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Molecular Pathogenesis of Campylobacter jejuni Enteritis

  • Michael E. Konkel
  • Witold CieplakJr.
Part of the Infectious Agents and Pathogenesis book series (IAPA)

Abstract

Campylobacter jejuni and Campylobacter coli are now recognized as among the most prevalent causes of bacterial enteritis in both developed and developing countries. Infection rates with C. jejuni in the United States and Great Britain have been estimated at 10 per 1000 population, thus equaling and likely surpassing the rates of Salmonella infection.(1) In addition to causing acute enterocolitis, C. jejuni infection has recently been implicated as a frequent antecedent to the development of Guillain-Barré-type polyneuropathy.(2,3) Despite the recognition of Campylobacter spp. as an important etiologic agent of enteritis, the biologic and molecular pathogenic aspects of Campylobacter enteritis remain ill-defined. There is considerable disagreement whether C. jejuni, like more well-recognized enteropathogens (e.g., Shigella, Escherichia coli, Vibrio cholerae, and Yersinia), produce any readily identifiable pathogenic/virulence determinants such as cytotoxins, entero-toxins, and invasion-related molecules during cultivation in vitro. Enteritis caused by C. jejuni and related species may represent an example of the interactions that occur between pathogens and the host environment and result in the expression of virulence determinants during the pathogenesis of disease.(4) This review summarizes the microbiology and immunology of C. jejuni and concentrates on the available knowledge concerning the molecular bases of disease causation by this organism.

Keywords

Cholera Toxin Outer Membrane Protein Molecular Pathogenesis Human Epithelial Cell Epithelial Cell Culture 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Skirrow, M. B., and Blaser, M. J., 1992, Clinical and epidemiologic considerations, in: Campylobacter jejuni: Current Status and Future Trends (I. Nachamkin, M. J. Blaser, and L. S. Tompkins, eds.), American Society for Microbiology, Washington, D.C., pp. 3–8.Google Scholar
  2. 2.
    Kuroki, S., Haruta, T., Yoshioka, M., Kobayashi, Y., Nukina, M., and Nakanishi, H., 1991, Guillain-Barré syndrome associated with Campylobacter infection, Pediatr. Infect. Dis. J. 10: 149–151.PubMedCrossRefGoogle Scholar
  3. 3.
    Yuki, N., Taki, T., Inagaki, R., Kasama, T., Takahashi, M., Saito, K., Handa, S., and Miyatake, T., 1993, A bacterium lipopolysaccharide that elicits Guillain-Barré syndrome has a GM1 ganglioside-like structure, J. Exp. Med. 178:1771–1775.PubMedCrossRefGoogle Scholar
  4. 4.
    Mekalanos, J. J., 1992, Environmental signals controlling expression of virulence determinants in bacteria, J. Bacteriol. 174:1–7.PubMedGoogle Scholar
  5. 5.
    Nachamkin, I., 1993, Campylobacter infections, Curr. Opin. Infect. Dis.: 6:72–76.CrossRefGoogle Scholar
  6. 6.
    Goossens, H., and Butzler, J.-R., 1992, Isolation and identification of Campylobacter spp., in: Campylobacter jejuni: Current Status and Future Trends (I. Nachamkin, M. J. Blaser, and L. S. Tompkins, eds.), American Society for Microbiology, Washington, D. C., pp. 93–109.Google Scholar
  7. 7.
    Guerrant, R. L., Lahita, R. G., Winn, W. C., Jr., and Roberts, R. B., 1978, Campylobacteriosis in man: Pathogenic mechanisms and review of 91 bloodstream infections, Am.]. Med. 65: 584–592.CrossRefGoogle Scholar
  8. 8.
    Cover, T. L., and Blaser, M. J., 1989, The pathobiology of Campylobacter infections in humans, Annu. Rev. Med. 40:269–285.PubMedCrossRefGoogle Scholar
  9. 9.
    Caldwell, M. B., Guerry, P., Lee, E. C., Burans, J. P., and Walker, R. L., 1985, Reversible expression of flagella in Campylobacter jejuni, Infect. Immun. 50:941–943.PubMedGoogle Scholar
  10. 10.
    Harris, L. A., Logan, S. M., Guerry, P., and Trust, T. J., 1987, Antigenic variation of Campylobacter flagella, J. Bacteriol. 169:5066–5071.PubMedGoogle Scholar
  11. 11.
    Skirrow, M. B., 1977, Campylobacter enteritis: A “new” disease, Br. Med. J. 2:9–11.PubMedCrossRefGoogle Scholar
  12. 12.
    Goossens, H., De Boeck, M., Coignau, H., Vlaes, L., Van den Borre, C., and Butzler, J. P., 1986, Modified selective medium for isolation of Campylobacter spp. from feces: Comparison with Preston medium, a blood-free medium, and a filtration system, J. Clin. Microbiol. 24: 840–843.PubMedGoogle Scholar
  13. 13.
    Endtz, H. P., Ruijs, G. J., Zwinderman, A. H., Van der Reijden, T., Biever, M., and Moulton, R. P., 1991, Comparison of six media, including a semisolid agar, for the isolation of various Campylobacter species from stool specimens, J. Clin. Microbiol. 29:1007–1110.PubMedGoogle Scholar
  14. 14.
    Walker, R. I., Caldwell, M. B., Lee, E. C., Guerry, P., Trust, T. J., and Ruiz-Palacios, G. M., 1986, Pathophysiology of Campylobacter enteritis, Microbiol. Rev. 50:81–94.PubMedGoogle Scholar
  15. 15.
    Goossens, H., Henocque, G., Kremp, L., Rocque, J., Boury, R., Alanio, G., Vlaes, L., Hemelhof, W., Van den Borre, C., Macart, M., and Butzler, J. P., 1986, Nosocomial outbreak of Campylobacter jejuni meningitis in newborn infants, Lancet 1:146–149.CrossRefGoogle Scholar
  16. 16.
    Haq, J. A., Rahman, K. M., and Akbar, M. S., 1985, Haemolytic-uraemic syndrome and Campylobacter, Med. J. Aust. 142:662–663.PubMedGoogle Scholar
  17. 17.
    Ebright, J. R., and Ryan, L. M., 1984, Acute erosive reactive arthritis associated with Campylobacter jejuni-induced colitis, Am. J. Med. 76:321–323.PubMedCrossRefGoogle Scholar
  18. 18.
    Doyle, M. P., and Jones, D. M., 1992, Food-borne transmission and antibiotic resistance of Campylobacter jejuni, in: Campylobacter jejuni: Current Status and Future Trends (I. Nachamkin, M. J. Blaser, and L. S. Tompkins, eds.), American Society for Microbiology, Washington, D.C., pp. 45–48.Google Scholar
  19. 19.
    Stern, N. J., 1992, Reservoirs for Campylobacter jejuni and approaches for intervention in poultry, in: Campylobacter jejuni: Current Status and Future Trends (I. Nachamkin, M.J. Blaser, and L. S. Tompkins, eds.), American Society for Microbiology, Washington, D.C., pp. 49–60.Google Scholar
  20. 20.
    Blaser, M. J., Cravens, J., Powers, B. W., Laforce, F. M., and Wang, W.-L. L., 1979, Campylobacter enteritis associated with unpasteurized milk, Am. J. Med. 67:715–718.PubMedCrossRefGoogle Scholar
  21. 21.
    Taylor, D. N., Porter, B. W., Williams, C. A., Miller, H. G., Bopp, C. A., and Blake, P. A., 1982, Campylobacter enteritis: A large outbreak traced to commercial raw milk, West. J. Med. 137: 365–369.PubMedGoogle Scholar
  22. 21a.
    Tauxe, R. V., Vogt, R. L., Sours, H. E., Barrett, T., Feldman, R. A., Dickinson, R. J., and Witherell, L., 1982, Campylobacter enteritis associated with contaminated water, Ann. Intern. Med. 96:292–296.Google Scholar
  23. 22.
    Blaser, M. J., Taylor, D. N., and Echeverria, P., 1986, Immune response to Campylobacter jejuni in a rural community in Thailand, J. Infect. Dis. 153:249–254.PubMedCrossRefGoogle Scholar
  24. 22a.
    Patton, C. M., and Wachsmuth, I. K., 1992, Typing schemes: Are current methods useful? in: Campylobacterjejuni: Current Status and Future Trends (I. Nachamkin, M. J. Blaser, and L. S. Tompkins, eds.), American Society for Microbiology, Washington, D.C., pp. 110–128.Google Scholar
  25. 23.
    Patton, C. M., Barrett, T. J., and Morris, G. K., 1985, Comparison of the Penner and Lior methods for serotyping Campylobacter spp., J. Clin. Microbiol. 22:558–565.PubMedGoogle Scholar
  26. 24.
    Dunn, B. E., Blaser, M. J., and Snyder, E. L., 1987, Two-dimensional gel electrophoresis and immunoblotting of Campylobacter outer membrane proteins, Infect. Immun. 55:1564–1572.PubMedGoogle Scholar
  27. 25.
    Nachamkin, I., and Hart, A. M., 1985, Western blot analysis of human antibody response to Campylobacter jejuni cellular antigens during gastrointestinal infection, J. Clin. Microbiol. 21: 33–38.PubMedGoogle Scholar
  28. 26.
    Wenman, W. M., Chai, J., Louie, T. J., Goudreau, C., Lior, H., Newell, D. G., Pearson, A. D., and Taylor, D. E., 1985, Antigenic analysis of Campylobacter flagellar protein and other proteins, J. Clin. Microbiol. 21:108–112.PubMedGoogle Scholar
  29. 27.
    Rüssel, R. G., Blaser, M. J., Sarmiento, J. I., and Fox, J., 1989, Experimental Campylobacter jejuni infection in Macaca nemestrina, Infect. Immun. 57:1438–1444.Google Scholar
  30. 28.
    Black, R. E., Levine, M. M., Clements, M. L., Hughes, T. P., and Blaser, M. J., 1988, Experimental Campylobacter infection in humans, J. Infect. Dis. 157:472–479.PubMedCrossRefGoogle Scholar
  31. 29.
    Mills, S. D., and Bradbury, W. C., 1984, Human antibody response to outer membrane proteins of Campylobacter jejuni during infection, Infect. Immun. 43:739–743.PubMedGoogle Scholar
  32. 30.
    Black, R. E., Perlman, D., Clements, M. L., Levine, M. M., and Blaser, M. J., 1992, Human volunteer studies with Campylobacterjejuni, in: Campylobacterjejuni: Current Status and Future Trends (I. Nachamkin, M. J. Blaser, and L. S. Tompkins, eds.), American Society for Microbiology, Washington, D.C., pp. 207–215.Google Scholar
  33. 31.
    Pennie, R. A., Pearson, R. D., Barrett, L.J., Lior, H., and Guerrant, R. L., 1986, Susceptibility of Campylobacter jejuni to strain-specific bactericidal activity in sera of infected patients, Infect. Immun. 52:702–706.PubMedGoogle Scholar
  34. 32.
    Lane, E. M., Batchelor, R. A., Bourgeois, A. L., Burr, D. H., and Olson, J. G., 1987, Urine and faecal IgA response during naturally acquired infection with Campylobacter jejuni, Lancet 1: 1141.PubMedCrossRefGoogle Scholar
  35. 33.
    Burr, D. H., Caldwell, M. B., Bourgeois, A. L., Morgan, H. R., Wistar, R., Jr., and Walker, R. L., 1988, Mucosal and systemic immunity to Campylobacter jejuni in rabbits after gastric inoculation, Infect. Immun. 56:99–105.PubMedGoogle Scholar
  36. 34.
    McSweegan, E., Burr, D. H., and Walker, R. I., 1987, Intestinal mucus gel and secretory antibody are barriers to Campylobacter jejuni adherence to INT 407 cells, Infect. Immun. 55: 1431–1435.PubMedGoogle Scholar
  37. 35.
    Rollwagen, F. M., Pacheco, N. D., Clements, J. D., Pavlovskis, O., Rollins, D. M., and Walker, R. L., 1993, Killed Campylobacter elicits immune response and protection when administered with an oral adjuvant, Vaccine 11:1316–1320.PubMedCrossRefGoogle Scholar
  38. 36.
    Aspinall, G. O., Fujimoto, S., McDonald, A. G., Pang, H., Kurjanczyk, L. A., and Penner, J. L., 1994, Lipopolysaccharides from Campylobacter jejuni associated with Guillain-Barré syndrome patients mimic human gangliosides in structure, Infect. Immun. 62:2122–2125.PubMedGoogle Scholar
  39. 37.
    Fox, J. G., 1992, In vivo models of enteric campylobacteriosis: Natural and experimental infections, in: Campylobacter jejuni: Current Status and Future Trends (I. Nachamkin, M. J. Blaser, and L. S. Tompkins, eds.), American Society for Microbiology, Washington, D.C., pp. 131–138.Google Scholar
  40. 38.
    Blaser, M. J., Duncan, D. J., Warren, G. H., and Wang, W.-L. L., 1983, Experimental Campylobacter jejuni infection of adult mice, Infect. Immun. 39:908–916.PubMedGoogle Scholar
  41. 39.
    Caldwell, M. B., Walker, R. I., Stewart, S. D., and Rogers, J. E., 1983, Simple adult rabbit model for Campylobacter jejuni enteritis, Infect. Immun. 42:1176–1182.PubMedGoogle Scholar
  42. 40.
    Babakhani, F. K., Bradley, G. A., and Joens, L. A., 1993, Newborn piglet model for cam-pylobacteriosis, Infect. Immun. 61:3466–3475.PubMedGoogle Scholar
  43. 41.
    Russell, R. G., 1992, Campylobacter jejuni colitis and immunity in primates: Epidemiology of natural infection, in: Campylobacter jejuni: Current Status and Future Trends (I. Nachamkin, M. J. Blaser, and L. S. Tompkins, eds.), American Society for Microbiology, Washington, D.C., pp. 148–157.Google Scholar
  44. 42.
    Russell, R. G., O’Donnoghue, M., Blake, D. C., Jr., Zulty, J., and DeTolla, L. J., 1993, Early colonic damage and invasion of Campylobacter jejuni in experimentally challenged infant Macaca mulatta, J. Infect. Dis. 168:210–215.PubMedCrossRefGoogle Scholar
  45. 43.
    Finlay, B. B., and Falkow, S., 1989, Common themes in microbial pathogenicity, Microbiol. Rev. 53:210–230.PubMedGoogle Scholar
  46. 44.
    Fauchere, J.-L., Rosenau, A., Veron, M., Moyen, E. N., Richard, S., and Pfister, A., 1986, Association with HeLa cells of Campylobacter jejuni and Campylobacter coli isolated from human feces, Infect. Immun. 54:283–287.PubMedGoogle Scholar
  47. 45.
    De Melo, M. A., and Pechere, J.-C., 1990, Identification of Campylobacter jejuni surface proteins that bind to eukaryotic cells in vitro, Infect. Immun. 58:1749–1756.PubMedGoogle Scholar
  48. 46.
    Fauchere, J.-L., Kervella, M., Rosenau, A., Mohanna, K., and Veron, M., 1989, Adhesion to HeLa cells of Campylobacter jejuni and C. coli outer membrane components, Res. Microbiol. 140:379–392.PubMedCrossRefGoogle Scholar
  49. 47.
    Pei, Z., and Blaser, M. J., 1993, PEB1, the major cell-binding factor of Campylobacter jejuni, is a homolog of the binding component in gram-negative nutrient transport systems, J. Biol. Chem. 268:18717–18725.PubMedGoogle Scholar
  50. 48.
    Newell, D. G., McBride, H., and Dolby, J. M., 1985, Investigations on the role of flagella in the colonization of infant mice with Campylobacter jejuni and the attachment of Campylobacter jejuni to human epithelial cells, J. Hyg. 95:215–227.CrossRefGoogle Scholar
  51. 49.
    McSweegan, E., and Walker, R. I., 1986, Identification and characterization of two Campylobacter jejuni adhesins for cellular and mucous substrates, Infect. Immun. 53:141–148.PubMedGoogle Scholar
  52. 50.
    Grant, C. C. R., Konkel, M. E., Cieplak, W., Jr., and Tompkins, L. S., 1993, Role of flagella in adherence, internalization, and translocation of Campylobacter jejuni in nonpolarized and polarized epithelial cell cultures, Infect. Immun. 61:1764–1771.PubMedGoogle Scholar
  53. 51.
    Newell, D. G., McBride, H., Saunders, F., Dehele, Y, and Pearson, A. D., 1985, The virulence of clinical and environmental isolates of Campylobacter jejuni, J. Hyg. 95:45–54.CrossRefGoogle Scholar
  54. 52.
    Konkel, M. E., and Joens, J. A., 1989, Adhesion to and invasion of HEp-2 cells by Campylobacter spp., Infect. Immun. 57:2984–2990.PubMedGoogle Scholar
  55. 53.
    Konkel, M. E., Hayes, S. F., Joens, L. A., and Cieplak, W., Jr., 1992, Characteristics of the internalization and intracellular survival of Campylobacter jejuni in human epithelial cell cultures, Microb. Pathog. 13:357–370.PubMedCrossRefGoogle Scholar
  56. 54.
    De Melo, M. A., Gabbiani, G., and Pechere, J.-C., 1989, Cellular events and intracellular survival of Campylobacter jejuni during infection of HEp-2 cells, Infect. Immun. 57:2214–2222.PubMedGoogle Scholar
  57. 55.
    Oelschlaeger, T. A., Guerry, P., and Kopecko, D. J., 1993, Unusual microtubule-dependent endocytosis mechanisms triggered by Campylobacter jejuni and Citrobacter freundii, Proc. Natl. Acad. Sci. USA 90:6884–6888.PubMedCrossRefGoogle Scholar
  58. 56.
    Konkel, M. E., and Cieplak, W., Jr., 1992, Altered synthetic response of Campylobacter jejuni to cocultivation with human epithelial cells is associated with enhanced internalization, Infect. Immun. 60:4945–4949.PubMedGoogle Scholar
  59. 57.
    Konkel, M. E., Mead, D. J., and Cieplak, W. Jr., 1993, Kinetic and antigenic characterization of altered protein synthesis by Campylobacter jejuni during cultivation with human epithelial cells, J. Infect. Dis. 168:948–954.PubMedCrossRefGoogle Scholar
  60. 58.
    Panigrahi, P., Losonsky, G., DeTolla, L. J., and Morris, J. G., Jr., 1992, Human immune response to Campylobacter jejuni proteins expressed in vitro, Infect. Immun. 60:4938–4944.PubMedGoogle Scholar
  61. 59.
    Wassenaar, T. M., Bleumink-Pluym, N. M. C., and Van der Zeijst, B. A. M., 1991, Inactivation of Campylobacter jejuni flagellin genes by homologous recombination demonstrates that flaA but not flaB is required for invasion, EMBO J. 10:2055–2061.PubMedGoogle Scholar
  62. 60.
    Konkel, M. E., Mead, D. J., Hayes, S. F., and Cieplak, W., Jr., 1992, Translocation of Campylobacter jejuni across human polarized epithelial cell monolayer cultures, J. Infect. Dis. 166:308–315.PubMedCrossRefGoogle Scholar
  63. 61.
    Everest, P. H., Goossens, H., Butzler, J.-R., Lloyd, D., Knutton, S., Ketley, J. M., and Williams, P. H., 1992, Differentiated Caco-2 cells as a model for enteric invasion by Campylobacter jejuni and C. coli, J. Med. Microbiol. 37:319–325.PubMedCrossRefGoogle Scholar
  64. 62.
    Kiehlbauch, J. A., Albach, R. A., Baum, L. L., and Chang, K. P., 1985, Phagocytosis of Campylobacter jejuni and its intracellular survival in mononuclear phagocytes, Infect. Immun. 48:446–451.PubMedGoogle Scholar
  65. 63.
    Purdy, D., and Park, S. F., 1994, Cloning, nucleotide sequence and characterization of a gene encoding Superoxide dismutase from Campylobacter jejuni and Campylobacter coli, Microbiology 140:1203–1208.PubMedCrossRefGoogle Scholar
  66. 64.
    Pesci, E. C., Cottle, D. L., and Pickett, C. L., 1994, Genetic, enzymatic, and pathogenic studies of the iron Superoxide dismutase of Campylobacter jejuni, Infect. Immun. 62:2687–2694.PubMedGoogle Scholar
  67. 65.
    Guerrant, R. L., Wanke, C. A., Pennie, R. A., Barrett, L.J., Lima, A. A. M., and O’Brien, A. D., 1987, Production of a unique cytotoxin by Campylobacter jejuni, Infect. Immun. 55:2526–2530.PubMedGoogle Scholar
  68. 66.
    Mahajan, S., and Rodgers, F. G., 1990, Isolation, characterization, and host-cell-binding properties of a cytotoxin from Campylobacter jejuni, J. Clin. Microbiol. 28:1314–1320.PubMedGoogle Scholar
  69. 67.
    Belbouri, A., and Megraud, F., 1988, Enterotoxin-like activity produced by Campylobacter jejuni and Campylobacter coli isolated from patients and healthy controls in Algeria, FEMS Microbiol. Lett. 51:25–28.CrossRefGoogle Scholar
  70. 68.
    Daikoku, T., Kawaguchi, M., Takama, K., and Suzuki, S., 1990, Partial purification and characterization of the enterotoxin produced by Campylobacter jejuni, Infect. Immun. 58: 2414–2419.PubMedGoogle Scholar
  71. 69.
    Goossens, H., Butzler, J.-R., and Takeda, Y, 1985, Demonstration of cholera-like enterotoxin production by Campylobacter jejuni, FEMS Microbiol. Lett. 29:73–76.CrossRefGoogle Scholar
  72. 70.
    Johnson, W. M., and Lior, H., 1986, Cytotoxic and cytotonic factors produced by Campylobacter jejuni, Campylobacter coli, and Campylobacter laridis, J. Clin. Microbiol. 24:275–281.PubMedGoogle Scholar
  73. 71.
    Klipstein, F. A., and Engert, R. F., 1985, Purification of Campylobacter jejuni enterotoxin, Lancet, 1:1123–1124.Google Scholar
  74. 72.
    McCardell, B. A., Madden, J. M., and Lee, E. C., 1986, Campylobacter jejuni and Campylobacter coli production of a cytotonic toxin immunologically similar to cholera toxin, J. FoodProt. 47: 943–949.Google Scholar
  75. 73.
    Ruiz-Palacios, G. M., Torres, J., Torres, N. I., Escamilla, E., Ruiz-Palacios, B. R., and Tamayo, J., 1983, Cholera-like enterotoxin produced by Campylobacter jejuni, characterisation and clinical significance, Lancet 2:250–253.PubMedCrossRefGoogle Scholar
  76. 74.
    Cover, T. L., Perez-Perez, G. I., and Blaser, M. J., 1990, Evaluation of cytotoxin activity in fecal filtrates from patients with Campylobacter jejuni or Campylobacter coli enteritis, FEMS Microbiol. Lett. 58:301–304.PubMedGoogle Scholar
  77. 75.
    Perez-Perez, G. I., Cohn, D. L., Guerrant, R. L., Patton, C. M., Relier, L. B., and Blaser, M. J., 1989, Clinical and immunologic significance of cholera-like toxin and cytotoxin production by Campylobacter species in patients with acute inflammatory diarrhea in the USA, J. Infect. Dis. 160:460–468.PubMedCrossRefGoogle Scholar
  78. 76.
    Wadstrom, T., Baloda, S. B., Krovacek, K., Faris, A., Bengtson, S., and Walder, M., 1983, Swedish isolates of Campylobacter jejuni/coli do not produce cytotonic or cytotoxic entero-toxins, Lancet 2:911.PubMedCrossRefGoogle Scholar
  79. 77.
    Konkel, M. E., Lobet, Y, and Cieplak, W., Jr., 1992, Examination of multiple isolates of Campylobacterjejuni for evidence of cholera toxin-like activity, in: Campylobacterjejuni: Current Status and Future Trends (I. Nachamkin, M. J. Blaser, and L. S. Tompkins, eds.), American Society for Microbiology, Washington, D.C., pp. 193–198.Google Scholar
  80. 78.
    Baig, B. H., Wachsmuth, I. K., Morris, G. K., and Hill, W. E., 1986, Probing Campylobacter jejuni DNA coding for Escherichia coli heat-labile enterotoxin, J. Infect. Dis. 154:542.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Michael E. Konkel
    • 1
  • Witold CieplakJr.
    • 2
  1. 1.Department of MicrobiologyWashington State UniversityPullmanUSA
  2. 2.Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, National Institute of Allergy and Infectious DiseasesNational Institutes of HealthHamiltonUSA

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