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Dormancy ofMycobacterium tuberculosis and latency of disease

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Abstract

There is ample circumstantial evidence from observation of the natural history of tuberculosis in humans and experimental animals thatMycobacterium tuberculosis is capable of adapting to prolonged periods of dormancy in tissues, and that these dormant bacilli are responsible for latency of the disease itself. Furthermore, the dormant bacilli are resistant to killing by antimycobacterial agents. A systematic evaluation of the mechanism of dormancy, and of attempts to abrogate latency will require a better understanding of the physiologic events that attend the shiftdown into dormancy. There are probably two or more stages in the shiftdown ofMycobacterium tuberculosis from active replication to dormancy as bacilli in unagitated cultures settle through a self-generated O2 gradient into a sediment where O2 is severely limited. One step involves a shift from rapid to slow replication. The other involves complete shutdown of replication, but not death. Presumably this last step includes completion of a round of DNA synthesis. The shiftup on resumption of aeration includes at least three discrete sequential steps, the production of RNA, the ensuing synchronized cell division and, finally, the initiation of a new round of synthesis of DNA. Three markers of the process of shiftdown ofMycobacterium tuberculosis to dormancy have been described, namely the changes in tolerance to anaerobiosis, the production of a unique antigen and the ten-fold increase in glycine dehydrogenase production. Additional markers represented in the shiftup and shiftdown process may yet be discovered, and determination of their specific functions should provide insights into the mechanisms of dormancy and latency in tuberculosis, and into strategies for preventing reactivation of the bacilli and development of disease.

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References

  1. Snider DE, Roper WL The new tuberculosis. New England Journal of Medicine 1992, 326: 703–705.

    PubMed  Google Scholar 

  2. Pearson ML, Jereb JA, Frieden TR, Crawford JT, Davis BJ, Dooley SW, Jarvis WR Nosocomial transmission of multidrug-resistantMycobacterium tuberculosis. A risk to patients and health care workers. Annals of Internal Medicine 1992, 117: 191–196.

    PubMed  Google Scholar 

  3. American Thoracic Society Control of tuberculosis in the United States. American Review of Respiratory Disease 1992, 146: 1623–1633.

    Google Scholar 

  4. Comstock GW, Edwards PQ The competing risks of tuberculosis and hepatitis for adult tuberculin reactors. American Review of Respiratory Disease 1975, 111: 573–577.

    PubMed  Google Scholar 

  5. Stead WW, Lofgren JP Does the risk of tuberculosis increase in old age? Journal of Infectious Diseases 1983, 147: 951–955.

    PubMed  Google Scholar 

  6. Stead WW, Dutt AK Tuberculosis in elderly persons. Annual Review of Medicine 1991, 42: 267–276.

    Article  PubMed  Google Scholar 

  7. Hobby GL Report of panel discussion on survival and revival of tubercle bacilli in healed tuberculous lesions. American Review of Tuberculosis 1957, 68: 477–495.

    Google Scholar 

  8. Auerbach O, Hobby GL, Small MJ, Lenert TF, Comer JV The clinicopathologic significance of the demonstration of viable tubercle bacilli in resected lesions. Journal of Thoracic Surgery 1955, 29: 109–132.

    PubMed  Google Scholar 

  9. Wayne LG, Salkin D The bacteriology of resected tuberculous pulmonary lesions. I: The effect of interval between reversal of infectiousness and subsequent surgery. American Review of Tuberculosis and Pulmonary Diseases 1956, 74: 376–387.

    Google Scholar 

  10. Wayne LG The bacteriology of resected tuberculous pulmonary lesions. II. Observations on bacilli which are stainable but which cannot be cultured. American Review of Respiratory Disease 1960, 82: 370–377.

    PubMed  Google Scholar 

  11. Jindani A, Aber VR, Edwards EA, Mitchison DA The early bactericidal activity of drugs in patients with pulmonary tuberculosis. American Review of Respiratory Disease 1980, 121: 939–949.

    PubMed  Google Scholar 

  12. Sever JL, Youmans GP Enumeration of viable tubercle bacilli from the organs of nonimmunized and immunized mice. American Review of Tuberculosis and Pulmonary Diseases 1957, 76: 616–635.

    Google Scholar 

  13. Orme IM A mouse model of the recrudescence of latent tuberculosis in the elderly. American Review of Respiratory Disease 1988, 137: 716–718.

    PubMed  Google Scholar 

  14. Grosset J, Truffot C, Fermanian J, Lecoeur H Activite sterilisante des differents antibiotiques dans la tuberculose experimentale de la souris. Pathologie et Biologie 1982, 30: 444–448.

    PubMed  Google Scholar 

  15. Grosset J, Truffot-Pernot C, Lecoeur H, Guelpa-Lauras CC Activite de la rifampicine administree quotiniennement et d'une maniere intermittente sur la tuberculose experimentale de la souris. Pathologie et Biologie. 1983, 31: 446–450.

    PubMed  Google Scholar 

  16. McCune RM, Lee SH, Deuschle K, McDermott W Ineffectiveness of isoniazid in modifying the phenomenon of microbial persistence. American Review of Tuberculosis and Pulmonary Diseases 1957, 76: 1106–1109.

    Google Scholar 

  17. McCune RM, Tompsett R, McDermott W The fate ofMycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. II: The conversion of tuberculosis infection to the latent state by the administration of pyrazinamide and a companion drug. Journal of Experimental Medicine 1956, 104: 763–802.

    Article  PubMed  Google Scholar 

  18. McCune RM, Tompsett R The fate ofMycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. I: The persistence of drug-susceptible tubercle bacilli in the tissues despite prolonged antimicrobial therapy. Journal of Experimental Medicine 1956, 104: 737–762.

    Article  PubMed  Google Scholar 

  19. North RJ, Izzo AA Mycobacterial virulence. Virulent strains ofMycobacterium tuberculosis have faster in vivo doubling times and are better equipped to resist growth growth-inhibiting functions of macrophages in the presence and absence of specific immunity. Journal of Experimental Medicine 1993, 177: 1723–1733.

    Article  PubMed  Google Scholar 

  20. Wayne LG Dynamics of submerged growth ofMycobacterium tuberculosis under aerobic and microaerophilic conditions. American Review of Respiratory Disease 1976, 114: 807–811.

    PubMed  Google Scholar 

  21. McCune RM, Tompsett R Fate ofMycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. I: The persistence of drug-susceptible tubercle bacilli in the tissues despite prolonged antimicrobial therapy. Journal of Experimental Medicine 1956, 104: 737–762.

    Article  PubMed  Google Scholar 

  22. Grosset J The sterilizing value of rifampicin and pyrazinamide in experimental short-course chemotherapy. Bulletin of the International Union against Tuberculosis 1978, 53: 5–12.

    PubMed  Google Scholar 

  23. Toyohara M Experimental study on the relapse of tuberculosis after the termination of antituberculous chemotherapy using immunodeficient nude mice. Microbiology and Immunology. 1991, 35: 825–830.

    PubMed  Google Scholar 

  24. Dannenberg AM Chemical and enzymatic host factors in resistance to tuberculosis. In: Kubica GP, Wayne LG (ed): The mycobacteria — a sourcebook, Marcel Dekker, New York, 1984, p. 721–760.

    Google Scholar 

  25. Segal W Growth dynamics of in vivo and in vitro grown mycobacterial pathogens. In: Kubica GP, Wayne LG (ed): The mycobacteria — a sourcebook. Marcel Dekker, New York 1984, p. 547–573.

    Google Scholar 

  26. Wayne LG, Diaz GA Autolysis and secondary growth ofMycobacterium tuberculosis in submerged culture. Journal of Bacteriology 1967, 93: 1374–1381.

    PubMed  Google Scholar 

  27. Fisher MW, Kirchheimer W Studies on the growth of mycobacteria. I: The occurrence of arithmetic linear growth. American Review of Tuberculosis 1952, 66: 758–761.

    PubMed  Google Scholar 

  28. Volk WA, Myrvik QN An explanation for the arithmetic linear growth of mycobacteria. Journal of Bacteriology 1953, 66: 386–388.

    PubMed  Google Scholar 

  29. Wayne LG, Lin KY Glyoxylate metabolism and adaptation ofMycobacterium tuberculosis to survival under anaerobic conditions. Infection and Immunity 1982, 37: 1042–1049.

    PubMed  Google Scholar 

  30. Wayne LG Synchronized replication ofMycobacterium tuberculosis. Infection and Immunity 1977, 17: 528–530.

    PubMed  Google Scholar 

  31. Wayne LG, Sramek HA Antigenic differences between extracts of actively replicating and synchronized resting cells ofMycobacterium tuberculosis. Infection and Immunity 1979, 24: 363–370.

    PubMed  Google Scholar 

  32. Goldman DS, Wagner MJ Enzyme systems in the mycobacteria. XIII: Glycine dehydrogenase and the glyoxylic acid cycle. Biochimica et Biophysica Acta 1962, 65: 297–306.

    Article  PubMed  Google Scholar 

  33. Hobby GL, Lenert TF The in vitro action of antituberculous agents against multiplying and nonmultiplying microbial cells. American Review of Tuberculosis and Pulmonary Diseases 1957, 76: 1031–1048.

    Google Scholar 

  34. Dickinson JM, Jackett PS, Mitchison DA The effect of pulse exposure to rifampin on the uptake of uridine-C14 byMycobacterium tuberculosis. American Review of Respiratory Disease 1972, 105: 519–527.

    PubMed  Google Scholar 

  35. Gangadharam PRJ, Pratt PF, Perumal VK, Iseman MD The effects of exposure time, drug concentration, and temperature on the activity of ethambutol versusMycobacterium tuberculosis. American Review of Respiratory Disease 1990, 141: 1478–1482.

    PubMed  Google Scholar 

  36. Dickinson JM, Mitchison DA Experimental models to explain the high sterilizing activity of rifampin in the chemotherapy of tuberculosis. American Review of Respiratory Disease 1981, 123: 367–371.

    PubMed  Google Scholar 

  37. Heifets L, Lindholm-Levy P Pyrazinamide sterilizing activity in vitro against semidormantMycobacterium tuberculosis bacterial populations. American Review of Respiratory Disease 1992, 145: 1223–1225.

    PubMed  Google Scholar 

  38. Kondo E, Kanai K An experimental model of chemotherapy on dormant tuberculous infection, with particular reference to rifampicin. Japanese Journal of Medical Science and Biology 1988, 41: 37–47.

    PubMed  Google Scholar 

  39. Comstock GW, Woolpert SF Preventive therapy. In: Kubica GP, Wayne LG (ed): The mycobacteria — a sourcebook. Marcel Dekker, New York, 1984, p. 1074–1075.

    Google Scholar 

  40. Wayne LG, Sramek HA Metronidazole is bactericidal to dormant cells ofMycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy 1994, 38: 2054–2058.

    PubMed  Google Scholar 

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Wayne, L.G. Dormancy ofMycobacterium tuberculosis and latency of disease. Eur. J. Clin. Microbiol. Infect. Dis. 13, 908–914 (1994). https://doi.org/10.1007/BF02111491

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