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Pathology of Tuberculosis: How the Pathology of Human Tuberculosis Informs and Directs Animal Models

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  • Authors: Randall J. Basaraba1, Robert L. Hunter2
  • Editors: William R. Jacobs Jr.3, Helen McShane4, Valerie Mizrahi5, Ian M. Orme6
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80524; 2: Department of Pathology and Laboratory Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030; 3: Howard Hughes Medical Institute, Albert Einstein School of Medicine, Bronx, NY 10461; 4: University of Oxford, Oxford OX3 7DQ, United Kingdom; 5: University of Cape Town, Rondebosch 7701, South Africa; 6: Colorado State University, Fort Collins, CO 80523
  • Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.TBTB2-0029-2016
  • Received 30 July 2016 Accepted 19 April 2017 Published 09 June 2017
  • R. J. Basaraba, Basaraba@colostate.edu
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  • Abstract:

    Tuberculosis (TB) is a chronic inflammatory disease caused by the pathogenic bacterium . A wide variety of host- and pathogen-associated variables influence the clinical manifestation of TB in different individuals within the human population. As a consequence, the characteristic granulomatous lesions that develop within the lung are heterogeneous in size and cellular composition. Due to the lack of appropriate tissues from human TB patients, a variety of animal models are used as surrogates to study the basic pathogenesis and to test experimental vaccines and new drug therapies. Few animal models mimic the clinical course and pathological response of seen in the naturally occurring disease in people. In particular, post-primary TB, which accounts for the majority of cases of active TB and is responsible for transmission between individuals via aerosol exposers, cannot be reproduced in animals and therefore cannot be adequately modeled experimentally. This article describes a new paradigm that explains the pathogenesis of post-primary TB in humans. This new evidence was derived from histological examination of tissues from patients with different stages of infection and that had not been treated with antimicrobial drugs. Gaining a better understanding of this unique stage of TB disease will lead to more effective treatment, diagnostic, and prevention strategies.

  • Citation: Basaraba R, Hunter R. 2017. Pathology of Tuberculosis: How the Pathology of Human Tuberculosis Informs and Directs Animal Models. Microbiol Spectrum 5(3):TBTB2-0029-2016. doi:10.1128/microbiolspec.TBTB2-0029-2016.

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Infectious Diseases
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Magnetic Resonance Imaging
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White Blood Cells
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Infection and Immunity
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/content/journal/microbiolspec/10.1128/microbiolspec.TBTB2-0029-2016
2017-06-09
2017-11-23

Abstract:

Tuberculosis (TB) is a chronic inflammatory disease caused by the pathogenic bacterium . A wide variety of host- and pathogen-associated variables influence the clinical manifestation of TB in different individuals within the human population. As a consequence, the characteristic granulomatous lesions that develop within the lung are heterogeneous in size and cellular composition. Due to the lack of appropriate tissues from human TB patients, a variety of animal models are used as surrogates to study the basic pathogenesis and to test experimental vaccines and new drug therapies. Few animal models mimic the clinical course and pathological response of seen in the naturally occurring disease in people. In particular, post-primary TB, which accounts for the majority of cases of active TB and is responsible for transmission between individuals via aerosol exposers, cannot be reproduced in animals and therefore cannot be adequately modeled experimentally. This article describes a new paradigm that explains the pathogenesis of post-primary TB in humans. This new evidence was derived from histological examination of tissues from patients with different stages of infection and that had not been treated with antimicrobial drugs. Gaining a better understanding of this unique stage of TB disease will lead to more effective treatment, diagnostic, and prevention strategies.

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Figures

Image of FIGURE 1
FIGURE 1

Well-delineated foci of granulomatous inflammation (granuloma) within the lung is a common manifestation of primary tuberculosis in humans and many laboratory animals. A low-magnification view of a primary lung granuloma from an -infected guinea pig has an area of central necrosis that is partially calcified . The wall of the lesion contains active lymphocytic and histiocytic inflammation and is well delineated from the surrounding normal lung parenchyma by a fibrous capsule that contains regenerative airway epithelium (black arrow). A higher-magnification view of the central dystrophic calcification (white arrow) shows residual tissue necrosis that harbors extracellular bacilli. Hematoxylin and eosin (H&E) stain.

Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.TBTB2-0029-2016
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Image of FIGURE 2
FIGURE 2

An important manifestation of post-primary TB in humans that is not seen in many small animal models is the formation of thin wall cavities. Cavity formation (C) represents one of the most destructive manifestations of active tuberculosis in humans and non-human primates. The lung parenchyma is replaced by an open space that often contains necrotic cellular debris (N) and myriads of extracellular and intracellular bacilli that can be transmitted between individuals though aerosol spread. The wall of the cavity consists of mixed inflammation similar to primary granulomas and similarly is delineated from the more normal parenchyma by a fibrous capsule that impairs the penetration of antimicrobial drugs. H&E stain.

Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.TBTB2-0029-2016
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Image of FIGURE 3
FIGURE 3

Cavity formation associated with post-primary TB is important in the transmission of bacilli between individuals due to the large numbers of extracellular and intracellular bacilli. High-magnification images of a cavitary lung lesion shown filling the lumen with necrotic cellular debris (white arrow). An acid-fast stain shows that bacilli within the necrotic debris are arranged in small clusters or as individuals (black arrow) and are mostly extracellular. The high numbers of bacilli within these lesions are important in the transmission of between individuals, especially when cavities communicate with lung airways. H&E stain.

Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.TBTB2-0029-2016
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Image of FIGURE 4
FIGURE 4

Intrapulmonary spread of mixed inflammatory cells within the lung parenchyma results in an obstructive lobar pneumonia and is involved in the early pathogenesis of post-primary TB. In contrast to primary lesions, the filling of alveoli with mixed inflammatory cells, including foamy macrophages, in the absence of necrosis contributes to airway obstruction and the development of post-primary TB. H&E stain.

Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.TBTB2-0029-2016
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Image of FIGURE 5
FIGURE 5

Similarities in the time course of humans and animal models of TB demonstrating that pathology does not correlate with increased numbers of bacteria. A central problem in TB research is to explain why immunity to infection does not enable mice, guinea pigs, rabbits, or susceptible humans to resolve lung infection and thereby stop the development of disease.

Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.TBTB2-0029-2016
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