ArticleProceedings of the National Academy of Sciences of the United States of America2024
Normalizing granuloma vasculature and matrix improves drug delivery and reduces bacterial burden in tuberculosis-infected rabbits.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 17 citations in OpenAlex.
- Host-pathogen interactions in tuberculosis: from immunological mechanisms to translational applications.Cell insight · 2026Review
- The study of immunological markers in tuberculosis across animal models and its translation to human research.Lab animal · 2026Review
- Article
- Sertraline Enhances Bacterial Control without Adversely Affecting the Pharmacodynamic-Pharmacokinetic Properties of Frontline Tuberculosis Drugs.ACS pharmacology & translational science · 2026Article
- Losartan Alleviates Chemical Burn-Induced Limbal Stem Cell Deficiency: Repurposing a Venerable Anti-Hypertension Drug.Investigative ophthalmology & visual science · 2026Article
- Levofloxacin-Catalase-PLGA Nanoparticles Potentiate Sonodynamic Therapy to Alleviate BCG-Induced Tuberculous Granulomas via PI3K/Akt/VEGF Pathway Suppression in Rats.International journal of nanomedicine · 2026Article
- Advancing Tuberculosis Chemotherapy: Targeted Nanomedicines for the Mycobacterium TB Granuloma.Small (Weinheim an der Bergstrasse, Germany) · 2025Review
- Rankings of tuberculosis antibiotic treatment regimens are sensitive to spatial scale, detection limit, and initial host bacterial burden.Journal of theoretical biology · 2025Article
- Insight into blood proteinase-inhibitor system and pathogenesis of renal tuberculosis induced by phylogenomically different Mycobacterium tuberculosis strains in rabbit model.BMC nephrology · 2025Article
- Advances in Host-Pathogen Interactions in Tuberculosis: Emerging Strategies for Therapeutic Intervention.International journal of molecular sciences · 2025Review
- Microenvironments of tuberculous granuloma: advances and opportunities for therapy.Frontiers in immunology · 2025Review
- Leveraging insights from cancer to improve tuberculosis therapy.Trends in molecular medicine · 2025Article
- Novel 3-D Macrophage Spheroid Model Reveals Reciprocal Regulation of Immunomechanical Stress and Mechano-Immunological Response.Cellular and molecular bioengineering · 2024Article
- Article
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Authors and funding
18 authors at 4 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.