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Matrix degradation in HIV-1-associated tuberculosis and tuberculosis immune reconstitution inflammatory syndrome: a prospective, observational study

Matrix degradation in HIV-1-associated tuberculosis and tuberculosis immune reconstitution inflammatory syndrome: a prospective, observational study
Matrix degradation in HIV-1-associated tuberculosis and tuberculosis immune reconstitution inflammatory syndrome: a prospective, observational study
Background: extensive immunopathology occurs in HIV-tuberculosis (TB) co-infection 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-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 ELISA and urinary lipoarabinomannan (LAM) by Alere Determine TB LAM assay. Peripheral blood mononuclear cells from healthy donors were cultured with Mycobacterium tuberculosis (Mtb) and extracellular matrix in a 3-D model of TB granuloma formation.

Findings: 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 extra-pulmonary extracellular matrix turnover associated with TB-IRIS, both before and during TB-IRIS onset. The predominant collagenase was MMP-8, which was likely neutrophil-derived and Mtb-antigen-driven. Mtb-induced matrix degradation was suppressed by the MMP inhibitor doxycycline in-vitro.

Interpretation: 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.
1058-4838
Walker, N.F.
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Wilkinson, K.A.
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Meintjes, G.
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Tezera, L.B.
c5598dbf-23a8-4934-96a4-7c783bf9e776
Goliath, R.
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Peyper, J.M.
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Tadokera, R.
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Opondo, C.
b82c5cf4-da40-494a-b73a-170fe5c7388f
Coussens, A.K.
5ad7e72b-9f19-41da-b9de-74b496a2b602
Wilkinson, R.J.
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Friedland, J.S.
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Elkington, P.T.
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Walker, N.F.
5f89ac75-7335-4d8a-bc46-f23d5933ac9f
Wilkinson, K.A.
85c0acc3-9f8f-409b-a580-d7ae715ce21c
Meintjes, G.
3ddec2e1-5c8b-420c-8d07-9c8751e78c53
Tezera, L.B.
c5598dbf-23a8-4934-96a4-7c783bf9e776
Goliath, R.
c8d7658d-ccec-4b0f-8d16-c3637270076e
Peyper, J.M.
c0da828a-43d7-4c61-a52f-8efc68094fea
Tadokera, R.
4e3f9fca-06c5-41bd-9e6d-edbb9ef808cc
Opondo, C.
b82c5cf4-da40-494a-b73a-170fe5c7388f
Coussens, A.K.
5ad7e72b-9f19-41da-b9de-74b496a2b602
Wilkinson, R.J.
43876444-23bb-417e-abc8-50a9d4ef55d4
Friedland, J.S.
66b7d55c-8a96-44b2-823f-cfd201d715f3
Elkington, P.T.
60828c7c-3d32-47c9-9fcc-6c4c54c35a15

Walker, N.F., Wilkinson, K.A., Meintjes, G., Tezera, L.B., Goliath, R., Peyper, J.M., Tadokera, R., Opondo, C., Coussens, A.K., Wilkinson, R.J., Friedland, J.S. and Elkington, P.T. (2017) Matrix degradation in HIV-1-associated tuberculosis and tuberculosis immune reconstitution inflammatory syndrome: a prospective, observational study. Clinical Infectious Diseases, 10 (1093). (doi:10.1093/cid/cix231).

Record type: Article

Abstract

Background: extensive immunopathology occurs in HIV-tuberculosis (TB) co-infection 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-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 ELISA and urinary lipoarabinomannan (LAM) by Alere Determine TB LAM assay. Peripheral blood mononuclear cells from healthy donors were cultured with Mycobacterium tuberculosis (Mtb) and extracellular matrix in a 3-D model of TB granuloma formation.

Findings: 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 extra-pulmonary extracellular matrix turnover associated with TB-IRIS, both before and during TB-IRIS onset. The predominant collagenase was MMP-8, which was likely neutrophil-derived and Mtb-antigen-driven. Mtb-induced matrix degradation was suppressed by the MMP inhibitor doxycycline in-vitro.

Interpretation: 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.

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CID_TB_MMP_vfinal - Accepted Manuscript
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Accepted/In Press date: 2 March 2017
e-pub ahead of print date: 5 May 2017
Published date: 1 July 2017
Additional Information: Running title: Matrix degradation in HIV-associated TB
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 406202
URI: https://eprints.soton.ac.uk/id/eprint/406202
ISSN: 1058-4838
PURE UUID: f78ab2a8-e01a-44e4-8dbf-d0634ddb804b
ORCID for L.B. Tezera: ORCID iD orcid.org/0000-0002-7898-6709
ORCID for P.T. Elkington: ORCID iD orcid.org/0000-0003-0390-0613

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Date deposited: 10 Mar 2017 10:42
Last modified: 10 Dec 2019 06:10

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Contributors

Author: N.F. Walker
Author: K.A. Wilkinson
Author: G. Meintjes
Author: L.B. Tezera ORCID iD
Author: R. Goliath
Author: J.M. Peyper
Author: R. Tadokera
Author: C. Opondo
Author: A.K. Coussens
Author: R.J. Wilkinson
Author: J.S. Friedland
Author: P.T. Elkington ORCID iD

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