Article information
Abstract
Confrontation between invading microbial pathogens and host defense systems involves intricate cellular and molecular interactions. Here we discuss the virulence factors as trumps, overriding the contest in favor of the tubercle bacillus (Mycobacterium tuberculosis). It evolved a number of molecular constituents, which can interfere with antigen presentation and Toll receptor function, thus impairing immune defenses. It also evolved stress responses, which can drive its cell cycle into a non-replicating, low metabolic mode. Although the low counts of latent bacilli prevent their direct detection, we contend that they retain a capacity to survive for long periods in foamy macrophages and within the necrotic parts of lung granulomas. We attributed significance to drainage of M. tuberculosis by the alveolar fluid: while out-flow is responsible for the clearance, the reverse-flow has an important capacity to re-infect the lungs and to transmit the infection to new recipients. We consider the cycling between replicating and latent organisms to be a continuous process, which is a departure from the concept of long-lived dormant organisms, with a capacity to resuscitate. These aspects impinge also on the actions of isoniazid (INH) chemotherapy and on the topography of human lung lesions. Eventually, fibrosis of the connective tissue of the lungs is known to encapsulate lung lesions, thus limiting the impact of both outward and reverse drainage. In conclusion, the novelty of our views on M. tuberculosis-host interactions rests in the dynamic perception of M. tuberculosis latency and its evolutionary importance for the pathogenesis of tuberculosis.
Keywords:
Tuberculosis
Immunology
Pathogenesis
Bacterial latency
Macrophages
Resumen
El enfrentamiento entre los patógenos invasivos y los sistemas defensivos del huésped implica interacciones celulares y moleculares. En el presente artículo se discuten los factores de virulencia como triunfos, favoreciendo el éxito de la contienda a favor del bacilo tuberculoso (Mycobacterium tuberculosis). Éste desarrolla un número de constituyentes moleculares que pueden interferir con la presentación antigénica y la función Toll receptor, deteriorando las defensas inmunes del huésped, así como respuestas al estrés que enlentecen su ciclo celular hasta convertirlo en no replicante. Aunque el recuento bajo de bacilos latentes previene su detección directa, postulamos que retienen cierta capacidad de sobrevivir dentro de macrófagos espumosos y en las partes necróticas de los granulomas pulmonares. Mientras que el circuito natural del fluido alveolar hacia las vías respiratorias superiores es el responsable de la eliminación de bacilos, su retorno para generar aerosoles de forma fisiológica también implica la posibilidad de que con él ciertos bacilos puedan reinfectar de forma endógena los pulmones y transmitir la infección a nuevos individuos. Consideramos, pues, la tuberculosis latente como un proceso continuo, en contraposición al concepto de la existencia de bacilos largamente durmientes y con capacidad de resucitar. Creemos, además, que la fibrosis del tejido conectivo de los pulmones, capaz en ocasiones de encapsular lesiones pulmonares, es la responsable de frenar el drenaje y la diseminación de bacilos, limitando el ciclo reinfectivo. En conclusión, la novedad de nuestra visión radica en la percepción dinámica de la latencia de M. tuberculosis y sus consecuencias sobre la patogénesis de la tuberculosis.
Palabras clave:
Tuberculosis
Inmunología
Patogénesis
Latencia bacteriana
Macrófagos
Full text is only aviable in PDF
References
[1.]
M. Gutiérrez, S. Brisse, R. Brosch, M. Fabre, B. Omaïs, M. Marmiesse, et al.
Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis.
PLoS Pathog, 1 (2005), pp. e5
[2.]
WHO. Global tuberculosis control: epidemiology, strategy, financing: WHO report 2009. Geneva: World Health Organization; 2009.
[3.]
J. Ivanyi.
Pathogenic and protective interactions in mycobacterial infections.
Immunological recognition of altered cell surfaces in infection and disease, pp. 127-157
[4.]
J. Ivanyi.
Local immune responses in tuberculosis.
Mucosal Immunology, pp. 1465-1474
[5.]
S.M. Mastorides, R. Oehler, J. Greene, J.T. Sinnott, M. Kranik, R.L. Sandin, et al.
The detection of airborne Mycobacterium tuberculosis using micropore membrane air sampling and polymerase chain reaction.
Chest, 115 (1999), pp. 19-25
[6.]
J. Gatfield, J. Pieters.
Essential role for cholesterol in entry of mycobacteria into macrophages.
Science, 288 (2000), pp. 1647-1650
[7.]
P.B. Kang, A.K. Azad, J.B. Torrelles, T.M. Kaufman, A. Beharka, E. Tibesar, et al.
The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannanmediated phagosome biogenesis.
J Exp Med, 202 (2005), pp. 987-999
[8.]
J. Torrelles, R. Knaup, A. Kolareth, T. Slepushkina, T. Kaufman, P. Kanf, et al.
Identification of Mycobacterium tuberculosis clinical isolates with altered phagocytosis by human macrophages due to a truncated lipoarabinomannan.
J Biol Chem, 283 (2008), pp. 31417-31428
[9.]
L. Grode, P. Seiler, S. Baumann, J. Hess, V. Brinkmann, A. Nasser Eddine, et al.
Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guérin mutants that secrete listeriolysin.
J Clin Invest, 115 (2005), pp. 2472-2479
[10.]
D. Kusner, J. Barton.
ATP stimulates human macrophages to kill intracellular virulent Mycobacterium tuberculosis via calcium-dependent phagosome-lysosome fusion.
J Immunol, 167 (2001), pp. 3308-3315
[11.]
J. Xu, O. Laine, M. Masciocchi, J. Manoranjan, J. Smith, S.J. Du, et al.
A unique Mycobacterium ESX-1 protein co-secretes with CFP-10/ESAT-6 and is necessary for inhibiting phagosome maturation.
Mol Microbiol, 66 (2007), pp. 787-800
[12.]
P.T. Liu, R.L. Modlin.
Human macrophage host defense against Mycobacterium tuberculosis.
Curr Opin Immunol, 20 (2008), pp. 371-376
[13.]
M. Chen, H. Gan, H.G. Remold.
A mechanism of virulence: virulent Mycobacterium tuberculosis strain H37Rv, but not attenuated H37Ra, causes significant mitochondrial inner membrane disruption in macrophages leading to necrosis.
J Immunol, 176 (2006), pp. 3707-3716
[14.]
C. Loeuillet, F. Martinon, C. Pérez, M. Muñoz, M. Thome, P.R. Meylan.
Mycobacterium tuberculosis subverts innate immunity to evade specific effectors.
J Immunol, 177 (2006), pp. 6245-6255
[15.]
T. Mustafa, H.G. Wiker, O. Morkve, L. Sviland.
Reduced apoptosis and increased inflammatory cytokines in granulomas caused by tuberculous compared to nontuberculous mycobacteria: role of MPT64 antigen in apoptosis and immune response.
Clin Exp Immunol, 150 (2007), pp. 105-113
[16.]
J.S. Park, M.H. Tamayo, M. González-Juarrero, I.M. Orme, D.J. Ordway.
Virulent clinical isolates of Mycobacterium tuberculosis grow rapidly and induce cellular necrosis but minimal apoptosis in murine macrophages.
J Leukoc Biol, 79 (2006), pp. 80-86
[17.]
V.A. Ríos-Barrera, V. Campos-Peña, D. Aguilar-León, L.R. Lascurain, M.A. Meraz-Ríos, J. Moreno, et al.
Macrophage and T lymphocyte apoptosis during experimental pulmonary tuberculosis: their relationship to mycobacterial virulence.
Eur J Immunol, 36 (2006), pp. 345-353
[18.]
H. Gan, J. Lee, F. Ren, M. Chen, H. Kornfeld, H.G. Remold.
Mycobacterium tuberculosis blocks crosslinking of annexin-1 and apoptotic envelope formation on infected macrophages to maintain virulence.
Nat Immunol, 9 (2008), pp. 1189-1197
[19.]
J. Lee, H. Remold, M. Ieong, H. Kornfeld.
Macrophage apoptosis in response to high intracellular burden of Mycobacterium tuberculosis is mediated by a novel caspaseindependent pathway.
J Immunol, 176 (2006), pp. 4267-4274
[20.]
N. Cáceres, G. Tapia, I. Ojanguren, F. Altare, O. Gil, S. Pinto, et al.
Evolution of foamy macrophages in the pulmonary granulomas of experimental tuberculosis models.
Tuberculosis (Edinb), 89 (2009), pp. 175-182
[21.]
O. Gil, I. Díaz, C. Vilaplana, G. Tapia, J. Díaz, M. Fort, et al.
Granuloma encapsulation is a key factor for controlling latent tuberculosis infection in mini-pigs.
PLoS One, 5 (2010), pp. e10030
[22.]
T. Bui, D. Dabdub, S. George.
Modeling bronchial circulation with application to soluble gas exchange: description and sensitivity analysis.
J Appl Physiol, 84 (1998), pp. 2070-2088
[23.]
L. Ramachandra, J. Smialek, S. Shank, M. Convery, W.H. Boom, C.V. Harding.
Phagosomal processing of Mycobacterium tuberculosis antigen 85B is modulated independently of mycobacterial viability and phagosome maturation.
Infect Immun, 73 (2005), pp. 1097-1105
[24.]
D. Riedel, S. Kaufmann.
Chemokine secretion by human polymorphonuclear granulocytes after stimulation with Mycobacterium tuberculosis and lipoarabinomannan.
Infect Immun, 65 (1997), pp. 4620-4623
[25.]
A. Tobian, N. Potter, L. Ramachandra, R. Pai, M. Convery, W.H. Boom, et al.
Alternate class I MHC antigen processing is inhibited by Toll-like receptor signaling pathogen-associated molecular patterns: Mycobacterium tuberculosis 19-kDa lipoprotein, CpG DNA, and lipopolysaccharide.
J Immunol, 171 (2003), pp. 1413-1422
[26.]
P.J. Cardona.
The granuloma in tuberculosis: friend or foe? (towards the resolution of the Citadel paradox).
11th International Symposium of KU Leuven,
[27.]
V. Kindler, A.P. Sappino, G.E. Grau, P.F. Piguet, P. Vassalli.
The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection.
Cell, 56 (1989), pp. 731-740
[28.]
D.R. Roach, A.G. Bean, C. Demangel, M.P. France, H. Briscoe, W.J. Britton.
TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection.
J Immunol, 168 (2002), pp. 4620-4627
[29.]
H.M. Algood, P.L. Lin, J.L. Flynn.
Tumor necrosis factor and chemokine interactions in the formation and maintenance of granulomas in tuberculosis.
Clin Infect Dis, 41 (2005), pp. S189-S193
[30.]
B.M. Saunders, W.J. Britton.
Life and death in the granuloma: immunopathology of tuberculosis.
Immunol Cell Biol, 85 (2007), pp. 103-111
[31.]
O. Gil, E. Guirado, S. Gordillo, J. Díaz, G. Tapia, C. Vilaplana, et al.
Intragranulomatous necrosis in lungs of mice infected by aerosol with Mycobacterium tuberculosis is related to bacterial load rather than to any one cytokine or T cell type.
Microbes Infect, 8 (2006), pp. 628-636
[32.]
A.R. Martineau, S.M. Newton, K.A. Wilkinson, B. Kampmann, B.M. Hall, N. Nawroly, et al.
Neutrophil-mediated innate immune resistance to mycobacteria.
J Clin Invest, 117 (2007), pp. 1988-1994
[33.]
X. Zhang, L. Majlessi, E. Deriaud, C. Leclerc, R. Lo-Man.
Coactivation of Syk kinase and MyD88 adaptor protein pathways by bacteria promotes regulatory properties of neutrophils.
Immunity, 31 (2009), pp. 761-771
[34.]
C.G. Feng, M. Kaviratne, A.G. Rothfuchs, A. Cheever, S. Hieny, H.A. Young, et al.
NK cell-derived IFN-γ differentially regulates innate resistance and neutrophil response in T cell-deficient hosts infected with Mycobacterium tuberculosis.
J Immunol, 177 (2006), pp. 7086-7093
[35.]
N. Serbina, T. Jia, T. Hohl, E. Pamer.
Monocyte-mediated defense against microbial pathogens.
Annu Rev Immunol, 26 (2008), pp. 421-452
[36.]
A.J. Wolf, L. Desvignes, B. Linas, N. Banaiee, T. Tamura, K. Takatsu, et al.
Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs.
J Exp Med, 205 (2008), pp. 105-115
[37.]
R.J. North, Y.J. Jung.
Immunity to tuberculosis.
Annu Rev Immunol, 22 (2004), pp. 599-623
[38.]
W.P. Gill, N.S. Harik, M.R. Whiddon, R.P. Liao, J.E. Mittler, D.E. Sherman.
A replication clock for Mycobacterium tuberculosis.
Nat Med, 15 (2009), pp. 211-214
[39.]
J.G. Wallace.
The heat resistance of tubercle bacilli in the lungs of infected mice.
Am Rev Respir Dis, 83 (1961), pp. 866-871
[40.]
E. Muñoz-Elías, J. Timm, T. Botha, W. Chan, J. Gómez, J.D. McKinney.
Replication dynamics of Mycobacterium tuberculosis in chronically infected mice.
Infect Immun, 73 (2005), pp. 546-551
[41.]
P. Andersen.
Host responses and antigens involved in protective immunity to Mycobacterium tuberculosis.
Scand J Immunol, 45 (1997), pp. 115-131
[42.]
P.J. 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
[43.]
P.J. Cardona, R. Llatjos, S. Gordillo, J. Díaz, I. Ojanguren, A. Ariza, et al.
Evolution of granulomas in lungs of mice infected aerogenically with Mycobacterium tuberculosis.
Scand J Immunol, 52 (2000), pp. 156-163
[44.]
H. D’Avila, N.R. Roque, R.M. Cardoso, H.C. Castro-Faria-Neto, R.C. Melo, P.R. Bozza.
Neutrophils recruited to the site of Mycobacterium bovis BCG infection undergo apoptosis and modulate lipid body biogenesis and prostaglandin E production by macrophages.
Cell Microbiol, 10 (2008), pp. 2589-2604
[45.]
G.R. Hemsworth, I. Kochan.
Secretion of antimycobacterial fatty acids by normal and activated macrophages.
Infect Immun, 19 (1978), pp. 170-177
[46.]
J.C. Leemans, T. Thepen, S. Weijer, S. Florquin, N. Van Rooijen, J.G. Van de Winkel, et al.
Macrophages play a dual role during pulmonary tuberculosis in mice.
J Infect Dis, 191 (2005), pp. 65-74
[47.]
D. Martínez, M. Vermeulen, E. Von Euw, J. Sabatté, J. Maggíni, A. Ceballos, et al.
Extracellular acidosis triggers the maturation of human dendritic cells and the production of IL-12.
J Immunol, 179 (2007), pp. 1950-1959
[48.]
G.M. Chisolm 3rd, S.L. Hazen, P.L. Fox, M.K. Cathcart.
The oxidation of lipoproteins by monocytes-macrophages. Biochemical and biological mechanisms.
J Biol Chem, 274 (1999), pp. 25959-25962
[49.]
D.G. Russell, P.J. Cardona, M.J. Kim, S. Allain, F. Altare.
Foamy macrophages and the progression of the human tuberculosis granuloma.
Nat Immunol, 10 (2009), pp. 943-948
[50.]
B. Sapoval, M. Filoche, E.R. Weibel.
Smaller is better—but not too small: a physical scale for the design of the mammalian pulmonary acinus.
Proc Natl Acad Sci U.S.A., 99 (2002), pp. 10411-10416
[51.]
Y. Jung, L. Ryan, R. LaCourse, R. North.
Properties and protective value of the secondary versus primary T helper type 1 response to airborne Mycobacterium tuberculosis infection in mice.
J Exp Med, 201 (2005), pp. 1915-1924
[52.]
P.J. Cardona.
A dynamic reinfection hypothesis of latent tuberculosis infection.
Infection, 37 (2009), pp. 80-86
[53.]
I.K. Mullarky, F.M. Szaba, K.N. Berggren, L.W. Kummer, L.B. Wilhelm, M.A. Parent, et al.
Tumor necrosis factor alpha and gamma interferon, but not hemorrhage or pathogen burden, dictate levels of protective fibrin deposition during infection.
Infect Immun, 74 (2006), pp. 1181-1188
[54.]
V.A. Fadok, D.L. Bratton, A. Konowal, P.W. Freed, J.Y. Westcott, P.M. Henson, et al.
Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.
J Clin Invest, 101 (1998), pp. 890-898
[55.]
R.S. Fraser.
Histology and gross anatomy of the respiratory tract.
Physiologic basis of respiratory disease,
[56.]
C.G. Plopper, J.R. Harkema.
The respiratory system and its use in research.
The laboratory primate, 30 (2005), pp. 503-526
[57.]
A.J. Lenaerts, D. Hoff, S. Aly, S. Ehlers, K. Andries, L. Cantarero, et al.
Location of persisting mycobacteria in a Guinea pig model of tuberculosis revealed by r207910.
Antimicrob Agents Chemother, 51 (2007), pp. 3338-3345
[58.]
M.L. Huynh, V.A. Fadok, P.M. Henson.
Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation.
J Clin Invest, 109 (2002), pp. 41-50
[59.]
J.S. Torday, V.K. Rehan.
The evolutionary continuum from lung development to homeostasis and repair.
Am J Physiol Lung Cell Mol Physiol, 292 (2007), pp. L608-11
[60.]
H.H. Hsu, B.G. Abbo.
Role of bicarbonate/CO2 buffer in the initiation of vesiclemediated calcification: mechanisms of aortic calcification related to atherosclerosis.
Biochim Biophys Acta, 1690 (2004), pp. 118-123
[61.]
G. Canetti.
The tubercle bacillus in the pulmonary lesion of man.
Histobacteriology and its bearing on the therapy of pulmonary tuberculosis, Springer Publishing Company, (1955),
[62.]
R. Rieder, Z. Zhao, B. Zavizion.
New approach for drug susceptibility testing: monitoring the stress response of mycobacteria.
Antimicrob Agents Chemother, 53 (2009), pp. 4598-4603
[63.]
G. Comstock.
How much isoniazid is needed for prevention of tuberculosis among immunocompetent adults?.
Int J Tuberc Lung Dis, 3 (1999), pp. 847-850
[64.]
V. Balasubramanian, E. Wiegeshaus, B. Taylor, D. Smith.
Pathogenesis of tuberculosis: pathway to apical localization.
Tuber Lung Dis, 75 (1994), pp. 168-178
[65.]
M. Vargas, M. Furuya, C. Pérez-Guzmán.
Effect of altitude on the frequency of pulmonary tuberculosis.
Int J Tuberc Lung Dis, 8 (2004), pp. 1321-1324
[66.]
M.K. Park, R.A. 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
[67.]
J. Milic-Emili.
Ventilation distribution..
Physiologic basis of respiratory disease., pp. 133-141
[68.]
V. Monroy, A. Amador, B. Ruiz, P. Espinoza-Cueto, W. Xolalpa, R. Mancilla, et al.
Binding and activation of human plasminogen by Mycobacterium tuberculosis.
Infect Immun, 68 (2000), pp. 4327-4330
[69.]
W. Xolalpa, A. Vallecillo, M. Lara, G. Mendoza-Hernández, M. Comini, R. Spallek, et al.
Identification of novel bacterial plasminogen-binding proteins in the human pathogen Mycobacterium tuberculosis.
Proteomics, 7 (2007), pp. 3332-3341
[70.]
J. West, F. Matthews.
Stresses, strains, and surface pressures in the lung caused by its weight.
J Appl Physiol, 32 (1972), pp. 332-345
[71.]
A. Casadevall, L.A. Pirofski.
The damage-response framework of microbial pathogenesis.
Nat Rev Microbiol, 1 (2003), pp. 17-24
[72.]
T. Pepper, P. Joseph, C. Mwenya, G. McKee, A. Haushalter, A. Carter, et al.
Normal chest radiography in pulmonary tuberculosis: implications for obtaining respiratory specimen cultures.
Int J Tuberc Lung Dis, 12 (2008), pp. 397-403
[73.]
A. Schwenk, D. Macallan.
Tuberculosis, malnutrition and wasting.
Curr Opin Clin Nutr Metab Care, 3 (2000), pp. 285-291
Copyright © 2011. Elsevier España S.L.. All rights reserved
