Matrix Degradation in Human Immunodeficiency Virus Type 1-Associated Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Syndrome: A Prospective Observational Study

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Title: Matrix Degradation in Human Immunodeficiency Virus Type 1-Associated Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Syndrome: A Prospective Observational Study
Authors: Walker, NF
Wilkinson, KA
Meintjes, G
Tezera, LB
Goliath, R
Peyper, JM
Tadokera, R
Opondo, C
Coussens, AK
Wilkinson, RJ
Friedland, JS
Elkington, PT
Item Type: Journal Article
Abstract: Background. Extensive immunopathology occurs in human immunodeficiency virus (HIV)/tuberculosis (TB) coinfection, but the underlying molecular mechanisms are not well-defined. Excessive matrix metalloproteinase (MMP) activity is emerging as a key process but has not been systematically studied in HIV-associated TB. Methods. We performed a cross-sectional study of matrix turnover in HIV type 1 (HIV-1)–infected and –uninfected TB patients and controls, and a prospective cohort study of HIV-1–infected TB patients at risk of TB immune reconstitution inflammatory syndrome (TB-IRIS), in Cape Town, South Africa. Sputum and plasma MMP concentrations were quantified by Luminex, plasma procollagen III N-terminal propeptide (PIIINP) by enzyme-linked immunosorbent assay, and urinary lipoarabinomannan (LAM) by Alere Determine TB LAM assay. Peripheral blood mononuclear cells from healthy donors were cultured with Mycobacterium tuberculosis and extracellular matrix in a 3D model of TB granuloma formation. Results. MMP activity differed between HIV-1–infected and –uninfected TB patients and corresponded with specific TB clinical phenotypes. HIV-1–infected TB patients had reduced pulmonary MMP concentrations, associated with reduced cavitation, but increased plasma PIIINP, compared to HIV-1–uninfected TB patients. Elevated extrapulmonary extracellular matrix turnover was associated with TB-IRIS, both before and during TB-IRIS onset. The predominant collagenase was MMP-8, which was likely neutrophil derived and M. tuberculosis–antigen driven. Mycobacterium tuberculosis–induced matrix degradation was suppressed by the MMP inhibitor doxycycline in vitro. Conclusions. MMP activity in TB differs by HIV-1 status and compartment, and releases matrix degradation products. Matrix turnover in HIV-1–infected patients is increased before and during TB-IRIS, informing novel diagnostic strategies. MMP inhibition is a potential host-directed therapy strategy for prevention and treatment of TB-IRIS.
Issue Date: 5-May-2017
Date of Acceptance: 29-Mar-2017
ISSN: 1058-4838
Publisher: Oxford University Press
Start Page: 121
End Page: 132
Journal / Book Title: Clinical Infectious Diseases
Volume: 65
Issue: 1
Copyright Statement: © 2017 The Author. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Wellcome Trust
Wellcome Trust
Wellcome Trust
Funder's Grant Number: 087754/Z/08/Z
Keywords: Science & Technology
Life Sciences & Biomedicine
Infectious Diseases
immune reconstitution inflammatory syndrome
matrix metalloproteinase
procollagen III N-terminal propeptide
procollagen III N-terminal propeptide.
06 Biological Sciences
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:Department of Medicine

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