Animal Models for Tuberculosis in Translational and Precision Medicine

Li, Zhan; Tang, Jun; Sun, Mengmeng; Qin, Chuan

doi:10.3389/fmicb.2017.00717

Cited by 62 publications

(58 citation statements)

References 112 publications

(210 reference statements)

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“…Recently the zebrafish tuberculosis model, using M. marinum , has been used to mimic aspects of LTBI due to its small size, rapid reproduction, formation of granulomas and advanced genetic tools, making it a suitable animal model for large-scale screening of novel therapeutic agents in early-stage preclinical studies. However, zebrafish are anatomically and physiologically different to humans and lack the clinical manifestations and symptoms of tuberculosis disease and moreover they cannot be infected with the pathogenic human strain M. tuberculosis [4,59–62]. …”

Section: Discussionmentioning

confidence: 99%

“…Animal models currently used in tuberculosis research include non-human primates (e.g. 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].…”

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%

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

Spiropoulos

Cooley

et al. 2018

Virulence

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“…First, the facility that houses animals with MTB infections is usually expensive, which hinders its extensive usage in TB research. In addition, the animals are not natural hosts for MTB, so they only partially mimic TB clinical signs, characteristic pathological lesions (granuloma formation and lung cavitation), and immunological indices [65,66]. Consequently, organoids are emerging as a promising technology to study host-MTB interactions in a dish.…”

Section: Organoid Modeling Of Pulmonary Tuberculosismentioning

confidence: 99%

Organoids as a Powerful Model for Respiratory Diseases

Liu

Wu²,

Sun³

et al. 2020

Stem Cells International

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Insults to the alveoli usually lead to inefficient gas exchange or even respiratory failure, which is difficult to model in animal studies. Over the past decade, stem cell-derived self-organizing three-dimensional organoids have emerged as a new avenue to recapitulate respiratory diseases in a dish. Alveolar organoids have improved our understanding of the mechanisms underlying tissue homeostasis and pathological alterations in alveoli. From this perspective, we review the state-of-the-art technology on establishing alveolar organoids from endogenous lung epithelial stem/progenitor cells or pluripotent stem cells, as well as the use of alveolar organoids for the study of respiratory diseases, including idiopathic pulmonary fibrosis, tuberculosis infection, and respiratory virus infection. We also discuss challenges that need to be overcome for future application of alveolar organoids in individualized medicine.

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“…Deciphering the impact of microenvironment variations around the granuloma remains a significant challenge, and researchers often rely on in vivo animal models or biological samples (e.g., blood, tissue biopsy), considered the gold standard for studying TB, to reconstruct this complex environment. These methods have laid the foundation for understanding the pathogenesis and immunology behind TB, yet many existing in vivo models do not accurately recapitulate Mtb infection as seen in humans (although recent advances in mouse models and the established zebrafish/ M. marinum model are closing this gap)(Cronan et al 2018; Myllymäki, Bäuerlein, and Rämet 2016; Gern et al 2017; Cronan and Tobin 2014; Zhan et al 2017; Yong, Her, and Chen 2018). Additionally, despite recreating the complexity of an in vivo environment, spatial manipulation and probing of the granuloma microenvironment through introduction or removal of immune and tissue components is difficult in most animal models.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, despite recreating the complexity of an in vivo environment, spatial manipulation and probing of the granuloma microenvironment through introduction or removal of immune and tissue components is difficult in most animal models. (Scanga and Flynn 2014; Foreman et al 2017; Zhan et al 2017) Further, human-derived biological samples provide detailed cellular information regarding the granuloma, the immune response, and disease status (Darboe et al 2019; Guyot-Revol et al 2006; Ogongo et al 2020; Berry et al 2010), but are inherently limited as they only reflect a singular point in time, rather than the dynamic interactions that occur during the early stages of infection or disease progression.…”

Section: Introductionmentioning

confidence: 99%

A modular microscale granuloma model for immune-microenvironment signaling studiesin vitro

Berry

Gower

et al. 2020

Preprint

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Tuberculosis (TB) is one of the most potent infectious diseases in the world, causing more deaths than any other single infectious agent. TB infection is caused by inhalation of Mycobacterium tuberculosis (Mtb) and subsequent phagocytosis and migration into the lung tissue by innate immune cells (e.g., alveolar macrophages, neutrophils, dendritic cells), resulting in the formation of a fused mass of immune cells known as the granuloma. Considered the pathological hallmark of TB, the granuloma is a complex microenvironment that is crucial for pathogen containment as well as pathogen survival. Disruption of the delicate granuloma microenvironment via numerous stimuli, such as variations in cytokine secretions, nutrient availability, and the makeup of immune cell population, can lead to an active infection. Herein, we present a novel in vitro model to examine the soluble factor signaling between a mycobacterial infection and its surrounding environment. Adapting a newly developed suspended microfluidic platform, known as Stacks, we established a modular microscale infection model containing human immune cells and a model mycobacterial strain that can easily integrate with different microenvironmental cues through simple spatial and temporal “stacking” of each module of the platform. We validate the establishment of suspended microscale (4 μL) infection cultures that secrete increased levels of proinflammatory factors IL-6, VEGF, and TNFα upon infection and form 3D aggregates (granuloma model) encapsulating the mycobacteria. As a proof of concept to demonstrate the capability of our platform to examine soluble factor signaling, we cocultured an in vitro angiogenesis model with the granuloma model and quantified morphology changes in endothelial structures as a result of culture conditions (P < 0.05 when comparing infected vs. uninfected coculture systems). We envision our modular in vitro granuloma model can be further expanded and adapted for studies focusing on the complex interplay between granulomatous structures and their surrounding microenvironment, as well as a complementary tool to augment in vivo signaling and mechanistic studies.

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Animal Models for Tuberculosis in Translational and Precision Medicine

Cited by 62 publications

References 112 publications

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

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

Organoids as a Powerful Model for Respiratory Diseases

A modular microscale granuloma model for immune-microenvironment signaling studiesin vitro

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