Airborne pathogens drive lung inflammation and are transmitted from person to person. Furthermore, immune-mediated tissue damage causes morbidity, organ failure and death. Matrix metalloproteinases (MMPs) have a central role in this immunopathology due to their unique ability to degrade the structural components of the lung extracellular matrix. Recently, we have demonstrated that MMPs are critical drivers of tissue damage in human tuberculosis (TB) (Elkington J Clin Invest 2011). Several MMP inhibitors have been developed for other inflammatory conditions and have a proven safety record in man. MMP inhibition may represent a novel adjunctive therapy to shorten the duration of infectivity, and reduce mortality from human airborne respiratory infections. Hypothesis: MMP activity drives matrix destruction, pathogen dissemination and respiratory failure in human airborne infection.
Aims : to investigate MMP inhibition as host-targeted therapy for airborne infectious disease by studying two globally important pathogens with contrasting pathologies: (i) Mycobacterium tuberculosis which causes chronic destruction of the lung matrix, and (ii) Influenza which drives rapid matrix remodeling and transmission. We will define the role of MMPs in TB and investigate the therapeutic effects of MMP inhibition to improve patient outcomes by studying in vitro human cellular models and in vivo MMP humanized mice. In vitro models of human TB granulomas will be developed using a bio-electrospray technology to produce 3-dimensional TB-impregnated spheroids to study MMP inhibitors. We will investigate the pathology of mycobacterial infection in MMP-1 humanized mice to define the effects of MMP activity and inhibition in vivo. We will study MMP upregulation by influenza A in epithelial cells monocytes and macrophages. A ferret model of influenza infection will be used to study MMP inhibitory activity in vivo and its ability to reduce immune-mediated tissue damage. Summary: This research identifies MMP inhibitors that limit pathology of airborne infection to reduce morbidity, transmission and mortality. The results are relevant not only to TB and pandemic influenza, but also to other rapidly fatal airborne infections (e.g., SARS coronavirus). We will establish a new therapeutic paradigm targeting excessive host MMP activity to improve outcomes in pulmonary infection.

Public Health Relevance

Airborne infection is a primary health threat to the world population, and there is a potential for rapid spread of both pandemic influenza and multidrug resistant agents. Pathogens drive destruction of the extracellular matrix to facilitate their spread and cause morbidity and mortality. Matrix metalloproteinases have a critical role in immune-mediated tissue damage. This project investigates matrix metalloproteinase inhibition as a new therapeutic approach to reduce morbidity and mortality from airborne infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants Phase II (R33)
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Study Section
Special Emphasis Panel (NSS)
Program Officer
Lacourciere, Karen A
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University of Southampton
United Kingdom
Zip Code
SO17 1BJ
Tezera, Liku B; Bielecka, Magdalena K; Elkington, Paul T (2017) Bioelectrospray Methodology for Dissection of the Host-pathogen Interaction in Human Tuberculosis. Bio Protoc 7:
Walker, Naomi F; Wilkinson, Katalin A; Meintjes, Graeme et al. (2017) Matrix Degradation in Human Immunodeficiency Virus Type 1-Associated Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Syndrome: A Prospective Observational Study. Clin Infect Dis 65:121-132
Brace, Patience T; Tezera, Liku B; Bielecka, Magdalena K et al. (2017) Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology. PLoS Pathog 13:e1006367
Chancellor, Andrew; Tocheva, Anna S; Cave-Ayland, Chris et al. (2017) CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains. Proc Natl Acad Sci U S A 114:E10956-E10964
Bielecka, Magdalena K; Tezera, Liku B; Zmijan, Robert et al. (2017) A Bioengineered Three-Dimensional Cell Culture Platform Integrated with Microfluidics To Address Antimicrobial Resistance in Tuberculosis. MBio 8:
Tezera, Liku B; Bielecka, Magdalena K; Chancellor, Andrew et al. (2017) Dissection of the host-pathogen interaction in human tuberculosis using a bioengineered 3-dimensional model. Elife 6:
Kubler, Andre; Larsson, Christer; Luna, Brian et al. (2016) Cathepsin K Contributes to Cavitation and Collagen Turnover in Pulmonary Tuberculosis. J Infect Dis 213:618-27
Elkington, Paul; Tebruegge, Marc; Mansour, Salah (2016) Tuberculosis: An Infection-Initiated Autoimmune Disease? Trends Immunol 37:815-818
Elkington, Paul; Zumla, Alimuddin (2015) Update in Mycobacterium tuberculosis lung disease 2014. Am J Respir Crit Care Med 192:793-8
Al Shammari, Basim; Shiomi, Takayuki; Tezera, Liku et al. (2015) The Extracellular Matrix Regulates Granuloma Necrosis in Tuberculosis. J Infect Dis 212:463-73

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