Walker, Naomi F., Wilkinson, Katalin A., Meintjes, Graeme, Tezera, Liku B., Goliath, Rene, Peyper, Janique M., Tadokera, Rebecca ORCID: https://orcid.org/0000-0001-5195-2376, Opondo, Charles, Coussens, Anna K., Wilkinson, Robert J., Friedland, Jon S. and Elkington, Paul T. (2017) Matrix Degradation in Human Immunodeficiency Virus Type 1-Associated Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Syndrome: A Prospective Observational Study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 65 (1). pp. 121-132.

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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.

Item Type:	Article
Status:	Published
DOI:	https://doi.org/10.1093/cid/cix231
School/Department:	School of Science, Technology and Health
URI:	https://ray.yorksj.ac.uk/id/eprint/9374

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