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Article: Automated quantitative assay of fibrosis characteristics in tuberculosis granulomas.

Song, Li / Zhang, Ding / Wang, Hankun / Xia, Xuan / Huang, Weifeng / Gonzales, Jacqueline / Via, Laura E / Wang, Decheng

Frontiers in microbiology

2024 Volume 14, Page(s) 1301141

Abstract: Introduction: Granulomas, the pathological hallmark of : Methods: In this study, samples were collected from patients with tuberculosis (spanning 16 organ types), and : Results: Histopathological examination revealed that most granulomas share ... ...

Abstract	Introduction: Granulomas, the pathological hallmark of Methods: In this study, samples were collected from patients with tuberculosis (spanning 16 organ types), and Results: Histopathological examination revealed that most granulomas share common features, including necrosis, solitary and compact structure, and especially the presence of multinuclear giant cells. Masson's trichrome staining showed that different granuloma types have varying degrees of fibrosis. SHG imaging uncovered a higher proportion (4%~13%) of aggregated collagens than of disseminated type collagens (2%~5%) in granulomas from matched tissues. Furthermore, most of the aggregated collagen presented as short and thick clusters (200~620 µm), unlike the long and thick (200~300 µm) disseminated collagens within the matched tissues. Matrix metalloproteinase-9, which is involved in fibrosis and granuloma formation, was strongly expressed in the granulomas in different tissues. Discussion: Our data illustrated that different tuberculosis granulomas have some degree of fibrosis in which collagen strings are short and thick. Moreover, this study revealed that the SHG imaging program could contribute to uncovering the fibrosis characteristics of tuberculosis granulomas.
Language	English
Publishing date	2024-01-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2023.1301141
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Article ; Online: A systematic efficacy analysis of tuberculosis treatment with BPaL-containing regimens using a multiscale modeling approach.

Budak, Maral / Via, Laura E / Weiner, Danielle M / Barry, Clifton E / Nanda, Pariksheet / Michael, Gabrielle / Mdluli, Khisimuzi / Kirschner, Denise

CPT: pharmacometrics & systems pharmacology

2024 Volume 13, Issue 4, Page(s) 673–685

Abstract: Tuberculosis (TB) is a life-threatening infectious disease. The standard treatment is up to 90% effective; however, it requires the administration of four antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol [HRZE]) over long time periods. ... ...

Abstract	Tuberculosis (TB) is a life-threatening infectious disease. The standard treatment is up to 90% effective; however, it requires the administration of four antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol [HRZE]) over long time periods. This harsh treatment process causes adherence issues for patients because of the long treatment times and a myriad of adverse effects. Therefore, the World Health Organization has focused goals of shortening standard treatment regimens for TB in their End TB Strategy efforts, which aim to reduce TB-related deaths by 95% by 2035. For this purpose, many novel and promising combination antibiotics are being explored that have recently been discovered, such as the bedaquiline, pretomanid, and linezolid (BPaL) regimen. As a result, testing the number of possible combinations with all possible novel regimens is beyond the limit of experimental resources. In this study, we present a unique framework that uses a primate granuloma modeling approach to screen many combination regimens that are currently under clinical and experimental exploration and assesses their efficacies to inform future studies. We tested well-studied regimens such as HRZE and BPaL to evaluate the validity and accuracy of our framework. We also simulated additional promising combination regimens that have not been sufficiently studied clinically or experimentally, and we provide a pipeline for regimen ranking based on their efficacies in granulomas. Furthermore, we showed a correlation between simulation rankings and new marmoset data rankings, providing evidence for the credibility of our framework. This framework can be adapted to any TB regimen and can rank any number of single or combination regimens.
MeSH term(s)	Animals ; Humans ; Antitubercular Agents/therapeutic use ; Linezolid/therapeutic use ; Tuberculosis/drug therapy ; Tuberculosis, Multidrug-Resistant/drug therapy ; Nitroimidazoles ; Diarylquinolines
Chemical Substances	Antitubercular Agents ; bedaquiline (78846I289Y) ; Linezolid (ISQ9I6J12J) ; pretomanid ; Nitroimidazoles ; Diarylquinolines
Language	English
Publishing date	2024-02-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.13117
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Article ; Online: Mathematical model of oxygen, nutrient, and drug transport in tuberculosis granulomas.

Datta, Meenal / Kennedy, McCarthy / Siri, Saeed / Via, Laura E / Baish, James W / Xu, Lei / Dartois, Véronique / Barry, Clifton E / Jain, Rakesh K

PLoS computational biology

2024 Volume 20, Issue 2, Page(s) e1011847

Abstract: Physiological abnormalities in pulmonary granulomas-pathological hallmarks of tuberculosis (TB)-compromise the transport of oxygen, nutrients, and drugs. In prior studies, we demonstrated mathematically and experimentally that hypoxia and necrosis emerge ...

Abstract	Physiological abnormalities in pulmonary granulomas-pathological hallmarks of tuberculosis (TB)-compromise the transport of oxygen, nutrients, and drugs. In prior studies, we demonstrated mathematically and experimentally that hypoxia and necrosis emerge in the granuloma microenvironment (GME) as a direct result of limited oxygen availability. Building on our initial model of avascular oxygen diffusion, here we explore additional aspects of oxygen transport, including the roles of granuloma vasculature, transcapillary transport, plasma dilution, and interstitial convection, followed by cellular metabolism. Approximate analytical solutions are provided for oxygen and glucose concentration, interstitial fluid velocity, interstitial fluid pressure, and the thickness of the convective zone. These predictions are in agreement with prior experimental results from rabbit TB granulomas and from rat carcinoma models, which share similar transport limitations. Additional drug delivery predictions for anti-TB-agents (rifampicin and clofazimine) strikingly match recent spatially-resolved experimental results from a mouse model of TB. Finally, an approach to improve molecular transport in granulomas by modulating interstitial hydraulic conductivity is tested in silico.
MeSH term(s)	Animals ; Mice ; Rabbits ; Oxygen/metabolism ; Tuberculosis/drug therapy ; Tuberculosis/pathology ; Granuloma/pathology ; Disease Models, Animal ; Nutrients ; Mycobacterium tuberculosis/metabolism
Chemical Substances	Oxygen (S88TT14065)
Language	English
Publishing date	2024-02-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1011847
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Article ; Online: One Size Fits All? Not in

Yang, Hee-Jeong / Wang, Decheng / Wen, Xin / Weiner, Danielle M / Via, Laura E

Frontiers in cellular and infection microbiology

2021 Volume 11, Page(s) 613149

Abstract: Tuberculosis (TB) remains a global health problem despite almost universal efforts to provide patients with highly effective chemotherapy, in part, because many infected individuals are not diagnosed and treated, others do not complete treatment, and a ... ...

Abstract	Tuberculosis (TB) remains a global health problem despite almost universal efforts to provide patients with highly effective chemotherapy, in part, because many infected individuals are not diagnosed and treated, others do not complete treatment, and a small proportion harbor
MeSH term(s)	Animals ; Antitubercular Agents/pharmacology ; Antitubercular Agents/therapeutic use ; Guinea Pigs ; Humans ; Lung ; Mice ; Mycobacterium tuberculosis ; Rabbits ; Tuberculosis/drug therapy ; Zebrafish
Chemical Substances	Antitubercular Agents
Language	English
Publishing date	2021-03-16
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2021.613149
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Article ; Online: Pathogenic mycobacterium upregulates cholesterol 25-hydroxylase to promote granuloma development via foam cell formation.

Zhou, Shuang / Zhang, Ding / Li, Dan / Wang, Hankun / Ding, Cairong / Song, Jingrui / Huang, Weifeng / Xia, Xuan / Zhou, Ziwei / Han, Shanshan / Jin, Zhu / Yan, Bo / Gonzales, Jacqueline / Via, Laura E / Zhang, Lu / Wang, Decheng

iScience

2024 Volume 27, Issue 3, Page(s) 109204

Abstract: Pathogenic mycobacteria orchestrate the complex cell populations known as granuloma that is the hallmark of tuberculosis. Foam cells, a lipid-rich cell-type, are considered critical for granuloma formation; however, the causative factor in foam cell ... ...

Abstract	Pathogenic mycobacteria orchestrate the complex cell populations known as granuloma that is the hallmark of tuberculosis. Foam cells, a lipid-rich cell-type, are considered critical for granuloma formation; however, the causative factor in foam cell formation remains unclear. Atherosclerosis is a chronic inflammatory disease characterized by the abundant accumulation of lipid-laden-macrophage-derived foam cells during which cholesterol 25-hydroxylase (CH25H) is crucial in foam cell formation. Here, we show that
Language	English
Publishing date	2024-02-12
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2024.109204
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Article ; Online: Normalizing granuloma vasculature and matrix improves drug delivery and reduces bacterial burden in tuberculosis-infected rabbits.

Datta, Meenal / Via, Laura E / Dartois, Véronique / Weiner, Danielle M / Zimmerman, Matthew / Kaya, Firat / Walker, April M / Fleegle, Joel D / Raplee, Isaac D / McNinch, Colton / Zarodniuk, Maksym / Kamoun, Walid S / Yue, Changli / Kumar, Ashwin S / Subudhi, Sonu / Xu, Lei / Barry, Clifton E / Jain, Rakesh K

Proceedings of the National Academy of Sciences of the United States of America

2024 Volume 121, Issue 14, Page(s) e2321336121

Abstract: Host-directed therapies (HDTs) represent an emerging approach for bacterial clearance during tuberculosis (TB) infection. While most HDTs are designed and implemented for immuno-modulation, other host targets-such as nonimmune stromal components found in ...

Abstract	Host-directed therapies (HDTs) represent an emerging approach for bacterial clearance during tuberculosis (TB) infection. While most HDTs are designed and implemented for immuno-modulation, other host targets-such as nonimmune stromal components found in pulmonary granulomas-may prove equally viable. Building on our previous work characterizing and normalizing the aberrant granuloma-associated vasculature, here we demonstrate that FDA-approved therapies (bevacizumab and losartan, respectively) can be repurposed as HDTs to normalize blood vessels and extracellular matrix (ECM), improve drug delivery, and reduce bacterial loads in TB granulomas. Granulomas feature an overabundance of ECM and compressed blood vessels, both of which are effectively reduced by losartan treatment in the rabbit model of TB. Combining both HDTs promotes secretion of proinflammatory cytokines and improves anti-TB drug delivery. Finally, alone and in combination with second-line antitubercular agents (moxifloxacin or bedaquiline), these HDTs significantly reduce bacterial burden. RNA sequencing analysis of HDT-treated lung and granuloma tissues implicates up-regulated antimicrobial peptide and proinflammatory gene expression by ciliated epithelial airway cells as a putative mechanism of the observed antitubercular benefits in the absence of chemotherapy. These findings demonstrate that bevacizumab and losartan are well-tolerated stroma-targeting HDTs, normalize the granuloma microenvironment, and improve TB outcomes, providing the rationale to clinically test this combination in TB patients.
MeSH term(s)	Humans ; Animals ; Rabbits ; Mycobacterium tuberculosis ; Bevacizumab/pharmacology ; Losartan/pharmacology ; Tuberculosis/microbiology ; Antitubercular Agents/pharmacology ; Granuloma ; Latent Tuberculosis/microbiology
Chemical Substances	Bevacizumab (2S9ZZM9Q9V) ; Losartan (JMS50MPO89) ; Antitubercular Agents
Language	English
Publishing date	2024-03-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2321336121
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Article ; Online: A Novel Tool to Identify Bactericidal Compounds against Vulnerable Targets in Drug-Tolerant M. tuberculosis found in Caseum.

Sarathy, Jansy P / Xie, Min / Jones, Richard M / Chang, Adrienne / Osiecki, Paulina / Weiner, Danielle / Tsao, Wen-Shan / Dougher, Maureen / Blanc, Landry / Fotouhi, Nader / Via, Laura E / Barry, Clifton E / De Vlaminck, Iwijn / Sherman, David R / Dartois, Véronique A

mBio

2023 Volume 14, Issue 2, Page(s) e0059823

Abstract: Caseous necrosis is a hallmark of tuberculosis (TB) pathology and creates a niche for drug-tolerant persisters within the host. Cavitary TB and high bacterial burden in caseum require longer treatment duration. ... ...

Abstract	Caseous necrosis is a hallmark of tuberculosis (TB) pathology and creates a niche for drug-tolerant persisters within the host. Cavitary TB and high bacterial burden in caseum require longer treatment duration. An
MeSH term(s)	Animals ; Mycobacterium tuberculosis/genetics ; Antitubercular Agents/pharmacology ; Antitubercular Agents/therapeutic use ; Tuberculosis/drug therapy ; Tuberculosis/microbiology ; Tuberculosis, Multidrug-Resistant ; Lipids
Chemical Substances	Antitubercular Agents ; Lipids
Language	English
Publishing date	2023-04-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mbio.00598-23
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Article ; Online: Sputum lipoarabinomannan (LAM) as a biomarker to determine sputum mycobacterial load: exploratory and model-based analyses of integrated data from four cohorts.

Jones, Aksana / Saini, Jay / Kriel, Belinda / Via, Laura E / Cai, Yin / Allies, Devon / Hanna, Debra / Hermann, David / Loxton, Andre G / Walzl, Gerhard / Diacon, Andreas H / Romero, Klaus / Higashiyama, Ryo / Liu, Yongge / Berg, Alexander

BMC infectious diseases

2022 Volume 22, Issue 1, Page(s) 327

Abstract: Background: Despite the high global disease burden of tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb) infection, novel treatments remain an urgent medical need. Development efforts continue to be hampered by the reliance on ... ...

Abstract	Background: Despite the high global disease burden of tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb) infection, novel treatments remain an urgent medical need. Development efforts continue to be hampered by the reliance on culture-based methods, which often take weeks to obtain due to the slow growth rate of Mtb. The availability of a "real-time" measure of treatment efficacy could accelerate TB drug development. Sputum lipoarabinomannan (LAM; an Mtb cell wall glycolipid) has promise as a pharmacodynamic biomarker of mycobacterial sputum load. Methods: The present analysis evaluates LAM as a surrogate for Mtb burden in the sputum samples from 4 cohorts of a total of 776 participants. These include those from 2 cohorts of 558 non-TB and TB participants prior to the initiation of treatment (558 sputum samples), 1 cohort of 178 TB patients under a 14-day bactericidal activity trial with various mono- or multi-TB drug therapies, and 1 cohort of 40 TB patients with data from the first 56-day treatment of a standard 4-drug regimen. Results: Regression analysis demonstrated that LAM was a predictor of colony-forming unit (CFU)/mL values obtained from the 14-day treatment cohort, with well-estimated model parameters (relative standard error ≤ 22.2%). Moreover, no changes in the relationship between LAM and CFU/mL were observed across the different treatments, suggesting that sputum LAM can be used to reasonably estimate the CFU/mL in the presence of treatment. The integrated analysis showed that sputum LAM also appears to be as good a predictor of time to Mycobacteria Growth Incubator Tube (MGIT) positivity as CFU/mL. As a binary readout, sputum LAM positivity is a strong predictor of solid media or MGIT culture positivity with an area-under-the-curve value of 0.979 and 0.976, respectively, from receiver-operator curve analysis. Conclusions: Our results indicate that sputum LAM performs as a pharmacodynamic biomarker for rapid measurement of Mtb burden in sputum, and thereby may enable more efficient early phase clinical trial designs (e.g., adaptive designs) to compare candidate anti-TB regimens and streamline dose selection for use in pivotal trials. Trial registration NexGen EBA study (NCT02371681).
MeSH term(s)	Biomarkers ; Humans ; Lipopolysaccharides/analysis ; Mycobacterium tuberculosis ; Sputum/microbiology
Chemical Substances	Biomarkers ; Lipopolysaccharides ; lipoarabinomannan
Language	English
Publishing date	2022-04-02
Publishing country	England
Document type	Clinical Study ; Journal Article
ZDB-ID	2041550-3
ISSN	1471-2334 ; 1471-2334
ISSN (online)	1471-2334
ISSN	1471-2334
DOI	10.1186/s12879-022-07308-3
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Article ; Online: E3 Ligase FBXW7 Facilitates

Song, Jingrui / Chao, Jin / Hu, Xiaohong / Wen, Xin / Ding, Cairong / Li, Dan / Zhang, Ding / Han, Shanshan / Yu, Xiang / Yan, Bo / Jin, Zhu / Song, Yinhong / Gonzales, Jacqueline / Via, Laura E / Zhang, Lu / Wang, Decheng

Frontiers in cellular and infection microbiology

2022 Volume 12, Page(s) 851197

Abstract: Tumor necrosis factor alpha (TNF-α) is a crucial factor in the control ... ...

Abstract	Tumor necrosis factor alpha (TNF-α) is a crucial factor in the control of
MeSH term(s)	Animals ; F-Box-WD Repeat-Containing Protein 7/genetics ; F-Box-WD Repeat-Containing Protein 7/metabolism ; Immune Evasion ; Mice ; Mycobacterium marinum/genetics ; Mycobacterium tuberculosis ; Tumor Necrosis Factor-alpha/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	F-Box-WD Repeat-Containing Protein 7 ; Tumor Necrosis Factor-alpha ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2022-05-16
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2022.851197
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Article ; Online: An In Vitro Caseum Binding Assay that Predicts Drug Penetration in Tuberculosis Lesions.

Sarathy, Jansy P / Liang, Hsin-Pin Ho / Weiner, Danielle / Gonzales, Jacqueline / Via, Laura E / Dartois, Véronique

Journal of visualized experiments : JoVE

2017 , Issue 123

Abstract: The eradication of tuberculosis disease requires drug regimens that can penetrate the multiple layers of complex pulmonary lesions. Drug distribution in the caseous cores of cavities and lesions is especially crucial because they harbor subpopulations of ...

Abstract	The eradication of tuberculosis disease requires drug regimens that can penetrate the multiple layers of complex pulmonary lesions. Drug distribution in the caseous cores of cavities and lesions is especially crucial because they harbor subpopulations of drug-tolerant bacteria also commonly referred to as persisters. Existing methods for the measurement of drug penetration in tuberculosis lesions involve costly and time-consuming in vivo pharmacokinetic studies coupled to bioanalytical or imaging techniques. The in vitro measurement of drug binding to caseum macromolecules was proposed as an alternative to such techniques since this binding hinders the passive diffusion of drug molecules through caseum. Rapid equilibrium dialysis is a fast and reliable system for performing plasma protein and tissue binding studies. In this protocol, we used a rapid equilibrium dialysis (RED) device to measure drug binding to homogenates of caseum that is excised from the lesions and cavities of tuberculosis-infected rabbits. The protocol also describes how to generate a surrogate matrix from lipid loaded THP-1 macrophages to use in place of caseum. This caseum/surrogate binding assay is an important tool in tuberculosis drug discovery and can be adapted to help study drug distribution in lesions or abscesses caused by other diseases.
MeSH term(s)	Animals ; Antitubercular Agents/metabolism ; Antitubercular Agents/pharmacokinetics ; Antitubercular Agents/pharmacology ; Antitubercular Agents/therapeutic use ; Biological Assay/methods ; Drug Discovery/methods ; In Vitro Techniques/methods ; Lung/drug effects ; Lung/pathology ; Macrophages/metabolism ; Rabbits ; Tuberculosis/drug therapy ; Tuberculosis/pathology
Chemical Substances	Antitubercular Agents
Language	English
Publishing date	2017-05-08
Publishing country	United States
Document type	Journal Article ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/55559
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