1887

Abstract

is an obligate intracellular bacterial pathogen that principally inhabits neutrophils. However, infection with results in a moderate to marked thrombocytopenia. In host neutrophils, uses sialylated ligands, primarily P-selectin glycoprotein ligand-1 (PSGL-1), to enter its host cell. PSGL-1 is expressed on a wide array of haematopoietic cells, including megakaryocytes. In this study, it was hypothesized that (i) cells of the megakaryocytic lineage (MEG-01 cells) would be susceptible to infection and (ii) infection may induce alterations in platelet production contributing to infection-induced thrombocytopenia. It was found that MEG-01 cells are susceptible to infection. MEG-01 cells expressing abundant sialylated ligands were the most susceptible to infection, and the absence of sialylation, or blocking of PSGL-1, limited infection susceptibility. However, infected MEG-01 cells produced proplatelets and platelet-like particles comparable to uninfected cells. These results highlight a novel target of pathogen infection and suggest that the pathogen may utilize similar strategies to gain access to megakaryocytes. Direct pathogen modification of platelet production may not play a role in infection-induced thrombocytopenia.

Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.47551-0
2008-04-01
2020-04-09
Loading full text...

Full text loading...

/deliver/fulltext/jmm/57/4/416.html?itemId=/content/journal/jmm/10.1099/jmm.0.47551-0&mimeType=html&fmt=ahah

References

  1. Bakken J. S., Krueth J., Wilson-Nordskog C., Tilden R. L., Asanovich K., Dumler J. S. 1996; Clinical and laboratory characteristics of human granulocytic ehrlichiosis. JAMA 275:199–205 [CrossRef]
    [Google Scholar]
  2. Bakken J. S., Aguero-Rosenfeld M. E., Tilden R. L., Wormser G. P., Horowitz H. W., Raffalli J. T., Baluch M., Riddell D., Walls J. J., Dumler J. S. 2001; Serial measurements of hematologic counts during the active phase of human granulocytic ehrlichiosis. Clin Infect Dis 32:862–870 [CrossRef]
    [Google Scholar]
  3. Battinelli E., Willoughby S. R., Foxall T., Valeri C. R., Loscalzo J. 2001; Induction of platelet formation from megakaryocytoid cells by nitric oxide. Proc Natl Acad Sci U S A 98:14458–14463 [CrossRef]
    [Google Scholar]
  4. Bedner E., Burfeind P., Hsieh T. C., Wu J. M., Aguero-Rosenfeld M. E., Melamed M. R., Horowitz H. W., Wormser G. P., Darzynkiewicz Z. 1998; Cell cycle effects and induction of apoptosis caused by infection of HL-60 cells with human granulocytic ehrlichiosis pathogen measured by flow and laser scanning cytometry. Cytometry 33:47–55 [CrossRef]
    [Google Scholar]
  5. Bexfield N. H., Villiers E. J., Herrtage M. E. 2005; Immune-mediated haemolytic anaemia and thrombocytopenia associated with Anaplasma phagocytophilum in a dog. J Small Anim Pract 46:543–548 [CrossRef]
    [Google Scholar]
  6. Borjesson D. L., Simon S. I., Tablin F., Barthold S. W. 2001; Thrombocytopenia in a mouse model of human granulocytic ehrlichiosis. J Infect Dis 184:1475–1479 [CrossRef]
    [Google Scholar]
  7. Borjesson D. L., Simon S. I., Hodzic E., Ballantyne C. M., Barthold S. W. 2002; Kinetics of CD11b/CD18 up-regulation during infection with the agent of human granulocytic ehrlichiosis in mice. Lab Invest 82:303–311 [CrossRef]
    [Google Scholar]
  8. Borjesson D. L., Brazzell J. L., Feferman R. 2005a; Platelet dysfunction after association with Anaplasma phagocytophilum in vitro . Ann N Y Acad Sci 1063:413–415 [CrossRef]
    [Google Scholar]
  9. Borjesson D. L., Kobayashi S. D., Whitney A. R., Voyich J. M., Argue C. M., Deleo F. R. 2005b; Insights into pathogen immune evasion mechanisms: Anaplasma phagocytophilum fails to induce an apoptosis differentiation program in human neutrophils. J Immunol 174:6364–6372 [CrossRef]
    [Google Scholar]
  10. Chen S. M., Dumler J. S., Bakken J. S., Walker D. H. 1994; Identification of a granulocytotropic Ehrlichia species as the etiologic agent of human disease. J Clin Microbiol 32:589–595
    [Google Scholar]
  11. Chuang J. L., Schleef R. R. 2001; Adenovirus-mediated expression and packaging of tissue-type plasminogen activator in megakaryocytic cells. Thromb Haemost 85:1079–1085
    [Google Scholar]
  12. Clarke M. C., Savill J., Jones D. B., Noble B. S., Brown S. B. 2003; Compartmentalized megakaryocyte death generates functional platelets committed to caspase-independent death. J Cell Biol 160:577–587 [CrossRef]
    [Google Scholar]
  13. Dumler J. S., Barbet A. F., Bekker C. P., Dasch G. A., Palmer G. H., Ray S. C., Rikihisa Y., Rurangirwa F. R. 2001; Reorganization of genera in the families Rickettsiaceae and Anaplasmataceae in the order Rickettsiales : unification of some species of Ehrlichia with Anaplasma , Cowdria with Ehrlichia and Ehrlichia with Neorickettsia , descriptions of six new species combinations and designation of Ehrlichia equi and ‘HGE agent’ as subjective synonyms of Ehrlichia phagocytophila . Int J Syst Evol Microbiol 51:2145–2165 [CrossRef]
    [Google Scholar]
  14. Frenette P. S., Denis C. V., Weiss L., Jurk K., Subbarao S., Kehrel B., Hartwig J. H., Vestweber D., Wagner D. D. 2000; P-Selectin glycoprotein ligand 1 (PSGL-1) is expressed on platelets and can mediate platelet-endothelial interactions in vivo. J Exp Med 191:1413–1422 [CrossRef]
    [Google Scholar]
  15. Ge Y., Rikihisa Y. 2006; Anaplasma phagocytophilum delays spontaneous human neutrophil apoptosis by modulation of multiple apoptotic pathways. Cell Microbiol 8:1406–1416 [CrossRef]
    [Google Scholar]
  16. Goodman J. L., Nelson C., Vitale B., Madigan J. E., Dumler J. S., Kurtti T. J., Munderloh U. G. 1996; Direct cultivation of the causative agent of human granulocytic ehrlichiosis. N Engl J Med 334:209–215 [CrossRef]
    [Google Scholar]
  17. Goodman J. L., Nelson C. M., Klein M. B., Hayes S. F., Weston B. W. 1999; Leukocyte infection by the granulocytic ehrlichiosis agent is linked to expression of a selectin ligand. J Clin Invest 103:407–412 [CrossRef]
    [Google Scholar]
  18. Herron M. J., Nelson C. M., Larson J., Snapp K. R., Kansas G. S., Goodman J. L. 2000; Intracellular parasitism by the human granulocytic ehrlichiosis bacterium through the P-selectin ligand, PSGL-1. Science 288:1653–1656 [CrossRef]
    [Google Scholar]
  19. Hodzic E., Feng S., Fish D., Leutenegger C. M., Freet K. J., Barthold S. W. 2001; Infection of mice with the agent of human granulocytic ehrlichiosis after different routes of inoculation. J Infect Dis 183:1781–1786 [CrossRef]
    [Google Scholar]
  20. Hsieh T. C., Aguero-Rosenfeld M. E., Wu J. M., Ng C., Papanikolaou N. A., Varde S. A., Schwartz I., Pizzolo J. G., Melamed M. other authors 1997; Cellular changes and induction of apoptosis in human promyelocytic HL-60 cells infected with the agent of human granulocytic ehrlichiosis (HGE. Biochem Biophys Res Commun 232:298–303 [CrossRef]
    [Google Scholar]
  21. Italiano J. E. Jr, Lecine P., Shivdasani R. A., Hartwig J. H. 1999; Blood platelets are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes. J Cell Biol 147:1299–1312 [CrossRef]
    [Google Scholar]
  22. Klein M. B., Miller J. S., Nelson C. M., Goodman J. L. 1997; Primary bone marrow progenitors of both granulocytic and monocytic lineages are susceptible to infection with the agent of human granulocytic ehrlichiosis. J Infect Dis 176:1405–1409 [CrossRef]
    [Google Scholar]
  23. Lester S. J., Breitschwerdt E. B., Collis C. D., Hegarty B. C. 2005; Anaplasma phagocytophilum infection (granulocytic anaplasmosis) in a dog from Vancouver Island. Can Vet J 46:825–827
    [Google Scholar]
  24. Li F., Erickson H. P., James J. A., Moore K. L., Cummings R. D., McEver R. P. 1996; Visualization of P-selectin glycoprotein ligand-1 as a highly extended molecule and mapping of protein epitopes for monoclonal antibodies. J Biol Chem 271:6342–6348 [CrossRef]
    [Google Scholar]
  25. Madigan J. E., Gribble D. 1987; Equine ehrlichiosis in northern California: 49 cases (1968–1981. J Am Vet Med Assoc 190:445–448
    [Google Scholar]
  26. Munderloh U. G., Lynch M. J., Herron M. J., Palmer A. T., Kurtti T. J., Nelson R. D., Goodman J. L. 2004; Infection of endothelial cells with Anaplasma marginale and A. phagocytophilum . Vet Microbiol 101:53–64 [CrossRef]
    [Google Scholar]
  27. Ogura M., Morishima Y., Ohno R., Kato Y., Hirabayashi N., Nagura H., Saito H. 1985; Establishment of a novel human megakaryoblastic leukemia cell line, MEG-01, with positive Philadelphia chromosome. Blood 66:1384–1392
    [Google Scholar]
  28. Ogura M., Morishima Y., Okumura M., Hotta T., Takamoto S., Ohno R., Hirabayashi N., Nagura H., Saito H. 1988; Functional and morphological differentiation induction of a human megakaryoblastic leukemia cell line (MEG-01s) by phorbol diesters. Blood 72:49–60
    [Google Scholar]
  29. Pusterla N., Pusterla J. B., Braun U., Lutz H. 1999; Experimental cross-infections with Ehrlichia phagocytophila and human granulocytic ehrlichia-like agent in cows and horses. Vet Rec 145:311–314 [CrossRef]
    [Google Scholar]
  30. Reneer D. V., Kearns S. A., Yago T., Sims J., Cummings R. D., McEver R. P., Carlyon J. A. 2006; Characterization of a sialic acid- and P-selectin glycoprotein ligand-1-independent adhesin activity in the granulocytotropic bacterium Anaplasma phagocytophilum . Cell Microbiol 8:1972–1984 [CrossRef]
    [Google Scholar]
  31. Sarkar M., Reneer D. V., Carlyon J. A. 2007; Sialyl-Lewis x-independent infection of human myeloid cells by Anaplasma phagocytophilum strains HZ and HGE1. Infect Immun 75:5720–5725 [CrossRef]
    [Google Scholar]
  32. Scorpio D. G., Akkoyunlu M., Fikrig E., Dumler J. S. 2004; CXCR2 blockade influences Anaplasma phagocytophilum propagation but not histopathology in the mouse model of human granulocytic anaplasmosis. Clin Diagn Lab Immunol 11:963–968
    [Google Scholar]
  33. Scorpio D. G., Von Loewenich F. D., Bogdan C., Dumler J. S. 2005; Innate immune tissue injury and murine HGA: tissue injury in the murine model of granulocytic anaplasmosis relates to host innate immune response and not pathogen load. Ann N Y Acad Sci 1063:425–428 [CrossRef]
    [Google Scholar]
  34. Takeuchi K., Satoh M., Kuno H., Yoshida T., Kondo H., Takeuchi M. 1998; Platelet-like particle formation in the human megakaryoblastic leukaemia cell lines, MEG-01 and MEG-01s. Br J Haematol 100:436–444 [CrossRef]
    [Google Scholar]
  35. 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]
    [Google Scholar]
  36. Wagers A. J., Stoolman L. M., Craig R., Knibbs R. N., Kansas G. S. 1998; An sLex-deficient variant of HL60 cells exhibits high levels of adhesion to vascular selectins: further evidence that HECA-452 and CSLEX1 monoclonal antibody epitopes are not essential for high avidity binding to vascular selectins. J Immunol 160:5122–5129
    [Google Scholar]
  37. White J. G. 2005; Platelets are covercytes, not phagocytes: uptake of bacteria involves channels of the open canalicular system. Platelets 16:121–131 [CrossRef]
    [Google Scholar]
  38. Wong S. J., Thomas J. A. 1998; Cytoplasmic, nuclear, and platelet autoantibodies in human granulocytic ehrlichiosis patients. J Clin Microbiol 36:1959–1963
    [Google Scholar]
  39. Yago T., Leppanen A., Carlyon J. A., Akkoyunlu M., Karmakar S., Fikrig E., Cummings R. D., McEver R. P. 2003; Structurally distinct requirements for binding of P-selectin glycoprotein ligand-1 and sialyl Lewis x to Anaplasma phagocytophilum and P-selectin. J Biol Chem 278:37987–37997 [CrossRef]
    [Google Scholar]
  40. Yoshiie K., Kim H. Y., Mott J., Rikihisa Y. 2000; Intracellular infection by the human granulocytic ehrlichiosis agent inhibits human neutrophil apoptosis. Infect Immun 68:1125–1133 [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.47551-0
Loading
/content/journal/jmm/10.1099/jmm.0.47551-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error