The Treated Pulmonary Lesion and Its Tubercle Bacillus Iii. Drug Susceptibility Studies

Kennedy, H. E.; Vandiviere, H. M.; Melvin, Irene G.; Willis, Henry Stuart

doi:10.1097/00000441-195706000-00010

Cited by 4 publications

(1 citation statement)

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“…The bacteria within such aerobic environments are likely to be highly susceptible to conventional chemotherapies. Caseous necrotic lesions are also abundant in resected lung tissue, with thick multicellular walls insulating them from the airways of the host, and these have been reported to contain relatively fewer bacilli (21,41). In this environment, it appears that the bacteria are less responsive to current chemotherapy (41);…”

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Tuberculous Granulomas Are Hypoxic in Guinea Pigs, Rabbits, and Nonhuman Primates

et al. 2008

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Understanding the physical characteristics of the local microenvironment in which Mycobacterium tuberculosis resides is an important goal that may allow the targeting of metabolic processes to shorten drug regimens. Pimonidazole hydrochloride (Hypoxyprobe) is an imaging agent that is bioreductively activated only under hypoxic conditions in mammalian tissue. We employed this probe to evaluate the oxygen tension in tuberculous granulomas in four animal models of disease: mouse, guinea pig, rabbit, and nonhuman primate. Following infusion of pimonidazole into animals with established infections, lung tissues from the guinea pig, rabbit, and nonhuman primate showed discrete areas of pimonidazole adduct formation surrounding necrotic and caseous regions of pulmonary granulomas by immunohistochemical staining. This labeling could be substantially reduced by housing the animal under an atmosphere of 95% O 2 . Direct measurement of tissue oxygen partial pressure by surgical insertion of a fiber optic oxygen probe into granulomas in the lungs of living infected rabbits demonstrated that even small (3-mm) pulmonary lesions were severely hypoxic (1.6 ؎ 0.7 mm Hg). Finally, metronidazole, which has potent bactericidal activity in vitro only under low-oxygen culture conditions, was highly effective at reducing total-lung bacterial burdens in infected rabbits. Thus, three independent lines of evidence support the hypothesis that hypoxic microenvironments are an important feature of some lesions in these animal models of tuberculosis.Active human pulmonary tuberculosis (TB) is a chronic, complex disease in which patients present a diverse spectrum of lesions ranging from diffuse areas of inflammation and swelling of alveoli to caseous, highly organized granulomas and open cavities in intimate contact with the airways (9, 25). Computed tomography (CT) has been used to study defined types of lesions and the rate of response of such lesions to chemotherapy. Open cavities, caseous lesions, centrilobular densities (i.e., nodules or branching linear structures of 2 to 4 mm in length that are well separated from the pleural surface or the septum between pulmonary lobes), ground-glass opacities, and tissue consolidations are all apparent in active tuberculosis patients by use of this technique (17,24,30). The most comprehensive study of CT findings during TB chemotherapy was that of Im and colleagues (17), who studied CT scans of patients undergoing TB chemotherapy for up to 20 months and then compared their findings with postmortem autopsy results to assist in interpretation. In this study there were significant differences in the rates at which different lesion types responded to chemotherapy.Surgical lung resection has been employed periodically as salvage therapy for patients who have failed chemotherapeutic treatment, and the resected tissues have proven useful for studying the heterogeneity of lesions that can occur within a single infected person (19,40,41). Studies on surgically removed tissues have revealed that most TB lesi...

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Tuberculous Granulomas Are Hypoxic in Guinea Pigs, Rabbits, and Nonhuman Primates

et al. 2008

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Mycobacteria Infection and Lipid Droplets: Host and Pathogen Stealing, Sharing and Storing Fat

Armstrong

Zahrt

2019

Tuberculosis Host-Pathogen Interactions

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Tuberculosis — metabolism and respiration in the absence of growth

Boshoff¹,

Barry²

2005

Nat Rev Microbiol

410

383

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Human tuberculosis is a complex disease caused by bacterial populations that are located in discrete lesions (microenvironments) in a single host. Some of these microenvironments are conducive to replication, whereas others restrict bacterial growth without necessarily sterilizing the infecting microorganisms. The physical and biochemical milieu in these lesions is poorly defined. None of the existing animal models for tuberculosis (except perhaps non-human primates) reproduce the diversity of disease progression that is seen in humans. Nonetheless, transcriptomics and studies using bacterial mutants have led to testable hypotheses about metabolic functions that are essential for viability in the absence of replication. A complete picture of bacterial metabolism must balance reducing equivalents while maintaining an energized membrane and basic cellular processes.

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The Treated Pulmonary Lesion and Its Tubercle Bacillus Iii. Drug Susceptibility Studies

Cited by 4 publications

References 0 publications

Tuberculous Granulomas Are Hypoxic in Guinea Pigs, Rabbits, and Nonhuman Primates

Tuberculous Granulomas Are Hypoxic in Guinea Pigs, Rabbits, and Nonhuman Primates

Mycobacteria Infection and Lipid Droplets: Host and Pathogen Stealing, Sharing and Storing Fat

Tuberculosis — metabolism and respiration in the absence of growth

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