Assistant Professor University of Notre Dame South Bend, Indiana, United States
Introduction: Tuberculosis (TB) remains a global scourge and results in millions of deaths annually. Current and novel antibacterial drugs are limited in their efficacy by physical barriers to drug delivery posed at the site of disease: the pulmonary granuloma. Targeting abnormal features of the granuloma microenvironment, including aberrant blood vessels and excessive extracellular matrix, with host-directed therapies offers a path forward to improving drug delivery and efficacy.
Materials and
Methods: In a rabbit model of TB, safe and repurposed agents—tested originally in the context of cancer—remodel granulomas, improve drug delivery, promote antibacterial host responses, and enhance therapeutic outcomes. 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.
Results, Conclusions, and Discussions: 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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