Elevated plasma matrix metalloproteinases associate with Mycobacterium tuberculosis blood stream infection and mortality in HIV-associated tuberculosis

N F Walker; C Schutz; A Ward; D Barr; C Opondo; M Shey; P T Elkington; K A Wilkinson; R J Wilkinson; G Meintjes

doi:10.1101/2023.12.12.23299845

Elevated plasma matrix metalloproteinases associate with Mycobacterium tuberculosis blood stream infection and mortality in HIV-associated tuberculosis

medRxiv [Preprint]. 2023 Dec 13:2023.12.12.23299845. doi: 10.1101/2023.12.12.23299845.

Authors

N F Walker^{1

2

3}, C Schutz^{2

4}, A Ward⁴, D Barr^{2

5

6}, C Opondo⁷, M Shey^{2

4}, P T Elkington⁸, K A Wilkinson^{2

4

9}, R J Wilkinson^{2

4

9

10}, G Meintjes^{2

4}

Affiliations

¹ Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, United Kingdom.
² Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa.
³ TB Centre and Department of Clinical Research, London School of Hygiene and Tropical Medicine, WC1E 7HT, United Kingdom.
⁴ Department of Medicine, University of Cape Town, Observatory 7925, South Africa.
⁵ Wellcome Liverpool Glasgow Centre for Global Health Research, University of Liverpool, Liverpool, L69 3BX, United Kingdom.
⁶ Department of Infectious Diseases, Queen Elizabeth University Hospital, Glasgow, G51 4TF.
⁷ Department of Medical Statistics, London School of Hygiene and Tropical Medicine, WC1E 7HT, United Kingdom.
⁸ NIHR Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, United Kingdom.
⁹ The Francis Crick Institute, London, NW1 1AT, United Kingdom.
¹⁰ Department of Infectious Diseases, Imperial College London, W12 0NN, United Kingdom.

Abstract

Mortality from HIV-associated tuberculosis (HIV-TB) is high, particularly among hospitalised patients. In 433 people living with HIV admitted to hospital with symptoms of TB, we investigated plasma matrix metalloproteinases (MMP) and matrix-derived biomarkers in relation to TB diagnosis, mortality and Mycobacterium tuberculosis (Mtb) blood stream infection (BSI). Compared to other diagnoses, MMP-8 was elevated in confirmed TB and in Mtb-BSI, positively correlating with extracellular matrix breakdown products. Baseline MMP-3, -7, -8, -10 and procollagen III N-terminal propeptide (PIIINP) associated with Mtb-BSI and 12-week mortality. These findings implicate MMP dysregulation in pathophysiology of advanced HIV-TB and support MMP inhibition as a host-directed therapeutic strategy for HIV-TB.

Keywords: HIV; Tuberculosis; matrix metalloproteinase; mortality.

Publication types

Preprint

Abstract

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