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Chapter 5 : Pathology of Tuberculosis: How the Pathology of Human Tuberculosis Informs and Directs Animal Models

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Abstract:

Progress toward developing new strategies to control the spread of is limited by a poor understanding of the basic pathogenesis of post-primary tuberculosis (TB). Progress is being made in developing more rapid diagnostic assays and implementing new anti-TB drug combinations, but we are failing to answer key scientific questions that will further advance the development of new treatment and prevention strategies. In a recent statement, Dr. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, said, “We need to better understand the delicate balance between the host and pathogen in the context of the entire biological system and this requires a radical and transformational approach.” has coevolved with its human host for centuries. The more recent emergence of antimicrobial drug-resistant strains represents an additional challenge to controlling the global spread of TB. No new TB vaccines have been shown to be more effective than the original bacillus Calmette-Guérin (BCG) developed over 100 years ago. The development of new anti-TB drugs lags far behind the need, and prospects for host-directed therapies have validated neither targets nor biomarkers.

Citation: Basaraba R, Hunter R. 2017. Pathology of Tuberculosis: How the Pathology of Human Tuberculosis Informs and Directs Animal Models, p 117-129. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0029-2016
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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.

Citation: Basaraba R, Hunter R. 2017. Pathology of Tuberculosis: How the Pathology of Human Tuberculosis Informs and Directs Animal Models, p 117-129. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. 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.

Citation: Basaraba R, Hunter R. 2017. Pathology of Tuberculosis: How the Pathology of Human Tuberculosis Informs and Directs Animal Models, p 117-129. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. 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.

Citation: Basaraba R, Hunter R. 2017. Pathology of Tuberculosis: How the Pathology of Human Tuberculosis Informs and Directs Animal Models, p 117-129. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. 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.

Citation: Basaraba R, Hunter R. 2017. Pathology of Tuberculosis: How the Pathology of Human Tuberculosis Informs and Directs Animal Models, p 117-129. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0029-2016
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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.

Citation: Basaraba R, Hunter R. 2017. Pathology of Tuberculosis: How the Pathology of Human Tuberculosis Informs and Directs Animal Models, p 117-129. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0029-2016
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