Modeling tuberculosis pathogenesis through ex vivo lung tissue infection

Carranza-Rosales, Pilar; Carranza-Torres, Irma Edith; Guzmán-Delgado, Nancy Elena; Lozano-Garza, Gerardo; Villarreal-Treviño, Licet; Molina-Torres, Carmen A.; Villarreal, Javier Vargas; Vera-Cabrera, Lucio; Castro-Garza, Jorge

doi:10.1016/j.tube.2017.09.002

Cited by 20 publications

(12 citation statements)

References 30 publications

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“…Towards this end, ex vivo lung models have been developed using tissues derived from rodents [238], pigs [239] and human donors [240]. Of these sources, pigs are arguably the best choice even though tissues from human donors are the most clinically relevant.…”

Section: Ex Vivo Lung Modelmentioning

confidence: 99%

“…4B) method [241], improves the consistency of cutting and offers the possibility of studying thin tissue cultures. PCLS has been successfully applied to tissues from various sources (mice, pigs and human donors) and successfully used to model diseases like CF lung infections and TB [238,239]. In this setup, lungs are first subjected to infusion with a low percentage (0.75%-1.75%), lowmelting point, agarose solution through airways and pulmonary arteries and are then hardened by cooling to facilitate cutting and slicing.…”

Section: Ex Vivo Lung Modelmentioning

confidence: 99%

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In vitro and ex vivo systems at the forefront of infection modeling and drug discovery

Shi

Wang

et al. 2019

Biomaterials

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A B S T R A C TBacterial infections and antibiotic resistant bacteria have become a growing problem over the past decade. As a result, the Centers for Disease Control predict more deaths resulting from microorganisms than all cancers combined by 2050. Currently, many traditional models used to study bacterial infections fail to precisely replicate the in vivo bacterial environment. These models often fail to incorporate fluid flow, bio-mechanical cues, intercellular interactions, host-bacteria interactions, and even the simple inclusion of relevant physiological proteins in culture media. As a result of these inadequate models, there is often a poor correlation between in vitro and in vivo assays, limiting therapeutic potential. Thus, the urgency to establish in vitro and ex vivo systems to investigate the mechanisms underlying bacterial infections and to discover new-age therapeutics against bacterial infections is dire. In this review, we present an update of current in vitro and ex vivo models that are comprehensively changing the landscape of traditional microbiology assays. Further, we provide a comparative analysis of previous research on various established organ-disease models. Lastly, we provide insight on future techniques that may more accurately test new formulations to meet the growing demand of antibiotic resistant bacterial infections. Lack of adequate model systemsCommonly, a variety of inconsistent, in vitro and in vivo models have been progressively utilized for antibiotic/drug development and pathophysiological studies. These systems range from simple in vitro models using microtiter plate assays and flow cells to more complex in https://doi.

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Section: Ex Vivo Lung Modelmentioning

confidence: 99%

Section: Ex Vivo Lung Modelmentioning

confidence: 99%

In vitro and ex vivo systems at the forefront of infection modeling and drug discovery

Shi

Wang

et al. 2019

Biomaterials

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“…In contrast, we were able to observe the histopathological characteristics of M. abscessus -induced damage and the pathogen’s interactions with lung parenchyma cells after a short time post-infection (6–48 h), while animal models need 10 to 60 days to develop lung damage [ 35 , 36 , 38 , 40 ]. Studies with M. tuberculosis [ 19 , 20 ] and other pathogens [ 41 – 45 ] using PCLS or tissue explants, where tissue lesions or inflammatory infiltrates are observed at 24–48 h post-infection, support the advantage of these ex vivo models.…”

Section: Discussionmentioning

confidence: 94%

“…With this approach, tissue explants have been successfully infected with Mycobacterium tuberculosis , M. abscessus , and Mycobacterium avium [ 19 ]. Similarly, we have reported a M. tuberculosis infection model using precision-cut lung slices (PCLS) [ 20 ]. PCLS are an ex vivo system that reflects the 3D tissue architecture, cellular composition, matrix complexity, metabolic function and immune response of the lung [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Ex vivo infection of murine precision-cut lung tissue slices with Mycobacterium abscessus: a model to study antimycobacterial agents

Molina-Torres

Flores-Castillo

Carranza-Torres

et al. 2020

Ann Clin Microbiol Antimicrob

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Background Multidrug-resistant infections due to Mycobacterium abscessus often require complex and prolonged regimens for treatment. Here, we report the evaluation of a new ex vivo antimicrobial susceptibility testing model using organotypic cultures of murine precision-cut lung slices, an experimental model in which metabolic activity, and all the usual cell types of the organ are found while the tissue architecture and the interactions between the different cells are maintained. Methods Precision cut lung slices (PCLS) were prepared from the lungs of wild type BALB/c mice using the Krumdieck® tissue slicer. Lung tissue slices were ex vivo infected with the virulent M. abscessus strain L948. Then, we tested the antimicrobial activity of two drugs: imipenem (4, 16 and 64 μg/mL) and tigecycline (0.25, 1 and 4 μg/mL), at 12, 24 and 48 h. Afterwards, CFUs were determined plating on blood agar to measure the surviving intracellular bacteria. The viability of PCLS was assessed by Alamar Blue assay and corroborated using histopathological analysis. Results PCLS were successfully infected with a virulent strain of M. abscessus as demonstrated by CFUs and detailed histopathological analysis. The time-course infection, including tissue damage, parallels in vivo findings reported in genetically modified murine models for M. abscessus infection. Tigecycline showed a bactericidal effect at 48 h that achieved a reduction of > 4log10 CFU/mL against the intracellular mycobacteria, while imipenem showed a bacteriostatic effect. Conclusions The use of this new organotypic ex vivo model provides the opportunity to test new drugs against M. abscessus, decreasing the use of costly and tedious animal models.

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“…The tissue architecture and the interactions between the different cells are maintained. PCLS have already been validated for the study of various respiratory pathogens (27)(28)(29). In chicken PCLS, mononuclear cells are highly motile and actively phagocytic (30).…”

Section: Introductionmentioning

confidence: 99%

Mycobacterial Infection of Precision-Cut Lung Slices Reveals Type 1 Interferon Pathway Is Locally Induced by Mycobacterium bovis but Not M. tuberculosis in a Cattle Breed

Rémot

Carreras

et al. 2021

Front. Vet. Sci.

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Tuberculosis exacts a terrible toll on human and animal health. While Mycobacterium tuberculosis (Mtb) is restricted to humans, Mycobacterium bovis (Mb) is present in a large range of mammalian hosts. In cattle, bovine TB (bTB) is a noticeable disease responsible for important economic losses in developed countries and underestimated zoonosis in the developing world. Early interactions that take place between mycobacteria and the lung tissue early after aerosol infection govern the outcome of the disease. In cattle, these early steps remain poorly characterized. The precision-cut lung slice (PCLS) model preserves the structure and cell diversity of the lung. We developed this model in cattle in order to study the early lung response to mycobacterial infection. In situ imaging of PCLS infected with fluorescent Mb revealed bacilli in the alveolar compartment, in adjacent or inside alveolar macrophages, and in close contact with pneumocytes. We analyzed the global transcriptional lung inflammation signature following infection of PCLS with Mb and Mtb in two French beef breeds: Blonde d'Aquitaine and Charolaise. Whereas, lungs from the Blonde d'Aquitaine produced high levels of mediators of neutrophil and monocyte recruitment in response to infection, such signatures were not observed in the Charolaise in our study. In the Blonde d'Aquitaine lung, whereas the inflammatory response was highly induced by two Mb strains, AF2122 isolated from cattle in the UK and Mb3601 circulating in France, the response against two Mtb strains, H37Rv, the reference laboratory strain, and BTB1558, isolated from zebu in Ethiopia, was very low. Strikingly, the type I interferon pathway was only induced by Mb but not Mtb strains, indicating that this pathway may be involved in mycobacterial virulence and host tropism. Hence, the PCLS model in cattle is a valuable tool to deepen our understanding of early interactions between lung host cells and mycobacteria. It revealed striking differences between cattle breeds and mycobacterial strains. This model could help in deciphering biomarkers of resistance vs. susceptibility to bTB in cattle as such information is still critically needed for bovine genetic selection programs and would greatly help the global effort to eradicate bTB.

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Modeling tuberculosis pathogenesis through ex vivo lung tissue infection

Cited by 20 publications

References 30 publications

In vitro and ex vivo systems at the forefront of infection modeling and drug discovery

In vitro and ex vivo systems at the forefront of infection modeling and drug discovery

Ex vivo infection of murine precision-cut lung tissue slices with Mycobacterium abscessus: a model to study antimycobacterial agents

Mycobacterial Infection of Precision-Cut Lung Slices Reveals Type 1 Interferon Pathway Is Locally Induced by Mycobacterium bovis but Not M. tuberculosis in a Cattle Breed

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