The role of Cathepsin S in PAR-1 mediated lung inflammation - a new paradigm for neutrophilic inflammation

Lead Research Organisation: Queen's University of Belfast
Department Name: Centre for Experimental Medicine

Abstract

During an infection the body normally responds by mounting an immune response. This generally involves the recruitment of white blood cells that play a role in removing the invading organism. A specific white blood cell, called the neutrophil, is pivotally involved in the process of removing bacteria from sites of infection including the lung. In some cases of disease, neutrophils arrive in significant numbers to the lung, and other organ sites, not as result of infection but as a result of a poorly-defined inflammatory process. When they arrive at the lung these neutrophils become involved in causing damage to the lung tissue. We have uncovered a new pathway by which neutrophils migrate to the lung involving the role of a protein called cathepsin S (CTSS). The identification of CTSS in this role has been uncovered by the use of specific inhibitors of CTSS but we now wish to confirm further the role of CTSS in neutrophil recruitment using novel genetically generated models in which key CTSS targets - called protease activated receptors (PARs) will be ablated thus allowing us to confirm the role of CTSS in neutrophil recruitment. We will also expand this project beyond simple mouse models to confirm a role for CTSS in neutrophil recruitment in unique porcine and human ex vivo lung perfusion (EVLP) models. The very clear application of this study is in the targeting of CTSS to regulate neutrophil recruitment in disease, particularly lung disease, although there is a potential role for this CTSS-mediated pathway in other disease processes including gastrointestinal and dermatological disorders. To this end, we have a very active collaboration with companies that are involved in the design and clinical testing of CTSS inhibitors including Virobay. Indeed, a lot of the preliminary data that we have generated for this project includes the use of the Virobay CTSS inhibitor. Future studies looking at the clinical evaluation of CTSS inhibitors in lung disease in collaboration with Virobay (or other Pharma developing clinical CTSS inhibitors) is a very real possibility as we are set-up to carry out such studies in Queen's Belfast as part of the UK Respiratory Translational Research Partnership.

Technical Summary

Neutrophil recruitment to sites of infection is a common and necessary process to remove bacteria in the lung. In some cases of disease, neutrophils arrive in significant numbers to the lung, and other organ sites, not as result of infection but as a result of a poorly-defined inflammatory process. In the case of acute lung inflammation, excessive neutrophil recruitment can lead to damage which is mediated, in part, by the neutrophil. We have uncovered a new pathway by which neutrophils migrate to the lung involving the role of the protease, cathepsin S (CTSS). The identification of CTSS in this role has been uncovered by the use of specific inhibitors of CTSS. We now wish to confirm further the role of CTSS in neutrophil recruitment using novel new genetically generated models in which a new target for CTSS activity - protease activated receptor 1 (PAR-1) is genetically ablated thus allowing us to confirm the role of CTSS in neutrophil recruitment via PAR-1. We will also expand this project beyond simple mouse models to confirm a role for CTSS in neutrophil recruitment in unique porcine and human ex vivo lung perfusion (EVLP) acute inflammation models and using specific PAR antagonists. The very clear application of this study is in the targeting of CTSS to regulate neutrophil recruitment in disease, particularly lung disease, although there is a potential role for this CTSS-mediated pathway in other disease processes including gastrointestinal and dermatological disorders. To this end, we have a very active collaboration with companies that are involved in the design and clinical testing of CTSS inhibitors including Virobay. Future studies looking at the evaluation of CTSS inhibitors in lung disease in collaboration with Virobay and other pharma is a very real possibility as we are set-up to carry out such studies in Queen's Belfast as part of the UK Respiratory Translational Research Partnership.

Planned Impact

Who Will Benefit from this Research?

The findings from this study will benefit the life science community especially those working in the area of innate host defense and regulation of inflammation. In addition, the findings may be of therapeutic value given that CTSS is a therapeutic target in other processes and disease including pain relief and cancer. For example, cathepsin S inhibitors are being developed by various companies including Virobay, Johnson & Johnson, Eli Lilly and Medavir and the opportunity exists to develop some of these CTSS inhibitors for treatment of dysregulated inflammation - CTSS inhibitors are currently being developed for the treatment of autoimmune disease so our findings may expand the disease-relevant targets for these companies. Clearly, charities linked to inflammatory diseases including the British Thoracic Society and the British Lung Foundation will also be interested in new data and potential targets for the treatment of inflammatory lung disease. Such societies/charities generally have excellent links with local and national governments who would also be interested in the development of new therapies, especially therapeutics that could reduce healthcare costs and improve quality of life as well as being of use in the treatment of other acute (and chronic) lung diseases with an inflammation/infection component which may be potentially related to increased CTSS activity including most significantly chronic obstructive pulmonary disease (COPD).

How will they benefit from this research?

We would be keen to pursue pre-clinical studies in collaboration with our contacts in the pharma industry (eg. Leslie Holsinger and Robert Booth at Virobay and other pharma companies developing CTSS inhibitors) by securing future funding from MRC perhaps via the MICA or DPFS funding stream. Subsequent studies could lead to a phase 1 clinical trial that could be carried out in conjunction with clinical colleagues in Queen's. We have an excellent pre-clinical and clinical trials programme at QUB led by Professor Danny McAuley (one of the co-PIs on this application) and there are clear pathways to development of CTSS inhibitors initially in the human LPS model and, if successful, ARDS patients. Such studies could be funded by NIHR/EME programmes. The development of CTSS inhibitors for treatment of lung disease patients could improve the lifestyle of these patients as well as increase their lifespan. There could also be spin-offs from our research leading to investigation of CTSS in other diseases such as COPD and colitis which represents a much larger patient cohort worldwide with greater impact on patient treatment as well as representing a much larger market for pharma companies developing CTSS inhibitors.

Publications

10 25 50
 
Description Cathepsin S inhibition as a treatment for rhinovirus-induced inflammation, infection and cell death in Chronic Obstructive Pulmonary Disease (COPD)
Amount £44,587 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2020 
End 09/2021
 
Description Cathepsin S targeting as a therapy for CF lung disease
Amount £143,586 (GBP)
Funding ID WELDON18G0 
Organisation Cystic Fibrosis Foundation 
Sector Charity/Non Profit
Country United States
Start 08/2018 
End 07/2020
 
Description Exosome protease-mediated inflammation, tissue damage and cellular senescence in pathogen-induced lung disease
Amount £55,000 (GBP)
Organisation Department for the Economy, Northern Ireland 
Sector Public
Country United Kingdom
Start 10/2021 
End 09/2024
 
Description Leveraged PhD studentship to support MRC grant - The role of Cathepsin S in PAR-1 mediated lung inflammation - a new paradigm for neutrophilic inflammation
Amount £54,000 (GBP)
Organisation Department for the Economy, Northern Ireland 
Sector Public
Country United Kingdom
Start 10/2017 
End 09/2020
 
Description Cathepsin S collaboration with Dr Pat Geraghty 
Organisation SUNY Downstate Medical Center
Country United States 
Sector Hospitals 
PI Contribution We have established a collaboration with Dr Pat Geraghty at SUNY Downstate Medical Center, New York. We have brought mechanistic insight to Dr Geraghty's study evaluating a role for cathepsin S in cigarette-related chronic obstructive lung disease. The data has contributed to a publication between both laboratories.
Collaborator Contribution We have obtained precious samples from Dr Geraghty's chronic cigarette smoking mouse model which has allowed us to evaluate cathepsin S activity and levels in the lungs of these mice.
Impact 1. Doherty DF, Nath S, Poon J, Foronjy RF, Ohlmeyer M, Dabo AJ, Salathe M, Birrell M, Belvisi M, Baumlin N, Kim MD, Weldon S, Taggart C, Geraghty P. Protein Phosphatase 2A Reduces Cigarette Smoke-induced Cathepsin S and Loss of Lung Function Am J Respir Crit Care Med. 2019 Jul 1;200(1):51-62 2. Foronjy RF, Taggart CC, Dabo AJ, Weldon S, Cummins N, Geraghty P. Type-I interferons induce lung protease responses following respiratory syncytial virus infection via RIG-I-like receptors. Mucosal Immunol. 2015 Jan;8(1):161-75 3. Foronjy RF, Dabo AJ, Taggart CC, Weldon S, Geraghty P. Respiratory syncytial virus infections enhance cigarette smoke induced COPD in mice. PLoS One. 2014 Feb 28;9(2):e90567
Start Year 2012
 
Description Collaboration with Dr Mark Birrell and Prof Maria Belvisi, Imperial College London 
Organisation Imperial College London
Department National Heart & Lung Institute (NHLI)
Country United Kingdom 
Sector Academic/University 
PI Contribution We highlighted to Dr Birrell and Prof Belvisi a potential role for cathepsin S in chronic obstructive pulmonary disease (COPD) which resulted in a co-authored publication
Collaborator Contribution We obtained mouse samples from Dr Birrell and Prof Belvisi to assess for cathepsin S activity
Impact Doherty DF, Nath S, Poon J, Foronjy RF, Ohlmeyer M, Dabo AJ, Salathe M, Birrell M, Belvisi M, Baumlin N, Kim MD, Weldon S, Taggart C, Geraghty P. Protein Phosphatase 2A Reduces Cigarette Smoke-induced Cathepsin S and Loss of Lung Function. Am J Respir Crit Care Med. 2019 Jul 1;200(1):51-62.
Start Year 2016
 
Description Collaboration with Dr Rich Williams 
Organisation Queen's University Belfast
Department Centre for Cancer Research and Cell Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution Dr Williams has provided us with important Cathepsin S inhibitors for our in vitro and in vivo studies as result of the termination of the relationship with Virobay Inc (Virobay stopped operating as a company and were no longer in a position to provide us with cathepsin S inhibitors). Fortunately, we were able to repeat many of the studies we had already carried out with the Virobay inhibitor (VBY-999) using Dr Williams inhibitor (I6) and obtained very similar data with Dr Williams inhibitor as we did with the VBY-999 inhibitor which is both reassuring and allowed us to keep the study going
Collaborator Contribution Provision of cathepsin S inhibitor, I6
Impact None as yet
Start Year 2019
 
Description Annual contribution to the Northern Ireland Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The festival presented a range of workshops, talks and interactive activities for young people, parents and schools
Year(s) Of Engagement Activity 2016,2017,2018,2019
URL http://www.nisciencefestival.com
 
Description Invited Seminar, Institute of Ageing and Inflammation, University of Birmingham 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact I gave this invited seminar at the University of Birmingham in November 2019 to outline the various aspects of my research programme in the areas of acute and chronic lung inflammation. The target audience was postgraduate students, postdocs and academic staff and clinical academics
Year(s) Of Engagement Activity 2019
 
Description Lab View 360 - Northern Ireland Science Festival 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 70 members of the public (with approximately 50% school-aged children) attended our annual Northern Ireland Science Festival sponsored event in our laboratories in the Wellcome Wolfson institute for Experimental Medicine on the 15th February 2020. The event comprised a laboratory tour of the whole building with the members of the public shown a variety of research themes (including demonstration of lab activities) during a 3 hour period
Year(s) Of Engagement Activity 2020
URL https://nisciencefestival.com/event.php?e=186
 
Description Sentinus Young Investigators meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact The Sentinus Young Investigator meeting brings together secondary school children from Northern Ireland and the Republic of Ireland to showcase research projects that they have been working on. As a judge, I was tasked with evaluating the projects and shortlisting finalists. The winner of the various age groups would then go on to represent Northern Ireland at an international schools competition in the USA.
Year(s) Of Engagement Activity 2018
 
Description Talk at Conference 3rd Pharma R&D meeting 22-24 Feburary 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact This was a talk given at the virtual 3rd Pharma R&D meeting on the 23rd February 2021
Year(s) Of Engagement Activity 2021
URL https://pharma-rd.com/