization. Global prevalence and incidence of selected cur-able sexually transmitted infections overview and estimates. 2001

WHO/HIV_AIDS/2001.02 and WHO/CDS/CSR/EDC/2001.10. World Health Organization, Geneva, Switzerland.

22. Stevens-Simon C, Sheeder J. Chlamydia trachomatis: Common misperceptions and misunderstandings. J Pediatr Adolesc Gynecol. 2005; 18: 231-243.

23. Cates W, Jr., Wasserheit JN. Genital chlamydial infections: Epidemiology and reproductive sequelae. Am J Obstet Gynecol. 1991; 164: 1771-1781.

24. Gonzales GF, Munoz G, Sanchez R, et al. Update on the impact of Chlamydia trachomatis infection on male fertility. Andrologia. 2004; 36: 1-23.

25. Chesson HW, Pinkerton SD. Sexually transmitted diseases and the increased risk for HIV transmission: Implications for cost-effectiveness analyses of sexu-ally transmitted disease prevention interventions. J Acquir Immune Defic Syndr.

2000; 24: 48-56.

26. Wu IB, Schwartz RA. Reiter's syndrome: The classic triad and more. J Am Acad Dermatol. 2008; 59: 113-121.

27. Mabey D, Peeling RW. Lymphogranuloma venereum. Sex Transm Infect. 2002;

78: 90-92.

28. Nieuwenhuis RF, Ossewaarde JM, Gotz HM, et al. Resurgence of lymphogranuloma venereum in Western Europe: An outbreak of Chlamydia trachomatis serovar L2 proctitis in the Netherlands among men who have sex with men. Clin Infect Dis. 2004; 39: 996-1003.

29. Klint M, Lofdahl M, Ek C, Airell A, Berglund T, Herrmann B. Lymphogranu-loma venereum prevalence in Sweden among men who have sex with men and characterization of Chlamydia trachomatis ompA genotypes. J Clin Microbiol.

2006; 44: 4066-4071.

30. Spaargaren J, Fennema HS, Morre SA, de Vries HJ, Coutinho RA. New lymphogranuloma venereum Chlamydia trachomatis variant, Amsterdam.

Emerg Infect Dis. 2005; 11: 1090-1092.

31. Alexander S, Saunders P, Chisholm S, Ali T, Powers C, Ison C. Sequence typ-ing of lymphogranuloma venereum specimens from the United Ktyp-ingdom: Are they all the same? In: The 18th International Society for STD Research, 28 June-1 July 2009, Queen Elizabeth II Conference Centre, London: International Society for Sexually Transmitted Diseases Research and British Association for Sexual Health and HIV. 2009; p. 111.

32. Spaargaren J, Schachter J, Moncada J, et al. Slow epidemic of lymphogranu-loma venereum L2b strain. Emerg Infect Dis. 2005; 11: 1787-1788.

33. Ripa T, Nilsson P. A variant of Chlamydia trachomatis with deletion in cryptic plasmid: Implications for use of PCR diagnostic tests. Euro Surveill. 2006; 11:

E061109 061102.

34. Ripa T, Nilsson PA. A Chlamydia trachomatis strain with a 377-bp deletion in the cryptic plasmid causing false-negative nucleic acid amplification tests. Sex Transm Dis. 2007; 34: 255-256.

35. Soderblom T, Blaxhult A, Fredlund H, Herrmann B. Impact of a genetic variant of Chlamydia trachomatis on national detection rates in Sweden. Euro Surveill.

2006; 11: E061207 061201.

36. Herrmann B, Torner A, Low N, et al. Emergence and spread of Chlamydia trachomatis variant, Sweden. Emerg Infect Dis. 2008; 14: 1462-1465.

37. Herrmann B. A new genetic variant of Chlamydia trachomatis. Sex Transm Infect. 2007; 83: 253-254.

38. Savage EJ, Ison CA, van de Laar MJ. Results of a Europe-wide investigation to assess the presence of a new variant of Chlamydia trachomatis. Euro Surveill.

2007; 12: E3-4.

39. Westh H, Jensen JS. Low prevalence of the new variant of Chlamydia tra-chomatis in Denmark. Sex Transm Infect. 2008; 84: 546-547.

40. Reinton N, Moi H, Bjerner J, Moghaddam A. [The Swedish chlamydia mutant nvC. trachomatis in Norway]. Tidsskr Nor Laegeforen. 130: 380-381.

41. Brunelle BW, Sensabaugh GF. The ompA gene in Chlamydia trachomatis dif-fers in phylogeny and rate of evolution from other regions of the genome. Infect Immun. 2006; 74: 578-585.

42. Gomes JP, Bruno WJ, Nunes A, et al. Evolution of Chlamydia trachomatis diversity occurs by widespread interstrain recombination involving hotspots.

Genome Res. 2007; 17: 50-60.

43. Jurstrand M, Falk L, Fredlund H, et al. Characterization of Chlamydia tra-chomatis omp1 genotypes among sexually transmitted disease patients in Swe-den. J Clin Microbiol. 2001; 39: 3915-3919.

44. Lysen M, Osterlund A, Rubin CJ, Persson T, Persson I, Herrmann B. Charac-terization of ompA genotypes by sequence analysis of DNA from all detected cases of Chlamydia trachomatis infections during 1 year of contact tracing in a Swedish county. J Clin Microbiol. 2004; 42: 1641-1647.

45. Pedersen LN, Herrmann B, Moller JK. Typing Chlamydia trachomatis: From egg yolk to nanotechnology. FEMS Immunol Med Microbiol. 2009; 55: 120-130.

46. Maiden MC. Multilocus sequence typing of bacteria. Annu Rev Microbiol.

2006; 60: 561-588.

47. van Belkum A, Tassios PT, Dijkshoorn L, et al. Guidelines for the validation and application of typing methods for use in bacterial epidemiology. Clin Mi-crobiol Infect. 2007; 13 Suppl 3: 1-46.

48. Klint M, Fuxelius HH, Goldkuhl RR, et al. High-resolution genotyping of Chlamydia trachomatis strains by multilocus sequence analysis. J Clin Micro-biol. 2007; 45: 1410-1414.

49. Klint M, Thollesson M, Bongcam-Rudloff E, Birkelund S, Nilsson A, Herrmann B. Mosaic structure of intragenic repetitive elements in histone h1-like protein hc2 varies within serovars of Chlamydia trachomatis. BMC Micro-biol. 2010; 10: 81.

50. Grieshaber NA, Sager JB, Dooley CA, Hayes SF, Hackstadt T. Regulation of the Chlamydia trachomatis histone h1-like protein hc2 is ispE dependent and ihtA independent. J Bacteriol. 2006; 188: 5289-5292.

51. Pannekoek Y, Morelli G, Kusecek B, et al. Multi locus sequence typing of Chlamydiales: Clonal groupings within the obligate intracellular bacteria Chla-mydia trachomatis. BMC Microbiol. 2008; 8: 42.

52. Dean D, Bruno WJ, Wan R, et al. Predicting phenotype and emerging strains among Chlamydia trachomatis infections. Emerg Infect Dis. 2009; 15: 1385-1394.

53. Pedersen LN, Podenphant L, Moller JK. Highly discriminative genotyping of Chlamydia trachomatis using omp1 and a set of variable number tandem re-peats. Clin Microbiol Infect. 2008; 14: 644-652.

54. Ikryannikova LN, Shkarupeta MM, Shitikov EA, Il'ina EN, Govorun VM.

Comparative evaluation of new typing schemes for urogenital Chlamydia tra-chomatis isolates. FEMS Immunol Med Microbiol. 59: 188-196.

55. Ehricht R, Slickers P, Goellner S, Hotzel H, Sachse K. Optimized DNA mi-croarray assay allows detection and genotyping of single PCR-amplifiable tar-get copies. Mol Cell Probes. 2006; 20: 60-63.

56. Borel N, Kempf E, Hotzel H, et al. Direct identification of Chlamydiae from clinical samples using a DNA microarray assay: A validation study. Mol Cell Probes. 2008; 22: 55-64.

57. Monecke S, Slickers P, Ehricht R. Assignment of Staphylococcus aureus iso-lates to clonal complexes based on microarray analysis and pattern recognition.

FEMS Immunol Med Microbiol. 2008; 53: 237-251.

58. Sachse K, Laroucau K, Vorimore F, et al. DNA microarray-based genotyping of Chlamydophila psittaci strains from culture and clinical samples. Vet Microbiol.

2009; 135: 22-30.

59. Schachter J, Moncada J. Lymphogranuloma venereum: How to turn an endemic disease into an outbreak of a new disease? Start looking. Sex Transm Dis. 2005;

32: 331-332.

60. Fenton KA, Imrie J. Increasing rates of sexually transmitted diseases in homo-sexual men in Western Europe and the United States: Why? Infect Dis Clin North Am. 2005; 19: 311-331.

61. Stephens RS. The cellular paradigm of chlamydial pathogenesis. Trends Micro-biol. 2003; 11: 44-51.

62. Brunham RC, Peeling RW. Chlamydia trachomatis antigens: Role in immunity and pathogenesis. Infect Agents Dis. 1994; 3: 218-233.

63. Brunham RC, Rekart ML. Considerations on Chlamydia trachomatis disease expression. FEMS Immunol Med Microbiol. 2009; 55: 162-166.

64. Darville T, Hiltke TJ. Pathogenesis of genital tract disease due to Chlamydia trachomatis. J Infect Dis. 201 Suppl 2: S114-125.

65. Bailey RL, Natividad-Sancho A, Fowler A, et al. Host genetic contribution to the cellular immune response to Chlamydia trachomatis: Heritability estimate from a Gambian twin study. Drugs Today (Barc). 2009; 45 Suppl B: 45-50.

66. den Hartog JE, Ouburg S, Land JA, et al. Do host genetic traits in the bacterial sensing system play a role in the development of Chlamydia trachomatis-associated tubal pathology in subfertile women? BMC Infect Dis. 2006; 6: 122.

67. Hunter PR, Gaston MA. Numerical index of the discriminatory ability of typing systems: An application of Simpson's index of diversity. J Clin Microbiol.

1988; 26: 2465-2466.

68. Wang Y, Skilton RJ, Cutcliffe LT, Andrews E, Clarke IN, Marsh P. Evaluation of a high resolution genotyping method for Chlamydia trachomatis using rou-tine clinical samples. PLoS One. 6: e16971.

69. Klint M, Hadad R, Christerson L, et al. Prevalence trends in Sweden of the new variant of Chlamydia trachomatis. Clin Microbiol Infect. 2011; 17: 683-689.

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