机构：[1]Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556[2]Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114[3]Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Disease, NIH, Bethesda, MD 20892[4]Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110[5]Hackensack Meridian School of Medicine, Hackensack Meridian Health, Nutley, NJ 07110[6]Tuberculosis Imaging Program, Division of Intramural Research, National Institute of Allergy and Infectious Disease, NIH, Bethesda, MD 20892[7]Bioinformatics and Computational Bioscience Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892
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.
基金：
Bill and Melinda Gates Foundation [OPP1140482, INV-006974]; NIH [F31-HL126449, R35-CA197743, U01-CA224348, R01-CA259253, R01-CA208205, R01-NS118929, U01CA261842, R35-GM151041, R01-NS126187, R01-DC020724]; Intramural research program of the NIH NIAID; NIAID BCBB Support Services Contract [HHSN316201300006W/75N93022F00001]; Ludwig Cancer Center at Harvard; Nile Albright Research Foundation; National Foundation for Cancer Research; Jane's Trust Foundation; Department of Defense; American Cancer Society; Children's Tumor Foundation; Bill and Melinda Gates Foundation [OPP1140482] Funding Source: Bill and Melinda Gates Foundation
第一作者机构：[1]Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556[2]Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
共同第一作者：
通讯作者：
通讯机构：[1]Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556[2]Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
推荐引用方式(GB/T 7714)：
Datta Meenal,Via Laura E.,Dartois Veronique,et al.Normalizing granuloma vasculature and matrix improves drug delivery and reduces bacterial burden in tuberculosis- infected rabbits[J].PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA.2024,121(14):doi:10.1073/pnas.2321336121.
APA：
Datta, Meenal,Via, Laura E.,Dartois, Veronique,Weiner, Danielle M.,Zimmerman, Matthew...&Jain, Rakesh K..(2024).Normalizing granuloma vasculature and matrix improves drug delivery and reduces bacterial burden in tuberculosis- infected rabbits.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,121,(14)
MLA：
Datta, Meenal,et al."Normalizing granuloma vasculature and matrix improves drug delivery and reduces bacterial burden in tuberculosis- infected rabbits".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 121..14(2024)
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