1887

Abstract

is an obligately intracellular bacterium and is the causative agent of human granulocytic anaplasmosis (HGA), an emerging and major tick-borne disease in the USA and other parts of the world. This study showed that the prenylation inhibitor manumycin A effectively blocked infection in host cells (HL-60 or RF/6A cells). infection activated extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase in host cells, and manumycin A treatment reduced ERK activation in infected host cells. As ERK activation is required for infection, we examined whether manumycin A inhibited the bacteria directly or through host ERK signalling. Treatment of alone with manumycin A significantly reduced the bacterial infectivity of host cells and bacterial viability in the absence of host cells, whereas pre-treatment of host cells did not inhibit bacterial infection in host cells. The inhibitory effect of manumycin A on infection in host cells was achieved even at a concentration 100 times lower than that required for effective inhibition of mammalian cell signalling. These results suggested that manumycin A directly inactivates the bacterium, resulting in reduced infection and ERK1/2 activation. Thus, the manumycin group of drugs may have a therapeutic potential for HGA.

Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.029231-0
2011-06-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/jmm/60/6/744.html?itemId=/content/journal/jmm/10.1099/jmm.0.029231-0&mimeType=html&fmt=ahah

References

  1. Ali B. R., Pal A., Croft S. L., Taylor R. J., Field M. C. 1999; The farnesyltransferase inhibitor manumycin A is a novel trypanocide with a complex mode of action including major effects on mitochondria. Mol Biochem Parasitol 104:67–80 [View Article][PubMed]
    [Google Scholar]
  2. Bakken J. S., Dumler J. S. 2000; Human granulocytic ehrlichiosis. Clin Infect Dis 31:554–560 [View Article][PubMed]
    [Google Scholar]
  3. Bakken J. S., Dumler S. 2008; Human granulocytic anaplasmosis. Infect Dis Clin North Am 22:433–448, viii [View Article][PubMed]
    [Google Scholar]
  4. Brodasky T. F., Stroman D. W., Dietz A., Mizsak S. 1983; U-56,407, a new antibiotic related to asukamycin: isolation and characterization. J Antibiot (Tokyo) 36:950–956[PubMed] [CrossRef]
    [Google Scholar]
  5. Buitrago M. I., Ijdo J. W., Rinaudo P., Simon H., Copel J., Gadbaw J., Heimer R., Fikrig E., Bia F. J. 1998; Human granulocytic ehrlichiosis during pregnancy treated successfully with rifampin. Clin Infect Dis 27:213–215 [View Article][PubMed]
    [Google Scholar]
  6. CDC 2010; Summary of notifiable diseases, United States, 2009. MMWR 59:1031
    [Google Scholar]
  7. 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[PubMed]
    [Google Scholar]
  8. 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[PubMed] [CrossRef]
    [Google Scholar]
  9. 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 [View Article][PubMed]
    [Google Scholar]
  10. Hall-Baker P. A., Nieves E., Jajosky R. A., Adams D. A., Sharp P., Anderson W. J., Aponte J. J., Aranas A. E., Katz S. B. et al. 2010; Summary of notifiable diseases – United States, 2008. MMWR 57:1–94
    [Google Scholar]
  11. Hara M., Akasaka K., Akinaga S., Okabe M., Nakano H., Gomez R., Wood D., Uh M., Tamanoi F. 1993; Identification of Ras farnesyltransferase inhibitors by microbial screening. Proc Natl Acad Sci U S A 90:2281–2285 [View Article][PubMed]
    [Google Scholar]
  12. Horowitz H. W., Hsieh T. C., Aguero-Rosenfeld M. E., Kalantarpour F., Chowdhury I., Wormser G. P., Wu J. M. 2001; Antimicrobial susceptibility of Ehrlichia phagocytophila . Antimicrob Agents Chemother 45:786–788 [View Article][PubMed]
    [Google Scholar]
  13. Ito T., Kawata S., Tamura S., Igura T., Nagase T., Miyagawa J. I., Yamazaki E., Ishiguro H., Matasuzawa Y. 1996; Suppression of human pancreatic cancer growth in BALB/c nude mice by manumycin, a farnesyl : protein transferase inhibitor. Jpn J Cancer Res 87:113–116[PubMed] [CrossRef]
    [Google Scholar]
  14. Kim H.-Y., Rikihisa Y. 1998; Characterization of monoclonal antibodies to the 44-kilodalton major outer membrane protein of the human granulocytic ehrlichiosis agent. J Clin Microbiol 36:3278–3284[PubMed]
    [Google Scholar]
  15. Klein M. B., Nelson C. M., Goodman J. L. 1997; Antibiotic susceptibility of the newly cultivated agent of human granulocytic ehrlichiosis: promising activity of quinolones and rifamycins. Antimicrob Agents Chemother 41:76–79[PubMed]
    [Google Scholar]
  16. Korzeniowski O. M. 1995; Antibacterial agents in pregnancy. Infect Dis Clin North Am 9:639–651[PubMed]
    [Google Scholar]
  17. Krause P. J., Corrow C. L., Bakken J. S. 2003; Successful treatment of human granulocytic ehrlichiosis in children using rifampin. Pediatrics 112:e252–e253 [View Article][PubMed]
    [Google Scholar]
  18. Lee H. C., Kioi M., Han J., Puri R. K., Goodman J. L. 2008; Anaplasma phagocytophilum-induced gene expression in both human neutrophils and HL-60 cells. Genomics 92:144–151 [View Article][PubMed]
    [Google Scholar]
  19. Lochary M. E., Lockhart P. B., Williams W. T. Jr 1998; Doxycycline and staining of permanent teeth. Pediatr Infect Dis J 17:429–431 [View Article][PubMed]
    [Google Scholar]
  20. 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 [View Article][PubMed]
    [Google Scholar]
  21. Murthy S., Tong H., Hohl R. J. 2005; Regulation of fatty acid synthesis by farnesyl pyrophosphate. J Biol Chem 280:41793–41804 [View Article][PubMed]
    [Google Scholar]
  22. Parkins M. D., Church D. L., Jiang X. Y., Gregson D. B. 2009; Human granulocytic anaplasmosis: first reported case in Canada. Can J Infect Dis Med Microbiol 20:e100–e102[PubMed]
    [Google Scholar]
  23. Pusterla N., Madigan J. E., Asanovich K. M., Chae J. S., Derock E., Leutenegger C. M., Pusterla J. B., Lutz H., Dumler J. S. 2000; Experimental inoculation with human granulocytic Ehrlichia agent derived from high- and low-passage cell culture in horses. J Clin Microbiol 38:1276–1278[PubMed]
    [Google Scholar]
  24. Rikihisa Y. 2003; Mechanisms to create a safe haven by members of the family Anaplasmataceae . Ann N Y Acad Sci 990:548–555 [View Article][PubMed]
    [Google Scholar]
  25. Rikihisa Y. 2006; Ehrlichia subversion of host innate responses. Curr Opin Microbiol 9:95–101 [View Article][PubMed]
    [Google Scholar]
  26. Rikihisa Y., Zhang Y., Park J. 1995; Role of Ca2+ and calmodulin in ehrlichial infection in macrophages. Infect Immun 63:2310–2316[PubMed]
    [Google Scholar]
  27. Rikihisa Y., Zhi N., Wormser G. P., Wen B., Horowitz H. W., Hechemy K. E. 1997; Ultrastructural and antigenic characterization of a granulocytic ehrlichiosis agent directly isolated and stably cultivated from a patient in New York state. J Infect Dis 175:210–213[PubMed] [CrossRef]
    [Google Scholar]
  28. Rikihisa Y., Lin M., Niu H. 2010; Type IV secretion in the obligatory intracellular bacterium Anaplasma phagocytophilum . Cell Microbiol 12:1213–1221 [View Article][PubMed]
    [Google Scholar]
  29. Roux P. P., Blenis J. 2004; ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68:320–344 [View Article][PubMed]
    [Google Scholar]
  30. Sattler I., Thiericke R., Zeeck A. 1998; The manumycin-group metabolites. Nat Prod Rep 15:221–240 [View Article][PubMed]
    [Google Scholar]
  31. Scharf W., Schauer S., Freyburger F., Petrovec M., Schaarschmidt-Kiener D., Liebisch G., Runge M., Ganter M., Kehl A. et al. 2011; Distinct host species correlate with Anaplasma phagocytophilum ankA gene clusters. J Clin Microbiol 49:790–796[PubMed] [CrossRef]
    [Google Scholar]
  32. Slechta L., Cialdella J. I., Mizsak S. A., Hoeksema H. 1982; Isolation and characterization of a new antibiotic U-62162. J Antibiot (Tokyo) 35:556–560[PubMed] [CrossRef]
    [Google Scholar]
  33. Sukumaran B., Mastronunzio J. E., Narasimhan S., Fankhauser S., Uchil P. D., Levy R., Graham M., Colpitts T. M., Lesser C. F., Fikrig E. 2011; Anaplasma phagocytophilum AptA modulates Erk1/2 signalling. Cell Microbiol 13:47–61[PubMed] [CrossRef]
    [Google Scholar]
  34. Xiong Q., Lin M., Rikihisa Y. 2009; Cholesterol-dependent Anaplasma phagocytophilum exploits the low-density lipoprotein uptake pathway. PLoS Pathog 5:e1000329 [View Article][PubMed]
    [Google Scholar]
  35. Xu G., Pan J., Martin C., Yeung S.-C. 2001; Angiogenesis inhibition in the in vivo antineoplastic effect of manumycin and paclitaxel against anaplastic thyroid carcinoma. J Clin Endocrinol Metab 86:1769–1777 [View Article][PubMed]
    [Google Scholar]
  36. Yeung S.-C., Xu G., Pan J., Christgen M., Bamiagis A. 2000; Manumycin enhances the cytotoxic effect of paclitaxel on anaplastic thyroid carcinoma cells. Cancer Res 60:650–656[PubMed]
    [Google Scholar]
  37. Zhang L., Liu Y., Ni D., Li Q., Yu Y., Yu X. J., Wan K., Li D., Liang G. et al. 2008; Nosocomial transmission of human granulocytic anaplasmosis in China. JAMA 300:2263–2270 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.029231-0
Loading
/content/journal/jmm/10.1099/jmm.0.029231-0
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