Normalizing granuloma vasculature and matrix improves drug delivery and reduces bacterial burden in tuberculosis- infected rabbits

• 成果类型: Article
• 署名作者: Datta, Meenal; Via, Laura E.; Dartois, Veronique; 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.
• 署名单位: Capital Medical University; University of Notre Dame; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; National Institutes of Health (NIH) - USA; Division of Intramural Research (DIR); NIH National Institute of Allergy & Infectious Diseases (NIAID); National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Division of Intramural Research (DIR); National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9333
• DOI: 10.1073/pnas.2321336121
• 发表日期: 2024-04-04
• 关键词: tumor microenvironment; strategies; GROWTH

摘要

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.