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. 1996 Jan;9(1):18–33. doi: 10.1128/cmr.9.1.18

Sequence-based identification of microbial pathogens: a reconsideration of Koch's postulates.

D N Fredericks 1, D A Relman 1
PMCID: PMC172879  PMID: 8665474

Abstract

Over 100 years ago, Robert Koch introduced his ideas about how to prove a causal relationship between a microorganism and a disease. Koch's postulates created a scientific standard for causal evidence that established the credibility of microbes as pathogens and led to the development of modern microbiology. In more recent times, Koch's postulates have evolved to accommodate a broader understanding of the host-parasite relationship as well as experimental advances. Techniques such as in situ hybridization, PCR, and representational difference analysis reveal previously uncharacterized, fastidious or uncultivated, microbial pathogens that resist the application of Koch's original postulates, but they also provide new approaches for proving disease causation. In particular, the increasing reliance on sequence-based methods for microbial identification requires a reassessment of the original postulates and the rationale that guided Koch and later revisionists. Recent investigations of Whipple's disease, human ehrlichiosis, hepatitis C, hantavirus pulmonary syndrome, and Kaposi's sarcoma illustrate some of these issues. A set of molecular guidelines for establishing disease causation with sequence-based technology is proposed, and the importance of the scientific concordance of evidence in supporting causal associations is emphasized.

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Selected References

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  1. Amann R. I., Ludwig W., Schleifer K. H. Phylogenetic identification and in situ detection of individual microbial cells without cultivation. Microbiol Rev. 1995 Mar;59(1):143–169. doi: 10.1128/mr.59.1.143-169.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anderson B. E., Dawson J. E., Jones D. C., Wilson K. H. Ehrlichia chaffeensis, a new species associated with human ehrlichiosis. J Clin Microbiol. 1991 Dec;29(12):2838–2842. doi: 10.1128/jcm.29.12.2838-2842.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Anderson B. E., Sumner J. W., Dawson J. E., Tzianabos T., Greene C. R., Olson J. G., Fishbein D. B., Olsen-Rasmussen M., Holloway B. P., George E. H. Detection of the etiologic agent of human ehrlichiosis by polymerase chain reaction. J Clin Microbiol. 1992 Apr;30(4):775–780. doi: 10.1128/jcm.30.4.775-780.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bakken J. S., Dumler J. S., Chen S. M., Eckman M. R., Van Etta L. L., Walker D. H. Human granulocytic ehrlichiosis in the upper Midwest United States. A new species emerging? JAMA. 1994 Jul 20;272(3):212–218. [PubMed] [Google Scholar]
  5. Brown M. S., Goldstein J. L. Koch's postulates for cholesterol. Cell. 1992 Oct 16;71(2):187–188. doi: 10.1016/0092-8674(92)90346-e. [DOI] [PubMed] [Google Scholar]
  6. Butler J. C., Peters C. J. Hantaviruses and hantavirus pulmonary syndrome. Clin Infect Dis. 1994 Sep;19(3):387–395. doi: 10.1093/clinids/19.3.387. [DOI] [PubMed] [Google Scholar]
  7. Böddinghaus B., Rogall T., Flohr T., Blöcker H., Böttger E. C. Detection and identification of mycobacteria by amplification of rRNA. J Clin Microbiol. 1990 Aug;28(8):1751–1759. doi: 10.1128/jcm.28.8.1751-1759.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Böttger E. C. Rapid determination of bacterial ribosomal RNA sequences by direct sequencing of enzymatically amplified DNA. FEMS Microbiol Lett. 1989 Nov;53(1-2):171–176. doi: 10.1016/0378-1097(89)90386-8. [DOI] [PubMed] [Google Scholar]
  9. Böttger E. C., Teske A., Kirschner P., Bost S., Chang H. R., Beer V., Hirschel B. Disseminated "Mycobacterium genavense" infection in patients with AIDS. Lancet. 1992 Jul 11;340(8811):76–80. doi: 10.1016/0140-6736(92)90397-l. [DOI] [PubMed] [Google Scholar]
  10. CHEARS W. C., Jr, ASHWORTH C. T. Electron microscopic study of the intestinal mucosa in Whipple's disease. Demonstration of encapsulated bacilliform bodies in the lesion. Gastroenterology. 1961 Aug;41:129–138. [PubMed] [Google Scholar]
  11. Carter K. C. Koch's postulates in relation to the work of Jacob Henle and Edwin Klebs. Med Hist. 1985 Oct;29(4):353–374. doi: 10.1017/s0025727300044689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Chang Y., Cesarman E., Pessin M. S., Lee F., Culpepper J., Knowles D. M., Moore P. S. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994 Dec 16;266(5192):1865–1869. doi: 10.1126/science.7997879. [DOI] [PubMed] [Google Scholar]
  13. Chapman L. E., Khabbaz R. F. Etiology and epidemiology of the Four Corners hantavirus outbreak. Infect Agents Dis. 1994 Oct;3(5):234–244. [PubMed] [Google Scholar]
  14. Chellappan S., Kraus V. B., Kroger B., Munger K., Howley P. M., Phelps W. C., Nevins J. R. Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4549–4553. doi: 10.1073/pnas.89.10.4549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Chen K., Neimark H., Rumore P., Steinman C. R. Broad range DNA probes for detecting and amplifying eubacterial nucleic acids. FEMS Microbiol Lett. 1989 Jan 1;48(1):19–24. doi: 10.1016/0378-1097(89)90139-0. [DOI] [PubMed] [Google Scholar]
  16. Chen S. M., Dumler J. S., Bakken J. S., Walker D. H. Identification of a granulocytotropic Ehrlichia species as the etiologic agent of human disease. J Clin Microbiol. 1994 Mar;32(3):589–595. doi: 10.1128/jcm.32.3.589-595.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Chiodini R. J. Crohn's disease and the mycobacterioses: a review and comparison of two disease entities. Clin Microbiol Rev. 1989 Jan;2(1):90–117. doi: 10.1128/cmr.2.1.90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Choo Q. L., Kuo G., Weiner A. J., Overby L. R., Bradley D. W., Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989 Apr 21;244(4902):359–362. doi: 10.1126/science.2523562. [DOI] [PubMed] [Google Scholar]
  19. Craig E. A., Weissman J. S., Horwich A. L. Heat shock proteins and molecular chaperones: mediators of protein conformation and turnover in the cell. Cell. 1994 Aug 12;78(3):365–372. doi: 10.1016/0092-8674(94)90416-2. [DOI] [PubMed] [Google Scholar]
  20. Dawson J. E., Anderson B. E., Fishbein D. B., Sanchez J. L., Goldsmith C. S., Wilson K. H., Duntley C. W. Isolation and characterization of an Ehrlichia sp. from a patient diagnosed with human ehrlichiosis. J Clin Microbiol. 1991 Dec;29(12):2741–2745. doi: 10.1128/jcm.29.12.2741-2745.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Dell'Isola B., Poyart C., Goulet O., Mougenot J. F., Sadoun-Journo E., Brousse N., Schmitz J., Ricour C., Berche P. Detection of Mycobacterium paratuberculosis by polymerase chain reaction in children with Crohn's disease. J Infect Dis. 1994 Feb;169(2):449–451. doi: 10.1093/infdis/169.2.449. [DOI] [PubMed] [Google Scholar]
  22. Distel D. L., DeLong E. F., Waterbury J. B. Phylogenetic characterization and in situ localization of the bacterial symbiont of shipworms (Teredinidae: Bivalvia) by using 16S rRNA sequence analysis and oligodeoxynucleotide probe hybridization. Appl Environ Microbiol. 1991 Aug;57(8):2376–2382. doi: 10.1128/aem.57.8.2376-2382.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Dobbins W. O., 3rd, Kawanishi H. Bacillary characteristics in Whipple's disease: an electron microscopic study. Gastroenterology. 1981 Jun;80(6):1468–1475. [PubMed] [Google Scholar]
  24. Donham K. J., Thorne P. S. Agents in organic dust: criteria for a causal relationship. Am J Ind Med. 1994 Jan;25(1):33–39. doi: 10.1002/ajim.4700250109. [DOI] [PubMed] [Google Scholar]
  25. Duchin J. S., Koster F. T., Peters C. J., Simpson G. L., Tempest B., Zaki S. R., Ksiazek T. G., Rollin P. E., Nichol S., Umland E. T. Hantavirus pulmonary syndrome: a clinical description of 17 patients with a newly recognized disease. The Hantavirus Study Group. N Engl J Med. 1994 Apr 7;330(14):949–955. doi: 10.1056/NEJM199404073301401. [DOI] [PubMed] [Google Scholar]
  26. Edberg S. C. Principles of nucleic acid hybridization and comparison with monoclonal antibody technology for the diagnosis of infectious diseases. Yale J Biol Med. 1985 Sep-Oct;58(5):425–442. [PMC free article] [PubMed] [Google Scholar]
  27. Elliott L. H., Ksiazek T. G., Rollin P. E., Spiropoulou C. F., Morzunov S., Monroe M., Goldsmith C. S., Humphrey C. D., Zaki S. R., Krebs J. W. Isolation of the causative agent of hantavirus pulmonary syndrome. Am J Trop Med Hyg. 1994 Jul;51(1):102–108. doi: 10.4269/ajtmh.1994.51.102. [DOI] [PubMed] [Google Scholar]
  28. Evans A. S. Causation and disease: the Henle-Koch postulates revisited. Yale J Biol Med. 1976 May;49(2):175–195. [PMC free article] [PubMed] [Google Scholar]
  29. Evans A. S. Limitation of Koch's postulates. Lancet. 1977 Dec 17;2(8051):1277–1278. doi: 10.1016/s0140-6736(77)92677-0. [DOI] [PubMed] [Google Scholar]
  30. Everett E. D., Evans K. A., Henry R. B., McDonald G. Human ehrlichiosis in adults after tick exposure. Diagnosis using polymerase chain reaction. Ann Intern Med. 1994 May 1;120(9):730–735. doi: 10.7326/0003-4819-120-9-199405010-00002. [DOI] [PubMed] [Google Scholar]
  31. Falkow S. Molecular Koch's postulates applied to microbial pathogenicity. Rev Infect Dis. 1988 Jul-Aug;10 (Suppl 2):S274–S276. doi: 10.1093/cid/10.supplement_2.s274. [DOI] [PubMed] [Google Scholar]
  32. Farci P., Alter H. J., Wong D., Miller R. H., Shih J. W., Jett B., Purcell R. H. A long-term study of hepatitis C virus replication in non-A, non-B hepatitis. N Engl J Med. 1991 Jul 11;325(2):98–104. doi: 10.1056/NEJM199107113250205. [DOI] [PubMed] [Google Scholar]
  33. Fishbein D. B., Dawson J. E., Robinson L. E. Human ehrlichiosis in the United States, 1985 to 1990. Ann Intern Med. 1994 May 1;120(9):736–743. doi: 10.7326/0003-4819-120-9-199405010-00003. [DOI] [PubMed] [Google Scholar]
  34. Giovannoni S. J., Britschgi T. B., Moyer C. L., Field K. G. Genetic diversity in Sargasso Sea bacterioplankton. Nature. 1990 May 3;345(6270):60–63. doi: 10.1038/345060a0. [DOI] [PubMed] [Google Scholar]
  35. Giovannoni S. J., DeLong E. F., Olsen G. J., Pace N. R. Phylogenetic group-specific oligodeoxynucleotide probes for identification of single microbial cells. J Bacteriol. 1988 Feb;170(2):720–726. doi: 10.1128/jb.170.2.720-726.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Gold T. The deep, hot biosphere. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6045–6049. doi: 10.1073/pnas.89.13.6045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Gupta R. S., Golding G. B. Evolution of HSP70 gene and its implications regarding relationships between archaebacteria, eubacteria, and eukaryotes. J Mol Evol. 1993 Dec;37(6):573–582. doi: 10.1007/BF00182743. [DOI] [PubMed] [Google Scholar]
  38. HILL A. B. THE ENVIRONMENT AND DISEASE: ASSOCIATION OR CAUSATION? Proc R Soc Med. 1965 May;58:295–300. [PMC free article] [PubMed] [Google Scholar]
  39. HUEBNER R. J. Criteria for etiologic association of prevalent viruses with prevalent diseases; the virologist's dilemma. Ann N Y Acad Sci. 1957 Apr 19;67(8):430–438. doi: 10.1111/j.1749-6632.1957.tb46066.x. [DOI] [PubMed] [Google Scholar]
  40. Haase A. T., Retzel E. F., Staskus K. A. Amplification and detection of lentiviral DNA inside cells. Proc Natl Acad Sci U S A. 1990 Jul;87(13):4971–4975. doi: 10.1073/pnas.87.13.4971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Hackney J. D., Linn W. S. Koch's postulates updated: a potentially useful application to laboratory research and policy analysis in environmental toxicology. Am Rev Respir Dis. 1979 Jun;119(6):849–852. doi: 10.1164/arrd.1979.119.6.849. [DOI] [PubMed] [Google Scholar]
  42. Hall P. A., Lemoine N. R. Koch's postulates revisited. J Pathol. 1991 Aug;164(4):283–284. doi: 10.1002/path.1711640402. [DOI] [PubMed] [Google Scholar]
  43. Hanson R. P. Koch is dead. J Wildl Dis. 1988 Apr;24(2):193–200. doi: 10.7589/0090-3558-24.2.193. [DOI] [PubMed] [Google Scholar]
  44. Henle G., Henle W., Diehl V. Relation of Burkitt's tumor-associated herpes-ytpe virus to infectious mononucleosis. Proc Natl Acad Sci U S A. 1968 Jan;59(1):94–101. doi: 10.1073/pnas.59.1.94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Hjelle B., Spiropoulou C. F., Torrez-Martinez N., Morzunov S., Peters C. J., Nichol S. T. Detection of Muerto Canyon virus RNA in peripheral blood mononuclear cells from patients with hantavirus pulmonary syndrome. J Infect Dis. 1994 Oct;170(4):1013–1017. doi: 10.1093/infdis/170.4.1013. [DOI] [PubMed] [Google Scholar]
  46. Hughes M. S., Beck L. A., Skuce R. A. Identification and elimination of DNA sequences in Taq DNA polymerase. J Clin Microbiol. 1994 Aug;32(8):2007–2008. doi: 10.1128/jcm.32.8.2007-2008.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Johnson R. T., Gibbs C. J. Editorial: Koch's postulates and slow infections of the nervous system. Arch Neurol. 1974 Jan;30(1):36–38. doi: 10.1001/archneur.1974.00490310038006. [DOI] [PubMed] [Google Scholar]
  48. Kaneshima H., Su L., Bonyhadi M. L., Connor R. I., Ho D. D., McCune J. M. Rapid-high, syncytium-inducing isolates of human immunodeficiency virus type 1 induce cytopathicity in the human thymus of the SCID-hu mouse. J Virol. 1994 Dec;68(12):8188–8192. doi: 10.1128/jvi.68.12.8188-8192.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Koehler J. E., Quinn F. D., Berger T. G., LeBoit P. E., Tappero J. W. Isolation of Rochalimaea species from cutaneous and osseous lesions of bacillary angiomatosis. N Engl J Med. 1992 Dec 3;327(23):1625–1631. doi: 10.1056/NEJM199212033272303. [DOI] [PubMed] [Google Scholar]
  50. Krawczynski K., Beach M. J., Bradley D. W., Kuo G., di Bisceglie A. M., Houghton M., Reyes G. R., Kim J. P., Choo Q. L., Alter M. J. Hepatitis C virus antigen in hepatocytes: immunomorphologic detection and identification. Gastroenterology. 1992 Aug;103(2):622–629. doi: 10.1016/0016-5085(92)90856-t. [DOI] [PubMed] [Google Scholar]
  51. Kreider J. W., Howett M. K., Wolfe S. A., Bartlett G. L., Zaino R. J., Sedlacek T., Mortel R. Morphological transformation in vivo of human uterine cervix with papillomavirus from condylomata acuminata. Nature. 1985 Oct 17;317(6038):639–641. doi: 10.1038/317639a0. [DOI] [PubMed] [Google Scholar]
  52. Ksiazek T. G., Peters C. J., Rollin P. E., Zaki S., Nichol S., Spiropoulou C., Morzunov S., Feldmann H., Sanchez A., Khan A. S. Identification of a new North American hantavirus that causes acute pulmonary insufficiency. Am J Trop Med Hyg. 1995 Feb;52(2):117–123. doi: 10.4269/ajtmh.1995.52.117. [DOI] [PubMed] [Google Scholar]
  53. Kuo G., Choo Q. L., Alter H. J., Gitnick G. L., Redeker A. G., Purcell R. H., Miyamura T., Dienstag J. L., Alter M. J., Stevens C. E. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science. 1989 Apr 21;244(4902):362–364. doi: 10.1126/science.2496467. [DOI] [PubMed] [Google Scholar]
  54. Kwok S., Higuchi R. Avoiding false positives with PCR. Nature. 1989 May 18;339(6221):237–238. doi: 10.1038/339237a0. [DOI] [PubMed] [Google Scholar]
  55. Lakhani S. R. Early clinical pathologists: Robert Koch (1843-1910). J Clin Pathol. 1993 Jul;46(7):596–598. doi: 10.1136/jcp.46.7.596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Lane D. J., Pace B., Olsen G. J., Stahl D. A., Sogin M. L., Pace N. R. Rapid determination of 16S ribosomal RNA sequences for phylogenetic analyses. Proc Natl Acad Sci U S A. 1985 Oct;82(20):6955–6959. doi: 10.1073/pnas.82.20.6955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Liesack W., Stackebrandt E. Occurrence of novel groups of the domain Bacteria as revealed by analysis of genetic material isolated from an Australian terrestrial environment. J Bacteriol. 1992 Aug;174(15):5072–5078. doi: 10.1128/jb.174.15.5072-5078.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Lisitsyn N., Lisitsyn N., Wigler M. Cloning the differences between two complex genomes. Science. 1993 Feb 12;259(5097):946–951. doi: 10.1126/science.8438152. [DOI] [PubMed] [Google Scholar]
  59. Lucey D., Dolan M. J., Moss C. W., Garcia M., Hollis D. G., Wegner S., Morgan G., Almeida R., Leong D., Greisen K. S. Relapsing illness due to Rochalimaea henselae in immunocompetent hosts: implication for therapy and new epidemiological associations. Clin Infect Dis. 1992 Mar;14(3):683–688. doi: 10.1093/clinids/14.3.683. [DOI] [PubMed] [Google Scholar]
  60. Maeda K., Markowitz N., Hawley R. C., Ristic M., Cox D., McDade J. E. Human infection with Ehrlichia canis, a leukocytic rickettsia. N Engl J Med. 1987 Apr 2;316(14):853–856. doi: 10.1056/NEJM198704023161406. [DOI] [PubMed] [Google Scholar]
  61. Maiwald M., Meier-Willersen H. J., Hartmann M., von Herbay A. Detection of Tropheryma whippelii DNA in a patient with AIDS. J Clin Microbiol. 1995 May;33(5):1354–1356. doi: 10.1128/jcm.33.5.1354-1356.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Malawista S. E., Barthold S. W., Persing D. H. Fate of Borrelia burgdorferi DNA in tissues of infected mice after antibiotic treatment. J Infect Dis. 1994 Nov;170(5):1312–1316. doi: 10.1093/infdis/170.5.1312. [DOI] [PubMed] [Google Scholar]
  63. Marley J. E., McMichael A. J. Principles behind practice. 6. Disease causation. The role of epidemiological evidence. Med J Aust. 1991 Jul 15;155(2):95–101. [PubMed] [Google Scholar]
  64. McCune J. M., Namikawa R., Kaneshima H., Shultz L. D., Lieberman M., Weissman I. L. The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science. 1988 Sep 23;241(4873):1632–1639. doi: 10.1126/science.241.4873.1632. [DOI] [PubMed] [Google Scholar]
  65. Meier-Willersen H. J., Maiwald M., von Herbay A. Morbus Whipple in Assoziation mit opportunistischen Infektionen. Dtsch Med Wochenschr. 1993 Jun 11;118(23):854–860. doi: 10.1055/s-2008-1059397. [DOI] [PubMed] [Google Scholar]
  66. Moore P. S., Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and without HIV infection. N Engl J Med. 1995 May 4;332(18):1181–1185. doi: 10.1056/NEJM199505043321801. [DOI] [PubMed] [Google Scholar]
  67. Murray R. G., Schleifer K. H. Taxonomic notes: a proposal for recording the properties of putative taxa of procaryotes. Int J Syst Bacteriol. 1994 Jan;44(1):174–176. doi: 10.1099/00207713-44-1-174. [DOI] [PubMed] [Google Scholar]
  68. Muñoz N. Is Helicobacter pylori a cause of gastric cancer? An appraisal of the seroepidemiological evidence. Cancer Epidemiol Biomarkers Prev. 1994 Jul-Aug;3(5):445–451. [PubMed] [Google Scholar]
  69. Müller C., Stain C., Burghuber O. Tropheryma whippelii in peripheral blood mononuclear cells and cells of pleural effusion. Lancet. 1993 Mar 13;341(8846):701–701. doi: 10.1016/0140-6736(93)90475-v. [DOI] [PubMed] [Google Scholar]
  70. Nakatsuji Y., Matsumoto A., Tanaka E., Ogata H., Kiyosawa K. Detection of chronic hepatitis C virus infection by four diagnostic systems: first-generation and second-generation enzyme-linked immunosorbent assay, second-generation recombinant immunoblot assay and nested polymerase chain reaction analysis. Hepatology. 1992 Aug;16(2):300–305. doi: 10.1002/hep.1840160204. [DOI] [PubMed] [Google Scholar]
  71. Negro F., Pacchioni D., Shimizu Y., Miller R. H., Bussolati G., Purcell R. H., Bonino F. Detection of intrahepatic replication of hepatitis C virus RNA by in situ hybridization and comparison with histopathology. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2247–2251. doi: 10.1073/pnas.89.6.2247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Nichol S. T., Spiropoulou C. F., Morzunov S., Rollin P. E., Ksiazek T. G., Feldmann H., Sanchez A., Childs J., Zaki S., Peters C. J. Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness. Science. 1993 Nov 5;262(5135):914–917. doi: 10.1126/science.8235615. [DOI] [PubMed] [Google Scholar]
  73. Nocton J. J., Dressler F., Rutledge B. J., Rys P. N., Persing D. H., Steere A. C. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in synovial fluid from patients with Lyme arthritis. N Engl J Med. 1994 Jan 27;330(4):229–234. doi: 10.1056/NEJM199401273300401. [DOI] [PubMed] [Google Scholar]
  74. Olsen G. J., Woese C. R. Ribosomal RNA: a key to phylogeny. FASEB J. 1993 Jan;7(1):113–123. doi: 10.1096/fasebj.7.1.8422957. [DOI] [PubMed] [Google Scholar]
  75. Parsonnet J., Friedman G. D., Vandersteen D. P., Chang Y., Vogelman J. H., Orentreich N., Sibley R. K. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med. 1991 Oct 17;325(16):1127–1131. doi: 10.1056/NEJM199110173251603. [DOI] [PubMed] [Google Scholar]
  76. Parsonnet J. Helicobacter pylori and gastric cancer. Gastroenterol Clin North Am. 1993 Mar;22(1):89–104. [PubMed] [Google Scholar]
  77. Persing D. H., Rutledge B. J., Rys P. N., Podzorski D. S., Mitchell P. D., Reed K. D., Liu B., Fikrig E., Malawista S. E. Target imbalance: disparity of Borrelia burgdorferi genetic material in synovial fluid from Lyme arthritis patients. J Infect Dis. 1994 Mar;169(3):668–672. doi: 10.1093/infdis/169.3.668. [DOI] [PubMed] [Google Scholar]
  78. Rady P. L., Yen A., Rollefson J. L., Orengo I., Bruce S., Hughes T. K., Tyring S. K. Herpesvirus-like DNA sequences in non-Kaposi's sarcoma skin lesions of transplant patients. Lancet. 1995 May 27;345(8961):1339–1340. doi: 10.1016/s0140-6736(95)92538-4. [DOI] [PubMed] [Google Scholar]
  79. Rand K. H., Houck H. Taq polymerase contains bacterial DNA of unknown origin. Mol Cell Probes. 1990 Dec;4(6):445–450. doi: 10.1016/0890-8508(90)90003-i. [DOI] [PubMed] [Google Scholar]
  80. Reed J. A., Brigati D. J., Flynn S. D., McNutt N. S., Min K. W., Welch D. F., Slater L. N. Immunocytochemical identification of Rochalimaea henselae in bacillary (epithelioid) angiomatosis, parenchymal bacillary peliosis, and persistent fever with bacteremia. Am J Surg Pathol. 1992 Jul;16(7):650–657. doi: 10.1097/00000478-199207000-00003. [DOI] [PubMed] [Google Scholar]
  81. Relman D. A., Falkow S., LeBoit P. E., Perkocha L. A., Min K. W., Welch D. F., Slater L. N. The organism causing bacillary angiomatosis, peliosis hepatis, and fever and bacteremia in immunocompromised patients. N Engl J Med. 1991 May 23;324(21):1514–1514. doi: 10.1056/NEJM199105233242117. [DOI] [PubMed] [Google Scholar]
  82. Relman D. A., Loutit J. S., Schmidt T. M., Falkow S., Tompkins L. S. The agent of bacillary angiomatosis. An approach to the identification of uncultured pathogens. N Engl J Med. 1990 Dec 6;323(23):1573–1580. doi: 10.1056/NEJM199012063232301. [DOI] [PubMed] [Google Scholar]
  83. Relman D. A., Schmidt T. M., MacDermott R. P., Falkow S. Identification of the uncultured bacillus of Whipple's disease. N Engl J Med. 1992 Jul 30;327(5):293–301. doi: 10.1056/NEJM199207303270501. [DOI] [PubMed] [Google Scholar]
  84. Relman D. A. The identification of uncultured microbial pathogens. J Infect Dis. 1993 Jul;168(1):1–8. doi: 10.1093/infdis/168.1.1. [DOI] [PubMed] [Google Scholar]
  85. Rickman L. S., Freeman W. R., Green W. R., Feldman S. T., Sullivan J., Russack V., Relman D. A. Brief report: uveitis caused by Tropheryma whippelii (Whipple's bacillus) N Engl J Med. 1995 Feb 9;332(6):363–366. doi: 10.1056/NEJM199502093320604. [DOI] [PubMed] [Google Scholar]
  86. Rivers T. M. Viruses and Koch's Postulates. J Bacteriol. 1937 Jan;33(1):1–12. doi: 10.1128/jb.33.1.1-12.1937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Rowley A. H., Wolinsky S. M., Relman D. A., Sambol S. P., Sullivan J., Terai M., Shulman S. T. Search for highly conserved viral and bacterial nucleic acid sequences corresponding to an etiologic agent of Kawasaki disease. Pediatr Res. 1994 Nov;36(5):567–571. doi: 10.1203/00006450-199411000-00003. [DOI] [PubMed] [Google Scholar]
  88. Rys P. N., Persing D. H. Preventing false positives: quantitative evaluation of three protocols for inactivation of polymerase chain reaction amplification products. J Clin Microbiol. 1993 Sep;31(9):2356–2360. doi: 10.1128/jcm.31.9.2356-2360.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  90. Saiki R. K., Scharf S., Faloona F., Mullis K. B., Horn G. T., Erlich H. A., Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. doi: 10.1126/science.2999980. [DOI] [PubMed] [Google Scholar]
  91. Scheffner M., Romanczuk H., Münger K., Huibregtse J. M., Mietz J. A., Howley P. M. Functions of human papillomavirus proteins. Curr Top Microbiol Immunol. 1994;186:83–99. doi: 10.1007/978-3-642-78487-3_5. [DOI] [PubMed] [Google Scholar]
  92. Scheffner M., Werness B. A., Huibregtse J. M., Levine A. J., Howley P. M. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell. 1990 Dec 21;63(6):1129–1136. doi: 10.1016/0092-8674(90)90409-8. [DOI] [PubMed] [Google Scholar]
  93. Schmidt T. M., DeLong E. F., Pace N. R. Analysis of a marine picoplankton community by 16S rRNA gene cloning and sequencing. J Bacteriol. 1991 Jul;173(14):4371–4378. doi: 10.1128/jb.173.14.4371-4378.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Schmidt T. M., Pace B., Pace N. R. Detection of DNA contamination in Taq polymerase. Biotechniques. 1991 Aug;11(2):176–177. [PubMed] [Google Scholar]
  95. Schmidt T. M., Relman D. A. Phylogenetic identification of uncultured pathogens using ribosomal RNA sequences. Methods Enzymol. 1994;235:205–222. doi: 10.1016/0076-6879(94)35142-2. [DOI] [PubMed] [Google Scholar]
  96. Silva M. T., Macedo P. M., Moura Nunes J. F. Ultrastructure of bacilli and the bacillary origin of the macrophagic inclusions in Whipple's disease. J Gen Microbiol. 1985 May;131(5):1001–1013. doi: 10.1099/00221287-131-5-1001. [DOI] [PubMed] [Google Scholar]
  97. Slater L. N., Welch D. F., Hensel D., Coody D. W. A newly recognized fastidious gram-negative pathogen as a cause of fever and bacteremia. N Engl J Med. 1990 Dec 6;323(23):1587–1593. doi: 10.1056/NEJM199012063232303. [DOI] [PubMed] [Google Scholar]
  98. Stoler M. H., Broker T. R. In situ hybridization detection of human papillomavirus DNAs and messenger RNAs in genital condylomas and a cervical carcinoma. Hum Pathol. 1986 Dec;17(12):1250–1258. doi: 10.1016/s0046-8177(86)80569-x. [DOI] [PubMed] [Google Scholar]
  99. Stoler M. H. In situ hybridization. Clin Lab Med. 1990 Mar;10(1):215–236. [PubMed] [Google Scholar]
  100. TRIER J. S., PHELPS P. C., EIDELMAN S., RUBIN C. E. WHIPPLE'S DISEASE: LIGHT AND ELECTRON MICROSCOPE CORRELATION OF JEJUNAL MUCOSAL HISTOLOGY WITH ANTIBIOTIC TREATMENT AND CLINICAL STATUS. Gastroenterology. 1965 Jun;48:684–707. [PubMed] [Google Scholar]
  101. Ward D. M., Weller R., Bateson M. M. 16S rRNA sequences reveal numerous uncultured microorganisms in a natural community. Nature. 1990 May 3;345(6270):63–65. doi: 10.1038/345063a0. [DOI] [PubMed] [Google Scholar]
  102. Wilson K. H., Blitchington R. B., Greene R. C. Amplification of bacterial 16S ribosomal DNA with polymerase chain reaction. J Clin Microbiol. 1990 Sep;28(9):1942–1946. doi: 10.1128/jcm.28.9.1942-1946.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Wilson K. H., Blitchington R., Frothingham R., Wilson J. A. Phylogeny of the Whipple's-disease-associated bacterium. Lancet. 1991 Aug 24;338(8765):474–475. doi: 10.1016/0140-6736(91)90545-z. [DOI] [PubMed] [Google Scholar]
  104. Woese C. R. Bacterial evolution. Microbiol Rev. 1987 Jun;51(2):221–271. doi: 10.1128/mr.51.2.221-271.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. YARDLEY J. H., HENDRIX T. R. Combined electron and light microscopy in Whipple's disease. Demonstration of "bacillary bodies" in the intestine. Bull Johns Hopkins Hosp. 1961 Aug;109:80–98. [PubMed] [Google Scholar]
  106. Zaki S. R., Greer P. W., Coffield L. M., Goldsmith C. S., Nolte K. B., Foucar K., Feddersen R. M., Zumwalt R. E., Miller G. L., Khan A. S. Hantavirus pulmonary syndrome. Pathogenesis of an emerging infectious disease. Am J Pathol. 1995 Mar;146(3):552–579. [PMC free article] [PubMed] [Google Scholar]
  107. Zeitz P. S., Butler J. C., Cheek J. E., Samuel M. C., Childs J. E., Shands L. A., Turner R. E., Voorhees R. E., Sarisky J., Rollin P. E. A case-control study of hantavirus pulmonary syndrome during an outbreak in the southwestern United States. J Infect Dis. 1995 Apr;171(4):864–870. doi: 10.1093/infdis/171.4.864. [DOI] [PubMed] [Google Scholar]

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