@article{Walker2023,
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. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement NFW was supported by an NIHR Academic Clinical Lectureship and funding from Academy of Medical Sciences UK, MRC UK, British Heart Foundation, Arthritis Research UK, Royal College of Physicians and Diabetes UK (Starter Grant for Clinical Lecturers) and British Infection Association (Project Grant). MS is supported by Wellcome (211360/Z/18/Z) and the National Research Foundation of South Africa (NRF, {\#}UID127558). PTE was supported by MRC MR/P023754/1 and MR/W025728/1. RJW is supported by the Francis Crick Institute which is funded by Wellcome (CC2112), Cancer Research UK (CC2112) and UKRI (CC2112). RJW also receives support from Wellcome (203135), EDCTP (SRIA 2015-1065) and NIH (U01AI115940). CS was funded by the South African Medical Research Council under the National Health Scholars Programme. GM was supported by Wellcome (098316, 214321/Z/18/Z, and 203135/Z/16/Z), and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787). The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. The opinions, findings and conclusions expressed in this manuscript reflect those of the authors alone. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the University of Cape Town Human Research Ethics Committee (HREC ref 057/2013) and London School of Hygiene and Tropical Medicine Research Ethics Committee (ref 11710). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All laboratory data in the present study are available upon reasonable request to the authors},
author = {Walker, N F and Schutz, Charlotte and Ward, A and Barr, David A and Opondo, C and Shey, Muki and Elkington, PT and Wilkinson, Katalin A and Wilkinson, Robert J and Meintjes, Graeme A},
doi = {10.1101/2023.12.12.23299845},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Walker et al. - 2023 - Elevated plasma matrix metalloproteinases associate with Mycobacterium tuberculosis blood stream infection and mo.pdf:pdf},
journal = {medRxiv},
keywords = {HIV,OA,Tuberculosis,fund{\_}ack,matrix metalloproteinase,mortality,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {dec},
pages = {2023.12.12.23299845},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Elevated plasma matrix metalloproteinases associate with \textit{Mycobacterium tuberculosis} blood stream infection and mortality in HIV-associated tuberculosis}},
url = {https://www.medrxiv.org/content/10.1101/2023.12.12.23299845v1 https://www.medrxiv.org/content/10.1101/2023.12.12.23299845v1.abstract},
year = {2023}
}

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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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement NFW was supported by an NIHR Academic Clinical Lectureship and funding from Academy of Medical Sciences UK, MRC UK, British Heart Foundation, Arthritis Research UK, Royal College of Physicians and Diabetes UK (Starter Grant for Clinical Lecturers) and British Infection Association (Project Grant). MS is supported by Wellcome (211360/Z/18/Z) and the National Research Foundation of South Africa (NRF, #UID127558). PTE was supported by MRC MR/P023754/1 and MR/W025728/1. RJW is supported by the Francis Crick Institute which is funded by Wellcome (CC2112), Cancer Research UK (CC2112) and UKRI (CC2112). RJW also receives support from Wellcome (203135), EDCTP (SRIA 2015-1065) and NIH (U01AI115940). CS was funded by the South African Medical Research Council under the National Health Scholars Programme. GM was supported by Wellcome (098316, 214321/Z/18/Z, and 203135/Z/16/Z), and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787). The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. The opinions, findings and conclusions expressed in this manuscript reflect those of the authors alone. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the University of Cape Town Human Research Ethics Committee (HREC ref 057/2013) and London School of Hygiene and Tropical Medicine Research Ethics Committee (ref 11710). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. 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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. {\\#}{\\#}{\\#} Competing Interest Statement The authors have declared no competing interest. {\\#}{\\#}{\\#} Funding Statement NFW was supported by an NIHR Academic Clinical Lectureship and funding from Academy of Medical Sciences UK, MRC UK, British Heart Foundation, Arthritis Research UK, Royal College of Physicians and Diabetes UK (Starter Grant for Clinical Lecturers) and British Infection Association (Project Grant). MS is supported by Wellcome (211360/Z/18/Z) and the National Research Foundation of South Africa (NRF, {\\#}UID127558). PTE was supported by MRC MR/P023754/1 and MR/W025728/1. RJW is supported by the Francis Crick Institute which is funded by Wellcome (CC2112), Cancer Research UK (CC2112) and UKRI (CC2112). RJW also receives support from Wellcome (203135), EDCTP (SRIA 2015-1065) and NIH (U01AI115940). CS was funded by the South African Medical Research Council under the National Health Scholars Programme. GM was supported by Wellcome (098316, 214321/Z/18/Z, and 203135/Z/16/Z), and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787). The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. The opinions, findings and conclusions expressed in this manuscript reflect those of the authors alone. {\\#}{\\#}{\\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the University of Cape Town Human Research Ethics Committee (HREC ref 057/2013) and London School of Hygiene and Tropical Medicine Research Ethics Committee (ref 11710). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All laboratory data in the present study are available upon reasonable request to the authors},\r\nauthor = {Walker, N F and Schutz, Charlotte and Ward, A and Barr, David A and Opondo, C and Shey, Muki and Elkington, PT and Wilkinson, Katalin A and Wilkinson, Robert J and Meintjes, Graeme A},\r\ndoi = {10.1101/2023.12.12.23299845},\r\nfile = {:C$\\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Walker et al. - 2023 - Elevated plasma matrix metalloproteinases associate with Mycobacterium tuberculosis blood stream infection and mo.pdf:pdf},\r\njournal = {medRxiv},\r\nkeywords = {HIV,OA,Tuberculosis,fund{\\_}ack,matrix metalloproteinase,mortality,original},\r\nmendeley-tags = {OA,fund{\\_}ack,original},\r\nmonth = {dec},\r\npages = {2023.12.12.23299845},\r\npublisher = {Cold Spring Harbor Laboratory Press},\r\ntitle = {{Elevated plasma matrix metalloproteinases associate with \\textit{Mycobacterium tuberculosis} blood stream infection and mortality in HIV-associated tuberculosis}},\r\nurl = {https://www.medrxiv.org/content/10.1101/2023.12.12.23299845v1 https://www.medrxiv.org/content/10.1101/2023.12.12.23299845v1.abstract},\r\nyear = {2023}\r\n}\r\n","author_short":["Walker, N F","Schutz, C.","Ward, A","Barr, D. 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