Chapter 36 : Animal Models of Tuberculosis

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Animal Models of Tuberculosis, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817657/9781555812959_Chap36-1.gif /docserver/preview/fulltext/10.1128/9781555817657/9781555812959_Chap36-2.gif


Testing of drugs or vaccines in animal models prior to studies in the human population are essential to avoid safety problems in the field. In this chapter, the mouse, guinea pig, rabbit, and nonhuman primate models are discussed. Each model has its strengths and weaknesses, and the choice of the most appropriate model for a study depends on a variety of factors, including cost, available housing, and the question being addressed. The mouse model provides an economical and easily manipulated tool with which to determine the role of specific host or bacterial components in the pathogenesis of tuberculosis. The development of a chronic infection is common to most mammals infected with . One important factor in using the aerosol model to assess the pathogenesis of is the use of bacterial cultures with high viability. Caseous necrosis in the form of small, spherical tubercles is a hallmark of human tuberculosis; indeed, it is the pathologic entity from which the disease derives its name. Nonhuman primates have been used in tuberculosis research for many decades, although cost and containment requirements have reduced the use of this model substantially in the last 30 years. The increasing sophistication of the animal models will lead the way to new findings of great importance in tuberculosis.

Citation: Flynn J, Cooper A, Bishai W. 2005. Animal Models of Tuberculosis, p 547-560. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch36

Key Concept Ranking

Tumor Necrosis Factor alpha
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1
Figure 1

Course of infection in mice. C57BL/6 mice were infected with ∼50 CFU of via an aerosolization chamber. At various times postinfection, the mice were euthanized and lung CFU were determined by plating homogenates on 7H10 plates. The acute phase lasts for up to 2 months postinfection, and the chronic phase begins after 3 months of infection. An arrow designates the time point where an interruption in the immune response could be experimentally performed to study reactivation of the infection.

Citation: Flynn J, Cooper A, Bishai W. 2005. Animal Models of Tuberculosis, p 547-560. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch36
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Adams, L. B.,, C. M. Mason,, J. K. Kolls,, D. Scollard,, J. L. Krahenbuhl,, and S. Nelson. 1995. Exacerbation of acute and chronic murine tuberculosis by adminstration of a tumor necrosis factor receptor-expressing adenovirus. J. Infect. Dis. 171: 400 405.
2. Allison, M. J.,, P. Zappasodi,, and M. B. Lurie. 1962. Hostparasite relationships in natively resistant and susceptible rabbits on quantitative inhalation of tubercle bacilli. Their significance for the nature of genetic resistance. Am. Rev. Respir. Dis. 85: 553 569.
3. Barclay, W. R.,, W. M. Busey,, D. W. Dalgard,, R. C. Good,, R. W. Janick,, J. E. Kasik,, E. Ribi,, C. E. Ulrich,, and E. Wolinsky. 1973. Protection of monkeys against airborne tuberculosis by aerosol vaccination with bacillus Calmette-Guérin. Am. Rev. Respir. Dis. 107: 351 358.
4. Bean, A. G. D.,, D. R. Roach,, H. Briscoe,, M. P. France,, H. Korner,, J. D. Sedgwick,, and W. J. Britton. 1999. Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin. J. Immunol. 162: 3504 3511.
5. Bishai, W. R.,, A. M. Dannenberg, Jr.,, N. Parrish,, R. Ruiz,, P. Chen,, B. C. Zook,, W. Johnson,, J. W. Boles,, and M. L. Pitt. 1999. Virulence of Mycobacterium tuberculosis CDC 1551 and H37Rv in rabbits evaluated by Lurie’s pulmonary tubercle count method. Infect. Immun. 67: 4931 4934.
6. Brandt, L.,, M. Elhay,, I. Rosenkrands,, E. B. Lindblad,, and P. Andersen. 2000. ESAT-6 subunit vaccination against Mycobacterium tuberculosis. Infect. Immun. 68: 791 795.
7. Capuano, S. V. I.,, D. A. Croix,, S. Pawar,, A. Zinovik,, A. Myers,, P. L. Lin,, S. Bissel,, C. Fuhrman,, E. Klein,, and J. L. Flynn. 2003. Experimental Mycobacterium tuberculosis infection of cynomolgus macaques closely resembles the various manifestations of human M. tuberculosis infection. Infect. Immun. 71: 5831 5844.
8. Cardona, P. J.,, A. Cooper,, M. Luquin,, A. Ariza,, F. Filipo,, I. M. Orme,, and V. Ausina. 1999. The intravenous model of murine tuberculosis is less pathogenic than the aerogenic model owing to a more rapid induction of systemic immunity. Scand J. Immunol. 49: 362 366.
9. Chan, J.,, K. Tanaka,, D. Carroll,, J. L. Flynn,, and B. R. Bloom. 1995. Effect of nitric oxide synthase inhibitors on murine infection with Mycobacterium tuberculosis. Infect. Immun. 63: 736 740.
10. Converse, P. J.,, A. M. Dannenberg,, J. E. Estep,, K. Sugisaki,, Y. Abe,, B. H. Schofield,, and M. L. M. Pitt. 1996. Cavitary tuberculosis produced in rabbits by aerosolized virulent tubercle bacilli. Infect. Immun. 64: 4776 4787.
11. Converse, P. J.,, A. M. Dannenberg,, T. Shigenaga,, D. N. McMurray,, S. W. Phalen,, J. L. Stanford,, G. A. W. Rook,, T. Koru-Sengul,, H. Abbey J. E. Estep, and M. L. M. Pitt. 1998. Pulmonary bovine-type tuberculosis in rabbits: bacillary virulence, inhaled dose effects, tuberculin sensitivity, and Mycobacterium vaccae immunotherapy. Clin. Diagn. Lab. Immunol. 5: 871 881.
12. Cooper, A. M.,, A. Kipnis,, J. Turner,, J. Magram,, J. Ferrante,, and I. M. Orme. 2002. Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present. J. Immunol. 168: 1322 1327.
13. Cooper, A. M.,, D. K. Dalton,, T. A. Stewart,, J. P. Griffen,, D. G. Russell,, and I. M. Orme. 1993. Disseminated tuberculosis in IFN-γ gene-disrupted mice. J. Exp. Med. 178: 2243 2248.
14. Cooper, A. M.,, J. Magram,, J. Ferrante,, and I. M. Orme. 1997. Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with Mycobacterium tuberculosis. J. Exp. Med. 186: 39 45.
15. Dai, G.,, S. Phalen,, and D. N. McMurray. 1998. Nutritional modulation of host responses to mycobacteria. Front Biosci. 3: E110 E122.
16. Dannenberg, A. M., Jr. 1993. Immunopathogenesis of pulmonary tuberculosis. Hosp. Pract. (Off. Ed.) 28: 51 58.
17. Dannenberg, A. M., Jr.,, and F. M. Collins. 2001. Progressive pulmonary tuberculosis is not due to increasing numbers of viable bacilli in rabbits, mice and guinea pigs, but is due to a continuous host response to mycobacterial products. Tuberculosis 81: 229 242.
18. Dannenberg, A. M.,, W. R. Bishai,, N. Parrish,, R. Ruiz,, W. Johnson,, B. C. Zook,, J. W. Boles,, and L. M. Pitt. 2001. Efficacies of BCG and vole bacillus ( Mycobacterium microti) vaccines in preventing clinically apparent pulmonary tuberculosis in rabbits: a preliminary report. Vaccine 19: 796 800.
19. Dannenberg, A. M. J. 2001. Pathogenesis of pulmonary Mycobacterium bovis infection: basic principles established by the rabbit model. Tuberculosis 81: 87 96.
20. D’Souza, C. D.,, A. M. Cooper,, A. A. Frank,, S. Ehlers,, J. Turner,, A. Bendelac,, and I. M. Orme. 2000. A novel nonclassic beta2-microglobulin-restricted mechanism influencing early lymphocyte accumulation and subsequent resistance to tuberculosis in the lung. Am. J. Respir. Cell Mol. Biol. 23: 188 193.
21. D’Souza, S.,, V. Rosseels,, M. Romano,, A. Tanghe,, O. Denis,, F. Jurion,, N. Castiglione,, A. Vanonckelen,, K. Palfliet,, and K. Huygen. 2003. Mapping of murine Th1 helper T-cell epitopes of mycolyl transferases Ag85A, Ag85B, and Ag85C from Mycobacterium tuberculosis. Infect. Immun. 71: 483 493.
22. Dudani, R.,, Y. Chapdelaine,, H. van Faassen,, D. K. Smith,, H. Shen,, L. Krishnan,, and S. Sad. 2002. Multiple mechanisms compensate to enhance tumor-protective CD8 + T-cell response in the long-term despite poor CD8 + T-cell priming initially: comparison between an acute versus a chronic intracellular bacterium expressing a model antigen. J. Immunol. 168: 5737 5745.
23. Flynn, J. L.,, and J. Chan. 2001. Tuberculosis: latency and reactivation. Infect. Immun. 69: 4195 4201.
24. Flynn, J. L.,, J. Chan,, K. J. Triebold,, D. K. Dalton,, T. A. Stewart,, and B. R. Bloom. 1993. An essential role for interferon-γ in resistance to Mycobacterium tuberculosis infection. J. Exp. Med. 178: 2249 2254.
25. Flynn, J. L.,, M. M. Goldstein,, J. Chan,, K. J. Triebold,, K. Pfeffer,, C. J. Lowenstein,, R. Schreiber,, T. W. Mak,, and B. R. Bloom. 1995. Tumor necrosis factor-α is required in the protective immune response against M. tuberculosis in mice. Immunity 2: 561 572.
26. Flynn, J. L.,, M. M. Goldstein,, K. J. Triebold,, B. Koller,, and B. R. Bloom. 1992. Major histocompatibility complex class I-restricted T cells are required for resistance to Mycobacterium tuberculosis infection. Proc. Natl. Acad. Sci. USA 89: 12013 12017.
27. Francis, J. 1956. Natural and experimental tuberculosis in monkeys with observations on immunization and chemotherapy. J. Comp. Pathol. 66: 123 135.
28. Francis, J. 1958. Tuberculosis in Animals and Man: a Study in Comparative Pathology. Cassell & Co., Ltd., London, United Kingdom.
29. Glickman, M. S.,, J. S. Cox,, and W. R. Jacobs, Jr. 2000. A novel mycolic acid cyclopropane synthetase is required for cording, persistence, and virulence of Mycobacterium tuberculosis. Mol. Cell 5: 717 727.
30. Gonzalez-Juarrero, M.,, O. C. Turner,, J. Turner,, P. Marietta,, J. V. Brooks,, and I. M. Orme. 2001. Temporal and spatial arrangement of lymphocytes within lung granulomas induced by aerosol infection with Mycobacterium tuberculosis. Infect. Immun. 69: 1722 1728.
31. Havlir, D. V.,, and P. F. Barnes. 1999. Tuberculosis in patients with human immunodeficiency virus infection. N. Engl. J. Med. 340: 367 373.
32. Hickman, S. P.,, J. Chan,, and P. Salgame. 2002. Mycobacterium tuberculosis induces differential cytokine production from dendritic cells and macrophages with divergent effects on naive T-cell polarization. J. Immunol. 168: 4636 4642.
33. Ho, R.,, J. S. Fok,, G. E. Harding,, and D. W. Smith. 1978. Host-parasite relationships in experimental airborne tuberculosis. VII. Fate of Mycobacterium tuberculosis in primary lung lesions and in primary lesion-free lung tissue infected as a result of bacillemia. J. Infect. Dis. 138: 237 241.
34. Huygen, K.,, E. Lozes,, B. Gilles,, A. Drowart,, K. Palfliet,, F. Jurion,, I. Roland,, M. Art,, M. Dufaux,, J. Nyabenda,, J. De Bruyn,, J. P. van Vooren,, and R. D. Lays. 1994. Mapping of TH1 helper T-cell epitopes on major secreted mycobacterial antigen 85A in mice infected with live Mycobacterium bovis BCG. Infect. Immun. 62: 363 370.
35. Jeevan, A.,, T. Yoshimura,, G. Foster,, and D. N. McMurray. 2002. Effect of Mycobacterium bovis BCG vaccination on interleukin-1β and RANTES mRNA expression in guinea pig cells exposed to attenuated and virulent mycobacteria. Infect. Immun. 70: 1245 1253.
36. Kaushal, D.,, B. G. Schroeder,, S. Tyagi,, T. Yoshimatsu,, C. Scott,, C. Ko,, L. Carpenter,, J. Mehrotra,, Y. C. Manabe,, R. D. Fleischmann,, and W. R. Bishai. 2002. Reduced immunopathology and mortality despite tissue persistence in a Mycobacterium tuberculosis mutant lacking alternative sigma factor, SigH. Proc. Natl. Acad. Sci. USA 99: 8330 8335.
37. Keane, J.,, S. Gershon,, R. P. Wise,, E. Mirabile-Levens,, J. Kasznica,, W. D. Schwieterman,, J. N. Siegel,, and M. M. Braun. 2001. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N. Engl. J. Med. 345: 1098 1104.
38. Koch, R. 1882. Aetiologie der Tuberculose. Berl. Klin. Wochenschr. 19: 221 230.
39. Koch, R. 1932. Die Aetiologie der Tuberculose. Translation by Berna Pinner and Max Pinner with an introduction by Allen K. Krause. Am. Rev. Tuberc. 25: 285 323.
40. Ladel, C. H.,, C. Blum,, A. Dreher,, K. Reifenberg,, M. Kopf,, and S. H. E. Kaufmann. 1997. Lethal tuberculosis in interleukin-6-deficient mutant mice. Infect. Immun. 65: 4843 4849.
41. Lammas, D. A.,, J. L. Casanova,, and D. S. Kumararatne. 2000. Clinical consequences of defects in the IL-12-dependent interferon-gamma (IFN-gamma) pathway. Clin. Exp. Immunol. 121: 417 425.
42. Langermans, J. A. M.,, P. Andersen,, D. van Soolingen,, R. A. W. Vervenne,, P. A. Frost,, T. van der Laan,, L. A. H. van Pinsteren,, J. van den Hombergh,, S. Kroom,, I. Peekel,, S. Florquin,, and A. W. Thomas. 2001. Divergent effect of bacillus Calmette-Guérin (BCG) vaccination on Mycobacterium tuberculosis infection in highly related macaque species: implications for primate models in tuberculosis vaccine research. Proc. Natl. Acad. Sci. USA 98: 11497 11502.
43. Lazarevic, V.,, and J. Flynn. 2002. CD8+ T cells in tuberculosis. Am. J. Respir. Crit. Care Med. 166: 1116 1121.
44. Lazarevic, V.,, A. J. Myers,, C. A. Scanga,, and J. L. Flynn. 2003. CD40, but not CD40L, is required for the optimal priming of T cells and control of aerosol M. tuberculosis infection. Immunity 19: 823 835.
45. Lenaerts, A. J.,, V. Gruppo,, J. V. Brooks,, and I. M. Orme. 2003. Rapid in vivo screening of experimental drugs for tuberculosis using gamma interferon gene-disrupted mice. Antimicrob. Agents Chemother. 47: 783 785.
46. Lowrie, D. B.,, R. E. Tascon,, V. L. D. Bonato,, V. M. F. Lima,, L. H. Faccioli,, E. Stavropoulos,, M. J. Colston,, R. G. Hewinson,, K. Moelling,, and C. L. Silva. 1999. Therapy of tuberculosis in mice by DNA vaccination. Nature 400: 269 271.
47. Lurie, M. B. 1932. The correlation between the histological changes and the fate of living tubercule bacilli in the organs of tuberculous rabbits. J. Exp. Med. 55: 31.
48. Lurie, M. B. 1964. Resistance to Tuberculosis: Experimental Studies in Native and Acquired Defense Mechanisms. Harvard University Press, Cambridge, Mass.
49. Lurie, M. B.,, P. Zappasodi,, E. Cardona-Lynch,, and A. M. J. Danneberg. 1952. The response of intracutaneous inoculation of BCG as an index of native resistance to tuberculosis. J. Immunol. 68: 369 387.
50. Lurie, M. B.,, P. Zappasodi,, A. M. J. Danneberg,, and E. Cardona-Lynch. 1953. The effect of cortisone and ACTH on the pathogenesis of tuberculosis. Ann. N.Y. Acad. Sci. 56: 779.
51. Lurie, M. B.,, P. Zappasodi,, A. M. Dannenberg, Jr.,, and G. H. Weiss. 1952. On the mechanism of genetic resistance to tuberculosis and its mode of inheritance. Am. J. Hum. Genet. 4: 302 314.
52. Lurie, M. B.,, P. Zappasodi,, and C. Tickner. 1955. On the nature of genetic resistance to tuberculosis in the light of the host-parasite relationships in natively resistant and susceptible rabbits. Am. Rev. Tuberc. 72: 297 329.
53. Mackaness, G. B. 1968. The immunology of antituberculous immunity. Am. Rev. Respir. Dis. 97: 337 344.
54. MacMicking, J.,, R. J. North,, R. LaCourse,, J. S. Mudgett,, S. K. Shah,, and C. F. Nathan. 1997. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc. Natl. Acad. Sci. USA 94: 5243 5248.
55. McCune, R. M.,, F. M. Feldman,, and W. McDermott. 1966. Microbial persistence. II. Characteristics of the sterile state of tubercle bacilli. J. Exp. Med. 123: 469 486.
56. McCune, R. M.,, F. M. Feldmann,, H. P. Lambert,, and W. McDermott. 1966. Microbial persistence I. The capacity of tubercle bacilli to survive sterilization in mouse tissues. J. Exp. Med. 123: 445 468.
57. McCune, R. M.,, R. Tompsett,, and W. McDermott. 1957. The fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. II. The conversion of tuberculous infection to the latent state by the administration of pyrazinamide and a companion drug. J. Exp. Med. 104: 763 802.
58. McKinney, J. D.,, K. Honer zu Bentrup,, A. Miczak,, B. Chen,, W.-T. Chan,, D. Swenson,, J. C. Sacchettini,, W. R. Jacobs, Jr.,, and D. G. Russell. 2000. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 406: 735 738.
59. McMurray, D. 2001. Disease model: pulmonary tuberculosis. Trends Mol. Med. 7: 135 137.
60. McMurray, D. N., 1994. Guinea pig model of tuberculosis, p. 135 147. In B. R. Bloom (ed.), Tuberculosis: Pathogenesis, Protection, and Control. American Society for Microbiology, Washington, D.C.
61. Middlebrook, G. 1952. An apparatus for airborne infection of mice. Proc. Soc. Exp. Biol. Med. 80: 105 110.
62. Mogues, T.,, M. E. Goodrich,, L. Ryan,, R. LaCourse,, and R. J. North. 2001. The relative importance of T-cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice. J. Exp. Med. 193: 271 280.
63. Moreira, A. L.,, L. Tsenova,, M. H. Aman,, L. G. Bekker,, S. Freeman,, B. Mangaliso,, U. Schroder,, J. Jagirdar,, W. N. Rom,, M. G. Tovey,, V. H. Freedman,, and G. Kaplan. 2002. Mycobacterial antigens exacerbate disease manifestations in Mycobacterium tuberculosis-infected mice. Infect. Immun. 70: 2100 2107.
64. North, R. J. 1973. Importance of thymus-derived lymphocytes in cell-mediated immunity to infection. Cell. Immunol. 7: 166 176.
65. Opie, E.,, and J. Aronson. 1927. Tubercle bacilli in latent tuberculous lesions and in lung tissue without tuberculous lesions. Arch. Pathol. 4: 1 21.
66. Orme, I. 1987. The kinetics of emergence and loss of mediator T lymphocytes acquired in response to infection with Mycobacterium tuberculosis. J. Immunol. 138: 293 298.
67. Orme, I. M. 1988. A mouse model of the recrudescence of latent tuberculosis in the elderly. Am. Rev. Respir. Dis. 137: 716 718.
68. Orme, I. M.,, D. N. McMurray,, and J. T. Belisle. 2001. Tuberculosis vaccine development: recent progress. Trends Microbiol. 9: 115 118.
69. Ottenhof, T. H.,, D. Kumararatne,, and J. L. Casanova. 1998. Novel human immunodeficiencies reveal the essential role of type-1 cytokines in immunity to intracellular bacteria. Immunol. Today 19: 491 494.
70. Palendira, U.,, A. G. Bean,, C. G. Feng,, and W. J. Britton. 2002. Lymphocyte recruitment and protective efficacy against pulmonary mycobacterial infection are independent of the route of prior Mycobacterium bovis BCG immunization. Infect. Immun. 70: 1410 1416.
71. Peters, W.,, H. M. Scott,, H. F. Chambers,, J. L. Flynn,, I. F. Charo,, and J. D. Ernst. 2001. Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA 98: 7958 7963.
72. Ratcliffe, H. L.,, and V. S. Palladino. 1953. Tuberculosis induced by droplet nuclei infection: initial homogeneous response of small mammals (rats, mice, guinea pigs, and hamsters) to human and to bovine bacilli, and the rate and pattern of tubercle development. J. Exp. Med. 97: 61 68.
73. Ratcliffe, H. L.,, and W. F. Wells. 1948. Tuberculosis of rabbits induced by droplet nuclei infection. J. Exp. Med. 87: 575 584.
74. Raviglione, M. C.,, D. E. Snider,, and A. Kochi. 1995. Global epidemiology of tuberculosis: morbidity and mortality of a global epidemic. JAMA 273: 220 226.
75. Rha, Y. H.,, C. Taube,, A. Haczku,, A. Joetham,, K. Takeda,, C. Duez,, M. Siegel,, M. K. Aydintug,, W. K. Born,, A. Dakhama,, and E. W. Gelfand. 2002. Effect of microbial heat shock proteins on airway inflammation and hyperresponsiveness. J. Immunol. 169: 5300 5307.
76. Rhoades, E. R.,, A. A. Frank,, and I. M. Orme. 1997. Progression of chronic pulmonary tuberculosis in mice aerogenically infected with virulent Mycobacterium tuberculosis. Tubercle Lung Dis. 78: 57 66.
77. Riley, R. L.,, C. C. Mills,, F. O’Grady,, L. U. Sultan,, F. Willstadt,, and D. N. Shivpuri. 1962. Infectiousness of air from a tuberculosis ward. Am. Rev. Respir. Dis. 85: 511 525.
78. Roberts, A. R.,, A. M. Cooper,, J. T. Belisle,, J. Turner,, M. Gonzalez-Juarrero,, and I. M. Orme. 2002. Murine models of tuberculosis. Methods Microbiol. 32: 433 462.
79. Safi, H.,, B. J. Gormus,, P. J. Didier,, J. L. Blanchard,, D. L. Lakey,, L. N. Martin,, M. Murphey-Corb,, R. Vankayalapati,, and P. F. Barnes. 2003. Spectrum of manifestations of Mycobacterium tuberculosis infection in primates infected with SIV. AIDS Res. Hum. Retroviruses 19: 585 595.
80. Saunders, B. M.,, A. A. Frank,, I. M. Orme,, and A. M. Cooper. 2000. Interleukin-6 induces early gama interferon production in the infected lung but is not required for generation of specific immunity to Mycobacterium tuberculosis infection. Infect. Immun. 68: 3322 3326.
81. Scanga, C. A.,, V. P. Mohan,, H. Joseph,, K. Yu,, J. Chan,, and J. L. Flynn. 1999. Reactivation of latent tuberculosis: variations on the Cornell murine model. Infect. Immun. 67: 4531 4538.
82. Schmidt, L. H. 1955. Induced pulmonary tuberculosis in the rhesus monkey: its usefulness in evaluating chemotherapeutic agents. Trans. Conf. Chemother. Tuberc. 14: 226 231.
83. Schmidt, L. H. 1956. Some observations on the utility of simian tuberculosis in defining thetherapeutic potentialities of isoniazid. Annu. Rev. Tuberc. Pulm. Dis. 74: 138 153.
84. Schmidt, L. H. 1966. Studies on the antituberculous activity of ethambutol in monkeys. Ann. N.Y. Acad. Sci. 135: 747 758.
85. Scott, H. M.,, and J. L. Flynn. 2002. Mycobacterium tuberculosis in chemokine receptor 2-deficient mice: influence of dose on disease progression. Infect. Immun. 70: 5946 5954.
86. Shen, Y.,, D. Zhou,, L. Qiu,, X. Lai,, M. Simon,, L. Shen,, Z. Kou,, Q. Wang,, L. Jiang,, J. Estep,, R. Hunt,, M. Clagett,, P. K. Sehgal,, Y. Li,, X. Zeng,, C. T. Morita,, M. B. Brenner,, N. L. Letvin,, and Z. W. Chen. 2002. Adaptive immune response of Vγ2Vδ2 + T cells during mycobacterial infections. Science 295: 2255 2258.
87. Shi, L.,, Y. J. Jung,, S. Tyagi,, M. L. Gennaro,, and R. J. North. 2003. Expression of Th1-mediated immunity in mouse lungs induces a Mycobacterium tuberculosis transcription pattern characteristic of nonreplicating persistence. Proc. Natl. Acad. Sci. USA 100: 241 246.
88. Smith, D. W.,, V. Balasubramanian,, and E. Wiegeshaus. 1991. A guinea pig model of experimental airborne tuberculosis for evaluation of the response to chemotherapy: the effect on bacilli in the initial phase of treatment. Tubercle 72: 223 231.
89. Smith, D. W.,, D. N. McMurray,, E. H. Wiegeshaus,, A. A. Grover,, G. E. Harding. 1970. Host-parasite relationships in experimental airborne tuberculosis. IV. Early events in the course of infection in vaccinated and nonvaccinated guinea pigs. Am. Rev. Respir. Dis. 102: 937 949.
90. Steenken, W., Jr.,, E. Wolinsky,, P. S. Pratt,, and W. J. Costigan. 1953. Effect of antibacterial agents on chronic pulmonary tuberculosis in rabbits: a roentgenographic, pathologic, and bacteriologic study. Trans. Annu. Meet. Natl. Tuberc. Assoc. 49: 218 220.
91. Stenger, S.,, D. A. Hanson,, R. Teitelbaum,, P. Dewan,, K. R. Niazi,, C. J. Froelich,, T. Ganz,, S. Thoma-Uszynski,, A. Melian,, C. Bogdan,, S. A. Porcelli,, B. R. Bloom,, A. M. Krensky,, and R. L. Modlin. 1998. An antimicrobial activity of cytolytic T cells mediated by granulysin. Science 282: 121 125.
92. Takeda, K.,, and K. Shinpo. 1942. On the meaning of the allergic tissue reaction as regards the development of pulmonary tuberculosis. Kekkaku 20: 208 221, 275 290, 472 489.
93. Tsenova, L.,, A. Bergtold,, V. H. Freedman,, R. A. Young,, and G. Kaplan. 1999. Tumor necrosis factor alpha is a determinant of pathogenesis and disease progression in mycobacterial infection in the central nervous system. Proc. Natl. Acad. Sci. USA 96: 5657 5662.
94. Tsenova, L.,, K. Sokol,, V. H. Freedman,, and G. Kaplan. 1998. A combination of thalidomide plus antibiotics protects rabbits from mycobacterial meningitis-associated death. J. Infect. Dis. 177: 1563 1572.
95. Tsenova, L.,, B. Mangaliso,, G. Muller,, Y. Chen,, V. H. Freedman,, D. Stirling,, and G. Kaplan. 2002. Use of IMiD3, a thalidomide analog, as an adjunct to therapy for experimental tuberculous meningitis. Antimicrob. Agents Chemother. 46: 1887 1895.
96. Tufariello, J. M.,, J. Chan,, and J. L. Flynn. 2003. Latent tuberculosis: mechanisms of host and bacillus that contribute to persistent infection. Lancet Infect. Dis. 3: 578 590.
97. Turner, J.,, C. D. D’Souza,, J. E. Pearl,, P. Marietta,, M. Noel,, A. A. Frank,, R. Appelberg,, I. M. Orme,, and A. M. Cooper. 2001. CD8- and CD95/95L-dependent mechanisms of resistance in mice with chronic pulmonary tuberculosis. Am. J. Respir. Cell Mol. Biol. 24: 203 209.
98. Walsh, G. P.,, E. V. Tan,, E. C. de la Cruz,, R. M. Abalos,, L. G. Villhermonsa,, L. J. Young,, R. V. Cellona,, J. B. Nazareno,, and M. A. Horwitz. 1996. The Philippine cynomolgus monkey ( Macaca fascularis) provides a new nonhuman primate model of tuberculosis that resembles human disease. Nat. Med. 2: 430 436.
99. Wells, W.,, and M. B. Lurie. 1941. Experimental airborne disease: quantitative natural respiratory contagion of tuberculosis. Am. J. Hyg. 34: 21.
100. Wiegeshaus, E.,, D. N. McMurray,, A. A. Grover,, G. E. Harding,, and D. W. Smith. 1970. Host-parasite relationships in experimental airborne tuberculosis. III. Relevance of microbial enumeration to acquired resistance in guinea pigs. Annu. Rev. Respir. Dis. 102: 422 429.
101. Winslow, G. M.,, A. D. Roberts,, M. A. Blackman,, and D. L. Woodland. 2003. Persistence and turnover of antigen-specific CD4 T cells during chronic tuberculosis infection in the mouse. J. Immunol. 170: 2046 2052.
102. Wolf, R. H.,, S. V. Gibson,, E. A. Watson,, and G. B. Baskin. 1988. Multidrug chemotherapy of tuberculosis in rhesus monkeys. Lab. Anim. Sci. 38: 25 33.
103. Yamamura, Y. 1958. The pathogenesis of tuberculous cavities. Adv. Tuberc. Res. 9: 13 37.
104. Yamamura, Y.,, Y. Ogawa,, and H. Yamagata. 1968. Prevention of tuberculous cavity formation by immunosuppressive drugs. Am. Rev. Respir. Dis. 98: 720 723.
105. Yamamura, Y.,, S. Yasaka,, M. Yamaguchi,, K. Endo,, H. Iwakura,, S. Nakamura,, and Y. Ogawa. 1954. Studies of the experimental tuberculosis cavity: the experimental formation of the tuberculous cavity in the rabbit lung. Med. J. Osaka Univ. 5: 187 197.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error