Heterogeneity in tuberculosis

Cadena, Anthony M.; Fortune, Sarah M.; Flynn, JoAnne L.

doi:10.1038/nri.2017.69

Cited by 390 publications

(422 citation statements)

References 128 publications

(142 reference statements)

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“…The hallmark of tuberculosis infection in humans is the granuloma; a highly organized and dynamic cellular structure where mycobacteria reside in a non-replicating dormant state known as LTBI [6]. Several types can be found in humans including the caseous, non-necrotizing, and fibrotic granulomas [56].…”

Section: Discussionmentioning

confidence: 99%

“…macaques), guinea pigs, rabbits, cattle, pigs, mice and zebrafish [4]. However working with such animals is difficult as the pathogenesis and progression of M. tuberculosis infection is complex and there is no single animal model that mimics all the aspects of pathogenesis in humans [5,6]. Mice are the most commonly used species (because of cost, availability of inbred lines, reproducibility of infection and availability of immunological reagents) [7], but granulomas and regions of hypoxia characteristic of LTBI, are not commonly seen in the lungs and no single mouse tuberculosis model can reflect the mechanistically and morphologically diverse forms of human tuberculosis [8].…”

Section: Introductionmentioning

confidence: 99%

“…the macaque [9,10]. However ethical, cost, and practical considerations limit widespread use [6]. To overcome these issues there is an urgent need for a rapid, well-characterized, low-cost, high-throughput model that mimics the key features of M. tuberculosis pathogenesis to further understand host-pathogen interactions, that can also be used to screen novel drug candidates and assess the efficacy of vaccine candidates in early stage development.…”

Section: Introductionmentioning

confidence: 99%

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Galleria mellonella - a novel infection model for the Mycobacterium tuberculosis complex

Spiropoulos

Cooley

et al. 2018

Virulence

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Animal models have long been used in tuberculosis research to understand disease pathogenesis and to evaluate novel vaccine candidates and anti-mycobacterial drugs. However, all have limitations and there is no single animal model which mimics all the aspects of mycobacterial pathogenesis seen in humans. Importantly mice, the most commonly used model, do not normally form granulomas, the hallmark of tuberculosis infection. Thus there is an urgent need for the development of new alternative in vivo models. The insect larvae, Galleria mellonella has been increasingly used as a successful, simple, widely available and cost-effective model to study microbial infections. Here we report for the first time that G. mellonella can be used as an infection model for members of the Mycobacterium tuberculosis complex. We demonstrate a dose-response for G. mellonella survival infected with different inocula of bioluminescent Mycobacterium bovis BCG lux, and demonstrate suppression of mycobacterial luminesence over 14 days. Histopathology staining and transmission electron microscopy of infected G. mellonella phagocytic haemocytes show internalization and aggregation of M. bovis BCG lux in granuloma-like structures, and increasing accumulation of lipid bodies within M. bovis BCG lux over time, characteristic of latent tuberculosis infection. Our results demonstrate that G. mellonella can act as a surrogate host to study the pathogenesis of mycobacterial infection and shed light on host-mycobacteria interactions, including latent tuberculosis infection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Galleria mellonella - a novel infection model for the Mycobacterium tuberculosis complex

Spiropoulos

Cooley

et al. 2018

Virulence

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“…The route of challenge (aerosol versus bronchoscopic challenge) in rhesus macaques influences the distribution of disease but not the overall outcome of the infection (25). We have used Chinese cynomolgus macaques (CCM) to demonstrate that most granulomas form from a single bacterium and that individual granulomas follow distinct trajectories even within the same host (26), highlighting the importance of local immune control in influencing host outcome (27). Importantly, the full range of granuloma types (e.g., caseous, nonnecrotic, fibrotic, etc.)…”

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confidence: 99%

Rhesus Macaques Are More Susceptible to Progressive Tuberculosis than Cynomolgus Macaques: a Quantitative Comparison

et al. 2018

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In the past 2 decades, it has become increasingly clear that nonhuman primates, specifically macaques, are useful models for human tuberculosis (TB). Several macaque species have been used for TB studies, and questions remain about the similarities and differences in TB pathogenesis among macaque species, which can complicate decisions about the best species for a specific experiment. Here we provide a quantitative assessment, using serial positron emission tomography and computed tomography (PET-CT) imaging and precise quantitative determination of bacterial burdens of low-dose Mycobacterium tuberculosis infection in cynomolgus macaques of Chinese origin, rhesus macaques of Chinese origin, and Mauritian cynomolgus macaques. This comprehensive study demonstrates that there is substantial variability in the outcome of infection within and among species. Overall, rhesus macaques have higher rates of disease progression, more lung, lymph node, and extrapulmonary involvement, and higher bacterial burdens than Chinese cynomolgus macaques. The small cohort of Mauritian cynomolgus macaques assessed here indicates that this species is more similar to rhesus macaques than to Chinese cynomolgus macaques in terms of M. tuberculosis infection outcome. These data provide insights into the differences among species, providing valuable data to the field for assessing macaque studies of TB.KEYWORDS Mycobacterium, PET CT, macaque, nonhuman primate, tuberculosis N ovel therapeutics for tuberculosis (TB) are greatly needed to curb the 10.4 million new cases and 1.8 million deaths that occur due to this global pandemic (1). Drugs have aided the fight against TB by saving an estimated 49 million lives between 2000 and 2015 (1). However, the current drug regimen is lengthy and cumbersome, and about 480,000 people developed multidrug-resistant TB in 2015 alone (1), so there is much room for improvement. The only licensed vaccine for TB, Mycobacterium bovis bacillus Calmette-Guérin (BCG), protects infants from severe manifestations of TB but does not provide long-lasting immunity against pulmonary TB (2). The urgent need for new therapeutics for TB has driven the development of novel drugs and vaccines that require preclinical evaluation in animal models. Many animal models are used in TB research, including mice, zebra fish, cattle, rabbits, guinea pigs, and nonhuman primates (NHPs) (3, 4). Mice and NHPs are the two animal models that are the most useful, as the other models suffer from a lack of resources available for immunologic studies. Mice have their shortcomings too, as their TB pathology is not fully representative of the pathology observed in humans, and they do not develop human-like latent TB infection (LTBI). NHPs recapitulate the full spectrum of Mycobacterium tuberculosis

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“…It is well-established that a biphasic reduction in bacterial load is observed under current TB therapy (32), a phenomenon which has been explained by two models: (i) the killing of actively dividing bacilli in an initial rapid killing phase, followed by the gradual decrease in the persistent population of bacteria, or (ii) the lack of treatment of bacterial populations due to the inaccessibility of bacteria within granulomas (49). Adding a further layer of complexity is the fact that the bacteria exist within both an intracellular and extracellular environment (50), an observation which is exacerbated by the knowledge that these lesions are very heterogeneous, often differing even within the same patient (4,14). …”

Section: Introductionmentioning

confidence: 99%

Drug permeation and metabolism in Mycobacterium tuberculosis: Prioritising local exposure as essential criterion in new TB drug development

et al. 2018

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Anti-tuberculosis (TB) drugs possess diverse abilities to penetrate the different host tissues and cell types in which infecting Mycobacterium tuberculosis bacilli are located during active disease. This is important since there is increasing evidence that the respective "lesion-penetrating" properties of the front-line TB drugs appear to correlate well with their specific activity in standard combination therapy. In turn, these observations suggest that rational efforts to discover novel treatment-shortening drugs and drug combinations should incorporate knowledge about the comparative abilities of both existing and experimental anti-TB agents to access bacilli in defined physiological states at different sites of infection, as well as avoid elimination by efflux or inactivation by host or bacterial metabolism. However, while there is a fundamental requirement to understand the mode of action and pharmacological properties of any current or experimental anti-TB agent within the context of the obligate human host, this is complex and, until recently, has been severely limited by the available methodologies and models. Here, we discuss advances in analytical models and technologies which have enabled investigations of drug metabolism and pharmacokinetics (DMPK) for new TB drug development. In particular, we consider the potential to shift the focus of traditional pharmacokinetic-pharmacodynamic analyses away from plasma to a more specific "site of action" drug exposure as an essential criterion for drug development and the design of dosing strategies. Moreover, in summarising approaches to determine DMPK data for the "unit of infection" comprising host macrophage and intracellular bacillus, we evaluate the potential benefits of including these analyses at an early stage in the preclinical drug development algorithm. © 2018 IUBMB Life, 70(9):926-937, 2018.

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Heterogeneity in tuberculosis

Cited by 390 publications

References 128 publications

Galleria mellonella - a novel infection model for the Mycobacterium tuberculosis complex

Galleria mellonella - a novel infection model for the Mycobacterium tuberculosis complex

Rhesus Macaques Are More Susceptible to Progressive Tuberculosis than Cynomolgus Macaques: a Quantitative Comparison

Drug permeation and metabolism in Mycobacterium tuberculosis: Prioritising local exposure as essential criterion in new TB drug development

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