title: Anti-vascular endothelial growth factor treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery.
abstract: Tuberculosis (TB) causes almost 2 million deaths annually, and an increasing number of patients are resistant to existing therapies. Patients who have TB require lengthy chemotherapy, possibly because of poor penetration of antibiotics into granulomas where the bacilli reside. Granulomas are morphologically similar to solid cancerous tumors in that they contain hypoxic microenvironments and can be highly fibrotic. Here, we show that TB-infected rabbits have impaired small molecule distribution into these disease sites due to a functionally abnormal vasculature, with a low-molecular-weight tracer accumulating only in peripheral regions of granulomatous lesions. Granuloma-associated vessels are morphologically and spatially heterogeneous, with poor vessel pericyte coverage in both human and experimental rabbit TB granulomas. Moreover, we found enhanced VEGF expression in both species. In tumors, antiangiogenic, specifically anti-VEGF, treatments can "normalize" their vasculature, reducing hypoxia and creating a window of opportunity for concurrent chemotherapy; thus, we investigated vessel normalization in rabbit TB granulomas. Treatment of TB-infected rabbits with the anti-VEGF antibody bevacizumab significantly decreased the total number of vessels while normalizing those vessels that remained. As a result, hypoxic fractions of these granulomas were reduced and small molecule tracer delivery was increased. These findings demonstrate that bevacizumab treatment promotes vascular normalization, improves small molecule delivery, and decreases hypoxia in TB granulomas, thereby providing a potential avenue to improve delivery and efficacy of current treatment regimens.
authors.affiliation: Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Department of Chemical and Biological Engineering, Tufts University, Medford, MA 02155;
authors.forename: Meenal
authors.initials: M
authors.lastname: Datta
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Laura E
authors.initials: LE
authors.lastname: Via
authors.affiliation: Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Walid S
authors.initials: WS
authors.lastname: Kamoun
authors.affiliation: Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Chong
authors.initials: C
authors.lastname: Liu
authors.affiliation: Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Giorgio
authors.initials: G
authors.lastname: Seano
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Weiner
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Daniel
authors.initials: D
authors.lastname: Schimel
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Kathleen
authors.initials: K
authors.lastname: England
authors.affiliation: Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; and.
authors.forename: John D
authors.identifier: http://orcid.org/0000-0002-9828-8203
authors.initials: JD
authors.lastname: Martin
authors.affiliation: Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Xing
authors.initials: X
authors.lastname: Gao
authors.affiliation: Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892; Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Rondebosch 7701, South Africa cbarry@mail.nih.gov jain@steele.mgh.harvard.edu.
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.affiliation: Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; cbarry@mail.nih.gov jain@steele.mgh.harvard.edu.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000068258:Bevacizumab; D001808:Blood Vessels / Q000187:drug effects* / Q000473:pathology; D004396:Coloring Agents / Q000493:pharmacokinetics; D015769:Granuloma, Respiratory Tract / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D020286:Pericytes / Q000473:pathology; D049268:Positron-Emission Tomography; D011817:Rabbits; D014057:Tomography, X-Ray Computed; D014376:Tuberculosis / Q000150:complications / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D004396:Coloring Agents; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab
keywords: Mycobacterium tuberculosis; antiangiogenesis; host-directed therapy; hypoxia; rabbit model