#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Inactivation of Genes for Antigenic Variation in the Relapsing Fever Spirochete Reduces Infectivity in Mice and Transmission by Ticks


Borrelia hermsii, an agent of tick-borne relapsing fever when infecting humans, employs antigenic variation of the variable major proteins (Vmps) to escape the host immune response. This mechanism allows the bacteria to persist in the blood of a mammal, which increases their potential for acquisition by their tick vector Ornithodoros hermsi. Once in the tick, the bacteria move from the midgut to salivary glands where the Vmps are replaced with another major surface protein, the variable tick protein (Vtp). We constructed two mutants, one that was unable to produce a Vmp (Vmp−) and another that was unable to produce Vtp (Δvtp). The Vmp− mutant could not reach as high bacterial levels in the blood of mice when infected by needle-inoculation and tick bite compared to the parent strain, and was incapable of relapsing. The Δvtp mutant was able to colonize ticks, but was non-infectious by tick bite. Our study provides insight into the roles of the Vmps and Vtp in the infectivity of B. hermsii by showing the importance of antigenic variation for prolonging bacteria levels in the host as well as the requirement of Vtp for mammalian infection by the bite of its tick vector.


Vyšlo v časopise: Inactivation of Genes for Antigenic Variation in the Relapsing Fever Spirochete Reduces Infectivity in Mice and Transmission by Ticks. PLoS Pathog 10(4): e32767. doi:10.1371/journal.ppat.1004056
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004056

Souhrn

Borrelia hermsii, an agent of tick-borne relapsing fever when infecting humans, employs antigenic variation of the variable major proteins (Vmps) to escape the host immune response. This mechanism allows the bacteria to persist in the blood of a mammal, which increases their potential for acquisition by their tick vector Ornithodoros hermsi. Once in the tick, the bacteria move from the midgut to salivary glands where the Vmps are replaced with another major surface protein, the variable tick protein (Vtp). We constructed two mutants, one that was unable to produce a Vmp (Vmp−) and another that was unable to produce Vtp (Δvtp). The Vmp− mutant could not reach as high bacterial levels in the blood of mice when infected by needle-inoculation and tick bite compared to the parent strain, and was incapable of relapsing. The Δvtp mutant was able to colonize ticks, but was non-infectious by tick bite. Our study provides insight into the roles of the Vmps and Vtp in the infectivity of B. hermsii by showing the importance of antigenic variation for prolonging bacteria levels in the host as well as the requirement of Vtp for mammalian infection by the bite of its tick vector.


Zdroje

1. BarbourAG, RestrepoBI (2000) Antigenic variation in vector-borne pathogens. Emerg Infect Dis 6: 449–457.

2. VinkC, RudenkoG, SeifertHS (2012) Microbial antigenic variation mediated by homologous DNA recombination. FEMS Microbiol Rev 36: 917–948.

3. PalmerGH, BankheadT, LukehartSA (2009) 'Nothing is permanent but change' - antigenic variation in persistent bacterial pathogens. Cell Microbiol 11: 1697–1705.

4. StoennerHG, DoddT, LarsenC (1982) Antigenic variation of Borrelia hermsii. J Exp Med 156: 1297–1311.

5. MeierJT, SimonMI, BarbourAG (1985) Antigenic variation is associated with DNA rearrangements in a relapsing fever Borrelia. Cell 41: 403–409.

6. PlasterkRHA, SimonMI, BarbourAG (1985) Transposition of structural genes to an expression sequence on a linear plasmid causes antigenic variation in the bacterium Borrelia hermsii. Nature 318: 257–263.

7. KittenT, BarbourAG (1990) Juxtaposition of expressed variable antigen genes with a conserved telomere in the bacterium Borrelia hermsii. Proc Natl Acad Sci USA 87: 6077–6081.

8. AlugupalliKR, LeongJM, WoodlandRT, MuramatsuM, NonjoT, et al. (2004) B1b lymphocytes confer T cell-independent long-lasting immunity. Immunity 21: 379–390.

9. AlugupalliKR, GersteinRM, ChenJ, Szomolanyi-TsudaE, WoodlandRT, et al. (2003) The resolution of relapsing fever borreliosis requires IgM and is concurrent with expansion of B1b lymphocytes. J Immunol 170: 3819–3827.

10. ConnollySE, BenachJL (2001) Cutting edge: the spirochetemia of murine relapsing fever is cleared by complement-independent bactericidal antibodies. J Immunol 167: 3029–3032.

11. BelperronAA, DaileyCM, BockenstedtLK (2005) Infection-induced marginal B cell production of Borrelia hermsii-specific antibody is impaired in the absence of CD1d1. J Immunol 174: 5681–5686.

12. BarbourAG, BundocV (2001) In vitro and in vivo neutralization of the relapsing fever agent Borrelia hermsii with serotype-specific immunoglobulin M antibodies. Infect Immun 69: 1009–1015.

13. CoffeyEM, EvelandWC (1967) Experimental relapsing fever initiated by Borrelia hermsi. II. Sequential appearence of major serotypes in the rat. J Infect Dis 117: 29–34.

14. SouthernPM, SanfordJP (1968) Relapsing fever: a clinical and microbiological review. Medicine 48: 129–149.

15. LopezJE, McCoyBN, KrajacichBJ, SchwanTG (2011) Acquisition and subsequent transmission of Borrelia hermsii by the soft tick Ornithodoros hermsi. J Med Entomol 48: 891–895.

16. DaiQ, RestrepoBI, PorcellaSF, RaffelSJ, SchwanTG, et al. (2006) Antigenic variation by Borrelia hermsii occurs through recombination between extragenic repetitive elements on linear plasmids. Mol Microbiol 60: 1329–1343.

17. RestrepoBI, KittenT, CarterCJ, InfanteD, BarbourAG (1992) Subtelomeric expression regions of Borrelia hermsii linear plasmids are highly polymorphic. Mol Microbiol 6: 3299–3311.

18. Hinnebusch BJ, Barbour AG, Restrepo BI, Schwan TG (1998) Population structure of the relapsing fever spirochete Borrelia hermsii as indicated by polymorphism of two multigene families that encode immunogenic outer surface lipoproteins. Infect Immun 66: 432 – 440.

19. BarbourAG, CarterCJ, BurmanN, FreitagCS, GaronCF, et al. (1991) Tandem insertion sequence-like elements define the expression site for variable antigen genes of Borrelia hermsii. Infect Immun 59: 390–397.

20. BarbourAG, BurmanN, CarterCJ, KittenT, BergstromS (1991) Variable antigen genes of the relapsing fever agent Borrelia hermsii are activated by promoter addition. Mol Microbiol 5: 489–493.

21. RestrepoBI, BarbourAG (1994) Antigen diversity in the bacterium B. hermsii through "somatic" mutations in rearranged vmp genes. Cell 78: 867–876.

22. SohaskeyCD, ZuckertWR, BarbourAG (1999) The extended promoters for two outer membrane lipoprotein genes of Borrelia spp. uniquely include a T-rich region. Mol Microbiol 33: 41–51.

23. SchwanTG, HinnebuschBJ (1998) Bloodstream- versus tick-associated variants of a relapsing fever bacterium. Science 280: 1938–1940.

24. Barbour AG (2003) Antigenic variation in Borrelia: relapsing fever and Lyme borreliosis. In: Craig A, Scherf A, editors. Antigenic Variation. London: Academic Press. pp. 319–356.

25. CarterCJ, BergstromS, NorrisSJ, BarbourAG (1994) A family of surface-exposed proteins of 20 kilodaltons in the genus Borrelia. Infect Immun 62: 2792–2799.

26. BarbourAG, CarterCJ, SohaskeyCD (2000) Surface protein variation by expression site switching in the relapsing fever agent Borrelia hermsii. Infect Immun 68: 7114–7121.

27. PorcellaSF, RaffelSJ, Anderson JrDE, GilkSD, BonoJL, et al. (2005) Variable tick protein in two genomic groups of the relapsing fever spirochete Borrelia hermsii in western North America. Infect Immun 73: 6647–6658.

28. Battisti JM, Raffel SJ, Schwan TG (2008) A system for site-specific genetic manipulation of the relapsing fever spirochete Borrelia hermsii. In: DeLeo FR, Otto M, editors. Methods in Molecular Biology 431: Bacterial Pathogenesis Methods and Protocols. Totowa: Humana Press. pp. 69–84.

29. BeaurepaireC, ChaconasG (2005) Mapping of essential replication functions of the linear plasmid lp17 of B. burgdorferi by targeted deletion walking. Mol Microbiol 57: 132–142.

30. GrimmD, EggersCH, CaimanoMJ, TillyK, StewartPE, et al. (2004) Experimental assessment of the roles of linear plasmids lp25 and lp28-1 of Borrelia burgdorferi throughout the infectious cycle. Infect Immun 72: 5938–5946.

31. StewartPE, ByramR, GrimmD, TillyK, RosaPA (2005) The plasmids of Borrelia burgdorferi: essential genetic elements of a pathogen. Plasmid 53: 1–13.

32. StewartPE, ThalkenR, BonoJL, RosaP (2001) Isolation of a circular plasmid region sufficient for autonomous replication and transformation of infectious Borrelia burgdorferi. Mol Microbiol 39: 714–721.

33. JewettMW, LawrenceK, BestorAC, TillyK, GrimmD, et al. (2007) The critical role of the linear plasmid lp36 in the infectious cycle of Borrelia burgdorferi. Mol Microbiol 64: 1358–1374.

34. DulebohnDP, BestorA, RegoRO, StewartPE, RosaPA (2011) Borrelia burgdorferi linear plasmid 38 is dispensable for completion of the mouse-tick infectious cycle. Infect Immun 79: 3510–3517.

35. McCoyBN, RaffelSJ, LopezJE, SchwanTG (2010) Bloodmeal size and spirochete acquisition of Ornithodoros hermsi (Acari: Argasidae) during feeding. J Med Entomol 47: 1164–1172.

36. ZhangJ-R, HardhamJM, BarbourAG, NorrisSJ (1997) Antigenic variation in Lyme disease borreliae by promiscuous recombination of VMP-like sequence cassettes. Cell 89: 275–285.

37. NorrisSJ (2006) Antigenic variation with a twist - the Borrelia story. Mol Microbiol 60: 1319–1322.

38. BartholdSW, de SouzaMS, JanotkaJL, SmithAL, PersingDH (1993) Chronic Lyme borreliosis in the laboratory mouse. Am J Pathol 143: 959–972.

39. StevensonB, BockenstedtLK, BartholdSW (1994) Expression and gene sequence of outer surface protein C of Borrelia burgdorferi reisolated from chronically infected mice. Infect Immun 62: 3568–3571.

40. SchwanTG, KarstensRH, SchrumpfME, SimpsonWJ (1991) Changes in antigenic reactivity of Borrelia burgdorferi, the Lyme disease spirochete, during persistent infection in mice. Can J Microbiol 37: 450–454.

41. LevineJF, WilsonML, SpielmanA (1985) Mice as reservoirs of the Lyme disease spirochete. Am J Trop Med Hyg 34: 355–360.

42. DonahueJG, PiesmanJ, SpielmanA (1987) Reservoir competence of white-footed mice for Lyme disease spirochetes. Am J Trop Med Hyg 36: 92–96.

43. Burgdorfer W, Schwan TG (1991) Lyme borreliosis: a relapsing fever-like disease. Scand J Infect Dis Suppl. 77: 17–22.

44. PurserJE, NorrisSJ (2000) Correlation between plasmid content and infectivity in Borrelia burgdorferi. Proc Natl Acad Sci U S A 97: 13865–13870.

45. BankheadT, ChaconasG (2007) The role of VlsE antigenic variation in the Lyme disease spirochete: persistence through a mechanism that differes from other pathogens. Mol Microbiol 65: 1547–1558.

46. KellyR (1971) Cultivation of Borrelia hermsi. Science 173: 443–444.

47. LopezJE, SchrumpfME, RaffelSJ, PolicastroPF, PorcellaSF, et al. (2008) Relapsing fever spirochetes retain infectivity after prolonged in vitro cultivation. Vector Borne Zoonotic Dis 8: 813–820.

48. SchwanTG, BurgdorferW, GaronCF (1988) Changes in infectivity and plasmid profile of the Lyme disease spirochete, Borrelia burgdorferi, as a result of in vitro cultivation. Infect Immun 56: 1831–1836.

49. BarbourAG (1988) Plasmid analysis of Borrelia burgdorferi, the Lyme disease agent. J Clin Microbiol 26: 475–478.

50. BarbourAG, TessierSL, StoennerHG (1982) Variable major proteins of Borrelia hermsii. J Exp Med 156: 1312–1324.

51. BarstadPA, ColiganJE, RaumMG, BarbourAG (1985) Variable major proteins of Borrelia hermsii. Epitope mapping and partial sequence analysis of CNBr peptides. J Exp Med 161: 1302–1314.

52. LaRoccaTJ, KatonaLI, ThanassiDG, BenachJL (2008) Bactericidal action of a complement-independent antibody against relapsing fever Borrelia resides in its variable region. J Immunol 180: 6222–6228.

53. AlugupalliKR, MichelsonAD, BernardMR, RobbinsD, CoburnJ, et al. (2001) Platelet activation by a relapsing fever spirochaete results in enhanced bacterium-platelet interaction via integrin ∂llb β3 activation. Mol Microbiol 39: 330–340.

54. AlugupalliKR, MichelsonAD, JorisI, SchwanTG, Hodivala-DilkeK, et al. (2003) Spirochete-platelet attachment and thrombocytopenia in murine relapsing fever borreliosis. Blood 102: 2843–2850.

55. BarbourAG, Putteeet-DriverAD, BunikisJ (2005) Horizontally acquired genes for purine salvage in Borrelia spp. causing relapsing fever. Infect Immun 73: 6165–6168.

56. SchwanTG, BattistiJM, PorcellaSF, RaffelSJ, SchrumpfME, et al. (2003) Glycerol-3-phosphate acquisition in spirochetes: distribution and biological activity of glycerophosphodiester phosphodiesterase (GlpQ) among Borrelia spirochetes. J Bacteriol 185: 1346–1356.

57. PetterssonJ, SchrumpfME, RaffelSJ, PorcellaSF, GuyardC, et al. (2007) Purine salvage pathways among Borrelia species. Infect Immun 75: 3877–3884.

58. BenoitVM, PetrichA, AlugupalliKR, Marty-RoixR, MoterA, et al. (2010) Genetic control of the innate immune response to Borrelia hermsii influences the course of relapsing fever in inbred strains of mice. Infect Immun 78: 586–594.

59. GuyardC, ChesterEM, RaffelSJ, SchrumpfME, PolicastroPF, et al. (2005) Relapsing fever spirochetes contain chromosomal genes with unique direct tandemly repeated sequences. Infect Immun 73: 3025–3037.

60. Barbour AG, Guo BP (2010) Pathogenesis of relapsing fever. In: Samuels DS, Radolf JD, editors. Borrelia: molecular biology, host interaction and pathogenesis. Norfolk, UK: Caister Academic Press. pp. 333–357.

61. IndestKJ, HowellJK, JacobsMB, Scholl-MeekerD, NorrisSJ, et al. (2001) Analysis of Borrelia burgdorferi vlsE gene expression and recombination in the tick vector. Infect Immun 69: 7083–7090.

62. OhnishiJ, SchneiderB, MesserWB, PiesmanJ, de SilvaAM (2003) Genetic variation at the vlsE locus of Borrelia burgdorferi within ticks and mice over the course of a single transmission cycle. J Bacteriol 185: 4432–4441.

63. BykowskiT, BabbK, von LackumK, RileySP, NorrisSJ, et al. (2006) Transcriptional regulation of the Borrelia burgdorferi antigenically variable VlsE surface protein. J Bacteriol 188: 4879–4889.

64. NosbischLK, de SilvaAM (2007) Lack of detectable variation at Borrelia burgdorferi vlsE locus in ticks. J Med Entomol 44: 168–170.

65. SchwanTG, PiesmanJ, GoldeWT, DolanMC, RosaPA (1995) Induction of an outer surface protein on Borrelia burgdorferi during tick feeding. Proc Natl Acad Sci USA 92: 2909–2913.

66. SchwanTG, PiesmanJ (2000) Temporal changes in outer surface proteins A and C of the Lyme disease-associated spirochete, Borrelia burgdorferi, during the chain of infection in ticks and mice. J Clin Microbiol 38: 383–388.

67. SchwanTG (2003) Temporal regulation of outer surface proteins of the Lyme-disease spirochaete Borrelia burgdorferi. Biochem Soc Trans 31: 108–112.

68. ColemanJL, GebbiaJA, PiesmanJ, DegenJL, BuggeTH, et al. (1997) Plasminogen is required for efficient dissemination of B. burgdorferi in ticks and for enhancement of spirochetemia in mice. Cell 89: 1111–1119.

69. GrimmD, TillyK, ByramR, StewartPE, KrumJG, et al. (2004) Outer-surface protein C of the Lyme disease spirochete: A protein induced in ticks for infection of mammals. Proc Natl Acad Sci USA 101: 3142–3147.

70. SamuelsDS (2011) Gene regulation in Borrelia burgdorferi. Annu Rev Microbiol 65: 479–499.

71. StevensonB, SchwanTG, RosaPA (1995) Temperature-related differential expression of antigens in the Lyme disease spirochete, Borrelia burgdorferi. Infect Immun 63: 4535–4539.

72. JutrasBL, ChenailAM, StevensonB (2013) Changes in bacterial growth rate govern expression of the Borrelia burgdorferi OspC and Erp infection-associated surface proteins. J Bacteriol 195: 757–764.

73. MarcsisinRA, CampeauSA, LopezJE, BarbourAG (2012) Alp, an arthropod-associated outer membrane protein of Borrelia species that cause relapsing fever. Infect Immun 80: 1881–1890.

74. BarbourAG, TravinskyB (2010) Evolution and distribution of the ospC gene, a transferable serotype determinant of Borrelia burgdorferi. mBio 1: e00153–00110.

75. TheisenM, FrederiksenB, LebechA-M, VuustJ, HansenK (1993) Polymorphism in ospC gene of Borrelia burgdorferi and immunoreactivity of OspC protein: implications for taxonomy and for use of OspC protein as a diagnostic antigen. J Clin Microbiol 31: 2570–2576.

76. SchwanTG, GageKL, HinnebuschBJ (1995) Analysis of relapsing fever spirochetes from the western United States. J Spirochetal Tick-Borne Dis 2: 3–8.

77. RestrepoBI, CarterCJ, BarbourAG (1994) Activation of a vmp pseudogene in Borrelia hermsii: an alternate mechanism of antigenic variation during relapsing fever. Mol Microbiol 13: 287–299.

78. BarbourAG (1984) Isolation and cultivation of Lyme disease spirochetes. Yale J Biol Med 57: 521–525.

79. SimpsonWJ, GaronCF, SchwanTG (1990) Analysis of supercoiled circular plasmids in infectious and non-infectious Borrelia burgdorferi. Microb Pathogen 8: 109–118.

80. SchwanTG, RaffelSJ, SchrumpfME, PolicastroPF, RawlingsJA, et al. (2005) Phylogenetic analysis of the spirochetes Borrelia parkeri and Borrelia turicatae and the potential for tick-borne relasping fever in Florida. J Clin Microbiol 43: 3851–3859.

81. SimpsonWJ, SchrumpfME, SchwanTG (1990) Reactivity of human Lyme borreliosis sera with a 39-kilodalton antigen specific to Borrelia burgdorferi. J Clin Microbiol 28: 1329–1337.

82. Barbour AG (1987) Immunobiology of relapsing fever. In: Cruse JM, Lewis RE, Jr., editors. Contributions to Microbiology and Immunology. Basel: Karger. pp. 125–137.

83. SchwanTG, KimeKK, SchrumpfME, CoeJE, SimpsonWJ (1989) Antibody response in white-footed mice (Peromyscus leucopus) experimentally infected with the Lyme disease spirochete (Borrelia burgdorferi). Infect Immun 57: 3445–3451.

84. SchwanTG, SchrumpfME, HinnebuschBJ, AndersonDE, KonkelME (1996) GlpQ: an antigen for serological discrimination between relapsing fever and Lyme borreliosis. J Clin Microbiol 34: 2483–2492.

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2014 Číslo 4
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#