1887

Abstract

is an obligately intracellular, tick-transmitted, bacterial pathogen of humans and other animals. In order to evade host immunity during the course of infection, utilizes gene conversion to shuffle approximately 100 functional pseudogenes into a single expression cassette of the gene, which encodes the major surface antigen, major surface protein 2 (Msp2). The role and extent of recombination in a reservoir host for have not been evaluated. In the current study, we explored patterns of recombination and expression site variability of the gene in three chronically infected woodrats, a reservoir for the disease in the Western USA. All three woodrats developed persistent infection of at least 6 months duration; two of them maintained active infection for at least 8 months. In total, we detected the emergence of 60 unique expression site variants with no common temporal patterns of expression site recombination among the three populations. Both the strength of infection (i.e. pathogen load) and the genetic diversity of pseudogenes detected at the expression site fluctuated periodically during the course of infection. An analysis of the genomic pseudogene exhaustion rate showed that the repertoire of pseudogenes available to the population could in theory become depleted within a year. However, the apparent emergence of variant pseudogenes suggests that the pathogen could potentially evade host immunity indefinitely. Our findings suggest a tightly co-evolved relationship between and woodrats in which the pathogen perpetually evades host immunity yet causes no detectable disease.

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2012-10-01
2019-10-20
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References

  1. Bakken J. S. , Krueth J. , Tilden R. L. , Dumler J. S. , Kristiansen B. E. . ( 1996; ). Serological evidence of human granulocytic ehrlichiosis in Norway. . Eur J Clin Microbiol Infect Dis 15:, 829–832. [CrossRef] [PubMed]
    [Google Scholar]
  2. Barbet A. F. , Lundgren A. M. , Alleman A. R. , Stuen S. , Bjöersdorff A. , Brown R. N. , Drazenovich N. L. , Foley J. E. . ( 2006; ). Structure of the expression site reveals global diversity in MSP2 (P44) variants in Anaplasma phagocytophilum . . Infect Immun 74:, 6429–6437. [CrossRef] [PubMed]
    [Google Scholar]
  3. Barbour A. G. . ( 1987; ). Immunobiology of relapsing fever. . Contrib Microbiol Immunol 8:, 125–137.[PubMed]
    [Google Scholar]
  4. Brayton K. A. , Meeus P. F. , Barbet A. F. , Palmer G. H. . ( 2003; ). Simultaneous variation of the immunodominant outer membrane proteins, MSP2 and MSP3, during Anaplasma marginale persistence in vivo. . Infect Immun 71:, 6627–6632. [CrossRef] [PubMed]
    [Google Scholar]
  5. Cao W. C. , Zhao Q. M. , Zhang P. H. , Yang H. , Wu X. M. , Wen B. H. , Zhang X. T. , Habbema J. D. . ( 2003; ). Prevalence of Anaplasma phagocytophila and Borrelia burgdorferi in Ixodes persulcatus ticks from northeastern China. . Am J Trop Med Hyg 68:, 547–550.[PubMed]
    [Google Scholar]
  6. Castro M. B. , Nicholson W. L. , Kramer V. L. , Childs J. E. . ( 2001; ). Persistent infection in Neotoma fuscipes (Muridae: Sigmodontinae) with Ehrlichia phagocytophila sensu lato. . Am J Trop Med Hyg 65:, 261–267.[PubMed]
    [Google Scholar]
  7. Centurion-Lara A. , LaFond R. E. , Hevner K. , Godornes C. , Molini B. J. , Van Voorhis W. C. , Lukehart S. A. . ( 2004; ). Gene conversion: a mechanism for generation of heterogeneity in the tprK gene of Treponema pallidum during infection. . Mol Microbiol 52:, 1579–1596. [CrossRef] [PubMed]
    [Google Scholar]
  8. Crow J. F. , Kimura M. . ( 1970; ). An Introduction to Population Genetics Theory. New York:: Burgess Publishing Company;.
    [Google Scholar]
  9. Des Vignes F. , Fish D. . ( 1997; ). Transmission of the agent of human granulocytic ehrlichiosis by host-seeking Ixodus scapularis (Acari:Ixodidae) in southern New York state. . J Med Entomol 34:, 379–382.[PubMed] [CrossRef]
    [Google Scholar]
  10. Diamond M. S. . ( 2003; ). Evasion of innate and adaptive immunity by flaviviruses. . Immunol Cell Biol 81:, 196–206. [CrossRef] [PubMed]
    [Google Scholar]
  11. Drazenovich N. , Foley J. , Brown R. N. . ( 2006; ). Use of real-time quantitative PCR targeting the msp2 protein gene to identify cryptic Anaplasma phagocytophilum infections in wildlife and domestic animals. . Vector Borne Zoonotic Dis 6:, 83–90. [CrossRef] [PubMed]
    [Google Scholar]
  12. Dumler J. S. , Choi K. S. , Garcia-Garcia J. C. , Barat N. S. , Scorpio D. G. , Garyu J. W. , Grab D. J. , Bakken J. S. . ( 2005; ). Human granulocytic anaplasmosis and Anaplasma phagocytophilum . . Emerg Infect Dis 11:, 1828–1834. [CrossRef] [PubMed]
    [Google Scholar]
  13. Dunning Hotopp J. C. , Lin M. , Madupu R. , Crabtree J. , Angiuoli S. V. , Eisen J. A. , Seshadri R. , Ren Q. , Wu M. . & other authors ( 2006; ). Comparative genomics of emerging human ehrlichiosis agents. . PLoS Genet 2:, e21. [CrossRef] [PubMed]
    [Google Scholar]
  14. Foley J. E. , Kramer V. , Weber D. . ( 2002; ). Experimental infection of dusky-footed wood rats (Neotoma fuscipes) with Ehrlichia phagocytophila sensu lato. . J Wildl Dis 38:, 194–198.[PubMed] [CrossRef]
    [Google Scholar]
  15. Foley J. E. , Foley P. , Brown R. N. , Lane R. S. , Dumlers J. S. , Madigan J. E. . ( 2004; ). Ecology of Anaplasma phagocytophilum and Borrelia burgdorferi in the western United States. . J Vector Ecol 29:, 41–50.[PubMed]
    [Google Scholar]
  16. Foley J. E. , Nieto N. C. , Barbet A. , Foley P. . ( 2009; ). Antigen diversity in the parasitic bacterium Anaplasma phagocytophilum arises from selectively-represented, spatially clustered functional pseudogenes. . PLoS ONE 4:, e8265. [CrossRef] [PubMed]
    [Google Scholar]
  17. French D. M. , Brown W. C. , Palmer G. H. . ( 1999; ). Emergence of Anaplasma marginale antigenic variants during persistent rickettsemia. . Infect Immun 67:, 5834–5840.[PubMed]
    [Google Scholar]
  18. Granquist E. G. , Stuen S. , Lundgren A. M. , Bråten M. , Barbet A. F. . ( 2008; ). Outer membrane protein sequence variation in lambs experimentally infected with Anaplasma phagocytophilum . . Infect Immun 76:, 120–126. [CrossRef] [PubMed]
    [Google Scholar]
  19. Granquist E. G. , Stuen S. , Crosby L. , Lundgren A. M. , Alleman A. R. , Barbet A. F. . ( 2010; ). Variant-specific and diminishing immune responses towards the highly variable MSP2(P44) outer membrane protein of Anaplasma phagocytophilum during persistent infection in lambs. . Vet Immunol Immunopathol 133:, 117–124. [CrossRef] [PubMed]
    [Google Scholar]
  20. Kline K. A. , Sechman E. V. , Skaar E. P. , Seifert H. S. . ( 2003; ). Recombination, repair and replication in the pathogenic Neisseriae: the 3 R’s of molecular genetics of two human-specific bacterial pathogens. . Mol Microbiol 50:, 3–13. [CrossRef] [PubMed]
    [Google Scholar]
  21. Larkin M. A. , Blackshields G. , Brown N. P. , Chenna R. , McGettigan P. A. , McWilliam H. , Valentin F. , Wallace I. M. , Wilm A. . & other authors ( 2007; ). clustal w and clustal_x version 2.0. . Bioinformatics 23:, 2947–2948. [CrossRef] [PubMed]
    [Google Scholar]
  22. Lin Q. , Rikihisa Y. . ( 2005; ). Establishment of cloned Anaplasma phagocytophilum and analysis of p44 gene conversion within an infected horse and infected SCID mice. . Infect Immun 73:, 5106–5114. [CrossRef] [PubMed]
    [Google Scholar]
  23. Lin Q. , Zhang C. , Rikihisa Y. . ( 2006; ). Analysis of involvement of the RecF pathway in p44 recombination in Anaplasma phagocytophilum and in Escherichia coli by using a plasmid carrying the p44 expression and p44 donor loci. . Infect Immun 74:, 2052–2062. [CrossRef] [PubMed]
    [Google Scholar]
  24. Linsdale J. , Tevis L. . ( 1951; ). The Dusky-Footed Woodrat: a Record of Observations Made on the Hastings Natural History Reservation. Berkeley, CA:: University of California Press;.
    [Google Scholar]
  25. Macleod J. , Gordon W. . ( 1933; ). Studies in tick-borne fever of sheep. I. Transmission by the tick, Ixodes ricinus, with a description of the disease produced. . Parasitology 25:, 273–285. [CrossRef]
    [Google Scholar]
  26. Nei M. , Kumar S. . ( 2000; ). Molecular Evolution and Phylogenetics. Oxford, UK:: Oxford University Press;.
    [Google Scholar]
  27. Nicholson W. L. . ( 1998; ). Epidemiology of human granulocytic ehrlichiosis, with special reference to the role of wild rodents and Ixodid ticks as natural hosts of Ehrlichia phagocytophila sensu lato. PhD thesis, Johns Hopkins School of Hygiene and Public Health. , Baltimore:, MD, USA;.
  28. Nicholson W. L. , Castro M. B. , Kramer V. L. , Sumner J. W. , Childs J. E. . ( 1999; ). Dusky-footed wood rats (Neotoma fuscipes) as reservoirs of granulocytic Ehrlichiae (Rickettsiales: Ehrlichieae) in northern California. . J Clin Microbiol 37:, 3323–3327.[PubMed]
    [Google Scholar]
  29. Nicholson W. L. , Allen K. E. , McQuiston J. H. , Breitschwerdt E. B. , Little S. E. . ( 2010; ). The increasing recognition of rickettsial pathogens in dogs and people. . Trends Parasitol 26:, 205–212. [CrossRef] [PubMed]
    [Google Scholar]
  30. Nieto N. C. , Foley J. E. . ( 2008; ). Evaluation of squirrels (Rodentia: Sciuridae) as ecologically significant hosts for Anaplasma phagocytophilum in California. . J Med Entomol 45:, 763–769. [CrossRef] [PubMed]
    [Google Scholar]
  31. Nieto N. C. , Foley J. E. . ( 2009; ). Reservoir competence of the redwood chipmunk (Tamias ochrogenys) for Anaplasma phagocytophilum . . Vector Borne Zoonotic Dis 9:, 573–577. [CrossRef] [PubMed]
    [Google Scholar]
  32. Nieto N. C. , Madigan J. E. , Foley J. E. . ( 2010; ). The dusky-footed woodrat (Neotoma fuscipes) is susceptible to infection by Anaplasma phagocytophilum originating from woodrats, horses, and dogs. . J Wildl Dis 46:, 810–817.[PubMed] [CrossRef]
    [Google Scholar]
  33. Ohashi N. , Inayoshi M. , Kitamura K. , Kawamori F. , Kawaguchi D. , Nishimura Y. , Naitou H. , Hiroi M. , Masuzawa T. . ( 2005; ). Anaplasma phagocytophilum-infected ticks, Japan. . Emerg Infect Dis 11:, 1780–1783. [CrossRef] [PubMed]
    [Google Scholar]
  34. Rejmanek D. , Bradburd G. , Foley J. . ( 2012a; ). Molecular characterization reveals distinct genospecies of Anaplasma phagocytophilum from diverse North American hosts. . J Med Microbiol 61:, 204–212. [CrossRef] [PubMed]
    [Google Scholar]
  35. Rejmanek D. , Foley P. , Barbet A. , Foley J. . ( 2012b; ). Evolution of antigen variation in the tick-borne pathogen Anaplasma phagocytophilum . . Mol Biol Evol 29:, 391–400. [CrossRef] [PubMed]
    [Google Scholar]
  36. Richter P. J. Jr , Kimsey R. B. , Madigan J. E. , Barlough J. E. , Dumler J. S. , Brooks D. L. . ( 1996; ). Ixodes pacificus (Acari: Ixodidae) as a vector of Ehrlichia equi (Rickettsiales: Ehrlichieae). . J Med Entomol 33:, 1–5.[PubMed] [CrossRef]
    [Google Scholar]
  37. Scorpio D. G. , Leutenegger C. , Berger J. , Barat N. , Madigan J. E. , Dumler J. S. . ( 2008; ). Sequential analysis of Anaplasma phagocytophilum msp2 transcription in murine and equine models of human granulocytic anaplasmosis. . Clin Vaccine Immunol 15:, 418–424. [CrossRef] [PubMed]
    [Google Scholar]
  38. Scorpio D. G. , Dumler J. S. , Barat N. C. , Cook J. A. , Barat C. E. , Stillman B. A. , DeBisceglie K. C. , Beall M. J. , Chandrashekar R. . ( 2011; ). Comparative strain analysis of Anaplasma phagocytophilum infection and clinical outcomes in a canine model of granulocytic anaplasmosis. . Vector Borne Zoonotic Dis 11:, 223–229. [CrossRef] [PubMed]
    [Google Scholar]
  39. Stuen S. , Engvall E. O. , Artursson K. . ( 1998; ). Persistence of Ehrlichia phagocytophila infection in lambs in relation to clinical parameters and antibody responses. . Vet Rec 143:, 553–555. [CrossRef] [PubMed]
    [Google Scholar]
  40. Taylor J. E. , Rudenko G. . ( 2006; ). Switching trypanosome coats: what’s in the wardrobe?. Trends Genet 22:, 614–620. [CrossRef] [PubMed]
    [Google Scholar]
  41. Telford S. R. III , Dawson J. E. , Katavolos P. , Warner C. K. , Kolbert C. P. , Persing D. H. . ( 1996; ). Perpetuation of the agent of human granulocytic ehrlichiosis in a deer tick-rodent cycle. . Proc Natl Acad Sci U S A 93:, 6209–6214. [CrossRef] [PubMed]
    [Google Scholar]
  42. Wang X. , Rikihisa Y. , Lai T. H. , Kumagai Y. , Zhi N. , Reed S. M. . ( 2004; ). Rapid sequential changeover of expressed p44 genes during the acute phase of Anaplasma phagocytophilum infection in horses. . Infect Immun 72:, 6852–6859. [CrossRef] [PubMed]
    [Google Scholar]
  43. Weir B. S. . ( 1990; ). Genetic Data Analysis. Sunderland, MA:: Sinauer;.
    [Google Scholar]
  44. Zhang J. R. , Hardham J. M. , Barbour A. G. , Norris S. J. . ( 1997; ). Antigenic variation in Lyme disease borreliae by promiscuous recombination of VMP-like sequence cassettes. . Cell 89:, 275–285. [CrossRef] [PubMed]
    [Google Scholar]
  45. Zhi N. , Ohashi N. , Rikihisa Y. . ( 1999; ). Multiple p44 genes encoding major outer membrane proteins are expressed in the human granulocytic ehrlichiosis agent. . J Biol Chem 274:, 17828–17836. [CrossRef] [PubMed]
    [Google Scholar]
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