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This article reviews the pathophysiology of the latent form of Mycobacterium tuberculosis along with its natural history and progression in infected tissues. The proposed hypotheses regarding the relationship between M tuberculosis and the associated immune response, the cause of granuloma necrosis, the tolerance of a certain concentration of the bacillus in host tissues, the constant turnover of cells in the lung, and the effect of chemotherapy form the basis for the design of the therapeutic vaccine RUTI against latent M tuberculosis infection. This vaccine is generated from detoxified M tuberculosis cell fragments that facilitate a balanced T helper (Th) 1/Th2/Th3 response to a wide range of antigens along with intense antibody production. Treatment with RUTI following chemotherapy has been demonstrated to be effective in experimental models in mice and guinea pigs and does not exhibit toxicity.
Key words:
Latent bacilli
Immunotherapy
Mycobacterium tuberculosis
Koch phenomenon
Foamy macrophages
Experimental models
Tolerance
Chemotherapy
Th1/Th2
En este artículo se revisan la fisiopatología de la forma la-tente de Mycobacterium tuberculosis, su naturaleza y su evo-lución en los tejidos infectados. Las hipótesis planteadas en-tre la relación de este bacilo con la respuesta inmunitaria generada, el origen de la necrosis intragranulomatosa, la to-lerancia hacia cierta concentración bacilar en los tejidos del hospedador, el constante recambio celular en los pulmona-res y el efecto inducido por el tratamiento quimioterápico permiten conocer las bases para el diseño de la vacuna terapéutica RUTI contra la infección latente por M. tuberculosis. Se trata de una vacuna generada a partir de fragmentos ce-lulares de M. tuberculosis biotransformados que permiten generar una respuesta equilibrada de tipo Th1/Th2/Th3 ante un amplio abanico de antígenos, además de una intensa producción de anticuerpos. El tratamiento con RUTI, posterior a la quimioterapia, ya ha demostrado su eficacia en mo-delos experimentales en ratones y cobayas, sin generar nin-guna respuesta tóxica.
Palabras clave:
Bacilos latentes
Inmunoterapia
Mycobacterium tuberculosis
Fenómeno de Koch
Macrófagos foamy
Modelos experimentales
Tolerancia
Quimioterapia
Th1/Th2
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REFERENCES
[1]
World Health Organization.
Global Tuberculosis Control: surveillance, planning, financing, WHO Report, (2004),
[2]
American Thoracic Society.
Targeted tuberculin testing and treatment of latent tuberculosis infection.
Am J Respir Crit Care Med, 161 (2000), pp. S221-SS47
[3]
Centers for Disease Control and Prevention.
Development of new vaccines for tuberculosis. Recommendations of the Advisory Council for the Elimination of Tuberculosis (ACET).
MMWR Recomm Rep, 47 (1998), pp. 1-6
[5]
CA Mason, T Egli.
Dynamics of microbial growth in the decelerating and stationary phase of batch culture.
Starvation in bacteria, pp. 81-102
[6]
R Hengge-Aronis.
The role of rpoS in early stationary-phase gene regulation in Escherichia coli K12.
Starvation in bacteria, pp. 171-200
[7]
ST Cole, R Brosch, J Parkhill, T Garnier, C Churcher, D Harris, et al.
Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence.
Nature, 393 (1998), pp. 537-544
[8]
PJ Brennan.
Structure, function, and biogenesis of the cell wall of Mycobacterium tuberculosis..
Tuberculosis (Edinb), 83 (2003), pp. 91-97
[9]
W Fox, GA Ellard, DA Mitchison.
Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946–1986, with relevant subsequent publications.
Int J Tuberc Lung Dis, 3 (1999), pp. S231-S279
[10]
DA Mitchison.
The action of antituberculosis drugs in short-course chemotherapy.
Tubercle, 66 (1985), pp. 219-225
[11]
HJ Corper, ML Cohn.
The viability and virulence of old cultures of tubercle bacilli: studies on twelve-year broth cultures maintained at incubator temperature.
Am Rev Tuberc, 28 (1933), pp. 856-874
[12]
G Canetti.
Exogenous reinfection: its relative impact with regard to development of pulmonary tuberculosis. A study of the pathology.
Tubercle, 31 (1950), pp. 224-233
[13]
EL Opie, JD Aronson.
Tubercle bacilli in latent tuberculous lesions and in lung tissue without tuberculous lesions.
Arch Pathol, 4 (1927), pp. 121
[14]
RM McCune, R Tompsett, W McDermott.
Fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. I. The persistence of drug susceptible bacilli in the tissues despite prolonged antimicrobial therapy.
J Exp Med, 104 (1956), pp. 737-762
[15]
AS Kaprelyants, JC Gottschal, DB Kell.
Dormancy in non-sporulating bacteria.
FEMS Microbiol Rev, 10 (1993), pp. 271-285
[16]
MO Shleeva, K Bagramyan, MV Telkov, GV Mukamolova, M Young, DB Kell, et al.
Formation and resuscitation of "non-culturable" cells of Rhodococcus rhodochrous and Mycobacterium tuberculosis in prolonged stationary phase.
Microbiology, 148 (2002), pp. 1581-1591
[17]
AL Koch.
Microbial physiology and ecology of slow growth.
Microbiol Mol Biol Rev, 61 (1997), pp. 305-318
[18]
LG Wayne.
Dormancy of Mycobacterium tuberculosis and latency of disease.
Eur J Clin Microbiol Infect Dis, 13 (1994), pp. 908-914
[19]
LG Wayne, KY Lin.
Glyoxylate metabolism and adaptation of Mycobacterium tuberculosis to survival under anaerobic conditions.
Infect Immun, 37 (1982), pp. 1042-1049
[20]
JD McKinney, ZU Honer, K Bentrup, EJ Muñoz-Elias, A Miczak, B Chen, et al.
Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase.
Nature, 406 (2000), pp. 735-738
[21]
IM Orme.
The latent tuberculosis bacillus (I'll let you know if I ever meet one).
Int J Tuberc Lung Dis, 5 (2001), pp. 589-593
[22]
RS Wallis, S Patil, SH Cheon, K Edmonds, M Phillips, MD Perkins, et al.
Drug tolerance in Mycobacterium tuberculosis..
Antimicrob Agents Chemother, 43 (1999), pp. 2600-2606
[23]
KH Mattman, KH Tunstall, WW Mathews, DL Gordon.
L variation in mycobacteria.
Am Rev Respir Dis, 82 (1960), pp. 202-211
[24]
LH Mattman.
Cell wall deficient forms. Stealth pathogens, CRC Press, (2001),
[25]
PJ Cardona, R Llatjós, S Gordillo, J Díaz, I Ojanguren, A Ariza, et al.
Evolution of granulomas in mice infected aerogenically with Mycobacterium tuberculosis..
Scan J Immunol, 52 (2000), pp. 156-163
[26]
PJ Cardona, V Ausina.
Histopatología de la tuberculosis. Aproximación a la evolución de las lesiones pulmonares en modelos de experimentación animal inducidos mediante aerosol.
Arch Bronconeumol, 36 (2000), pp. 645-650
[27]
GM Green.
Alveolobronchiolar transport mechanisms.
Arch Intern Med, 131 (1973), pp. 109-114
[28]
MJ Lefford.
Diseases in mice and rats.
The mycobacteria: a source book, pp. 947-977
[29]
PJ Cardona, S Gordillo, I Amat, J Díaz, J Lonca, C Vilaplana, et al.
Catalase-peroxidase activity has no influence on virulence in a murine model of tuberculosis.
Tuberculosis (Edinb), 83 (2003), pp. 351-359
[30]
PJ Cardona, A Cooper, M Luquin, A Ariza, F Filipo, IM Orme, et al.
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 (1999), pp. 362-366
[31]
PL Dunn, RJ North.
Virulence ranking of some Mycobacterium tuberculosis and Mycobacterium bovis strains according to their ability to multiply in the lungs, induce lung pathology, and cause mortality in mice.
Infect Immun, 63 (1995), pp. 3428-3437
[32]
P Andersen.
Host responses and antigens involved in protective immunity to Mycobacterium tuberculosis..
Scand J Immunol, 45 (1997), pp. 115-131
[33]
JM Grange.
Immunophysiology and immunopathology of tuberculosis.
Clinical tuberculosis, pp. 113-127
[34]
AM Dannenberg Jr.
Rabbit model of tuberculosis.
pp. 149-156
[35]
MB Lurie.
The correlation between the histological changes and the fate of living tubercle bacilli in the organs of tuberculous rabbits.
J Exp Med, 55 (1932), pp. 31-58
[37]
G Shwartzman.
Phenomenon of local tissue reactivity and its immunological, pathological and clinical significance, Paul B. Hober, (1937),
[38]
PJ Cardona, R Llatjós, S Gordillo, B Viñado, J Díaz, A Ariza, et al.
Towards a "human-like" model of tuberculosis: local inoculation of LPS in lungs of Mycobacterium tuberculosis aerogenically infected mice induces intragranulomatous necrosis.
Scand J Immunol, 53 (2001), pp. 65-71
[39]
AM Dannenberg Jr.
Delayed-type hypersensitivity and cell-mediated immunity in the pathogenesis of tuberculosis.
Immunol Today, 12 (1991), pp. 228-233
[40]
AM Cooper, DK Dalton, TA Stewart, JP Griffin, DG Russell, IM Orme.
Disseminated tuberculosis in interferon gamma gene-disrupted mice.
J Exp Med, 178 (1993), pp. 2243-2247
[41]
GW Comstock, LB Edwards, RN Philip, WA Winn.
A comparison in the United States of America of tuberculins PPD and RT23.
WHO Bull, 31 (1964), pp. 2-45
[42]
SL Baldwin, C d'Souza, AD Roberts, BP Kelly, AA Frank, MA Lui, et al.
Evaluation of new vaccines in the mouse and guinea pig model of tuberculosis.
Infect Immun, 66 (1998), pp. 2951-2959
[43]
AM Costello, A Kumar, V Narayan, MS Akbar, S Ahmed, C Abou-Zeid, et al.
Does antibody to mycobacterial antigens, including lipoarabinomannan, limit dissemination in childhood tuberculosis?.
Trans R Soc Trop Med Hyg, 86 (1992), pp. 686-692
[44]
C Sánchez-Rodríguez, C Estrada-Chávez, J García-Vigil, F Laredo-Sánchez, J Halabe-Cherem, A Pereira-Suárez, et al.
An IgG antibody response to the antigen 85 complex is associated with good outcome in Mexican Totonaca Indians with pulmonary tuberculosis.
[45]
GA Rook, R Hernández-Pando, K Dheda, G Teng Seah.
IL-4 in tuberculosis: implications for vaccine design.
Trends Immunol, 25 (2004), pp. 483-488
[46]
PRA Meylan, DD Richman, RS Konbluth.
Reduced intracellular growth of mycobacteria in human macrophages cultivated at physiologic oxygen pressure.
Am Rev Respir Dis, 145 (1992), pp. 947-953
[47]
MK Park, RA Myers, L Marzella.
Oxygen tensions and infections: modulation of microbial growth, activity of antimicrobial agents, and immunologic responses.
Clin Infect Dis, 14 (1992), pp. 720-740
[48]
R Pérez-Padilla, F Franco-Marina.
The impact of altitude on mortality from tuberculosis and pneumonia.
Int J Tuberc Lung Dis, 8 (2004), pp. 1315-1320
[49]
MH Vargas, ME Furuya, C Pérez-Guzmán.
Effect of altitude on the frequency of pulmonary tuberculosis.
Int J Tuberc Lung Dis, 8 (2004), pp. 1321-1324
[50]
KR Harmon, WA Marinelli, CA Henke, PB Bitterman.
Regulation of cell replication.
The lung: scientific foundations, pp. 105-129
[51]
P Seiler, T Ulrichs, S Bandermann, L Pradl, S Jorg, V Krenn, et al.
Cell-wall alterations as an attribute of Mycobacterium tuberculosis in latent infection.
J Infect Dis, 188 (2003), pp. 1326-1331
[52]
S Sturgill-Koszycki, PH Schlesinger, P Chakraborty, PL Haddix, HL Collins, AK Fok, et al.
Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase.
Science, 263 (1994), pp. 678-681
[53]
JG Wallace.
The heat resistance of tubercle bacilli in the lungs of infected mice.
Am Rev Respir Dis, 83 (1961), pp. 866-871
[54]
L Ramachandra, E Noss, WH Boom, CV Harding.
Processing of Mycobacterium tuberculosis antigen 85B involves intraphagosomal formation of peptide-major histocompatibility complex II complexes and is inhibited by live bacilli that decrease phagosome maturation.
J Exp Med, 194 (2001), pp. 1421-1432
[55]
E Moreno, J Pizarro-Cerdá.
Life and death of Brucella within cells.
Intracellular pathogens in membrane interactions and vacuole biogenesis, pp. 99-129
[56]
A Gross, A Terraza, S Ouahrani-Bettache, JP Liautard, J Dornand.
In vitro Brucella suis infection prevents the programmed cell death of human monocytic cells.
Infect Immun, 68 (2000), pp. 342-351
[57]
PJ Cardona, S Gordillo, J Díaz, G Tapia, I Amat, A Pallarés, et al.
Widespread bronchogenic dissemination makes DBA/2 mice more susceptible than C57BL/6 mice to experimental aerosol infection with Mycobacterium tuberculosis..
Infect Immun, 71 (2003), pp. 5845-5854
[58]
CA Scanga, VP Mohan, K Yu, H Joseph, K Tanaka, J Chan, JL Flynn.
Depletion of CD4(+) T cells causes reactivation of murine persistent tuberculosis despite continued expression of interferon gamma and nitric oxide synthase 2.
J Exp Med, 192 (2000), pp. 347-358
[59]
ER Rhoades, IM Orme.
Susceptibility of a panel of virulent strains of Mycobacterium tuberculosis to reactive nitrogen intermediates.
Infect Immun, 65 (1997), pp. 1189-1195
[60]
PA Stumbles, AS McWilliam, PG Holt.
Dendritic cells and mucosal macrophages.
Mucosal immunology, pp. 397-412
[61]
PJ Cardona, E Julián, X Vallés, S Gordillo, M Muñoz, M Luquin, et al.
Production of antibodies against glycolipids from the Mycobacterium tuberculosis cell wall in aerosol murine models of tuberculosis.
Scand J Immunol, 55 (2002), pp. 639-645
[62]
PJ Cardona, I Amat, S Gordillo, V Arcos, E Guirado, J Díaz, et al.
Immunotherapy with fragmented Mycobacterium tuberculosis cells increases the effectiveness of chemotherapy against a chronical infection in a murine model of tuberculosis.
Vaccine, 23 (2005), pp. 1393-1398
This work was supported by grants FIS 01/0644 and 01/3104 from the Spanish Ministry of Health, and by a grant from the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) 2003.
Copyright © 2006. Sociedad Española de Neumología y Cirugía Torácica (SEPAR)
