PhD Study : InflaTmP: A novel combination anti-inflammatory and anti-viral biotherapeutic for COVID-19 targeting the NLRP3 inflammasome and TMPRSS2

Summary

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus that emerged in late 2019 and has caused a pandemic of acute respiratory disease, named ‘coronavirus disease 2019’ (COVID-19), which threatens human health and public safety. The first approved vaccine for COVID was approved this week (2nd Dec 2020). It will however take some time to roll this vaccine out. The process of manufacturing and distributing it around the world will be complex. Even with a vaccine, people will continue to be infected.

We also don’t know how much immunity it will give us, or for how long. For as long as people continue to get sick with Covid-19, we need effective treatments to help them. In particular certain populations such as those with cardiovascular disease (CVD) appear to be at higher risk of worse outcomes. It is therefore essential to uncover and investigate therapeutic targets that could be of benefit especially to such a prevalent, high risk population. Therapies against COVID-19 to date have concentrated on tackling either the inflammatory response or the viral infection itself.

The antiviral remdesivir was shown to reduce the duration of hospitalisation in moderately ill patients, and efficacy was likely dependent on the time of drug administration. Furthermore, dexamethasone treatment resulted in reducing the death rate by 33% in very seriously ill patients but less so in less ill patients. Thus, there remains a huge need for targeted SARS-CoV-2-specific therapeutic interventions to treat COVID-19. As SARS-CoV-2 infection can result in massive inflammatory responses associated with severe pathology, antivirals alone will likely be insufficient to treat the disease.

Similarly, anti-inflammatories in the absence of antivirals will result in the ongoing activation of the inflammatory response for as long as the virus replicates. We hypothesise, therefore, that therapeutic options combining SARS-CoV-2-specific antiviral and anti-inflammatory activities will be highly effective in treating COVID-19 disease. Targeting host proteins implicated in virus entry is expected to provide antiviral activity. Additionally, preventing and treating the lung injury caused by excessive inflammatory response is a major challenge in the development of effective therapies.

Two such proteins that offer promise as targets are the NLRP3 inflammasome and TMPRSS2 proteins. The NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety of chronic inflammatory conditions. It appears to be the common denominator responsible for orchestrating and driving inflammation in patients with many chronic inflammatory conditions. Recent studies have suggested that the NLRP3 inflammasome is implicated in the excessive inflammatory response observed in severe cases of COVID-19.  It also appears to be key in the coordination of lung injury and plays a role in the COVID-19-associated inflammation.

Importantly, IL-1ß the product of NLRP3 inflammasome activation, promotes ventilator induced lung injury and given that 37% of patients put on ventilation do not recover regardless of the ventilation need, provides further evidence for the need for exploring this target. Transmembrane serine protease 2 (TMPRSS2) is a protease required for cleavage of ACE2 to promote viral uptake, and also for priming of the viral spike (S) protein to enable fusion with the host cell membrane (Pöhlmann lab collaborator).

Importantly, TMPRSS2 is dispensable for development and homeostasis and thus constitutes an attractive drug target. An antibody against TMPRSS2 that blocks enzyme activity could therefore be beneficial, whilst leaving other proteases free for ACE2 cleavage, when needed for other important functions. Dr McGilligan (primary supervisor) has recently developed a novel dual therapeutic cocktail which targets both the NLRP3 and TMPRSS2 proteins.

It is hoped that this approach should tackle the two major problems associated with SARS CoV- 2 infection and COVID-19 disease, namely viral replication and associated damage in the lungs and exuberant local and systemic inflammation.  Importantly this dual approach to therapy could also be a powerful treatment approach for other human CoVs and other viruses including Influenza virus which exploit similar entry mechanisms.

AIMS: The project will investigate the NLRP3 inflammasome and the TMPRSS2 protease as therapeutic targets in COVID-19 and in particular investigate these proteins in cardiovascular patients, a very high risk COVID-19 population. In parallel the project will carry out mechanistic studies to help characterise the newly developed InflaTmP therapeutic.

OBJECTIVES: This proposed study will (i) study a cohort of cardiovascular patients with COVID-19 (UK Biobank and NICSM) and measure the expression of NLRP3 inflammsome associated proteins and their association with COVID-19 severity (ii) characterise the new InflaTmP therapeutic in vitro, to better understand the mechanism of action and downstream effects; this will involve the use of peripheral blood, lung and CVD relevant cell lines.

The proposed project will complement a recently funded project comprising of an internationally renowned project team including Prof Ultan Power (QuB) and Prof Kingston Mills (TCD). The multidisiciplinary supervisory team includes Dr McGilligan (primary supervisor) who has developed the novel therapeutic to be tested in the proposed project. Prof Bjourson is Director of the Northern Ireland Centre for Stratified Medicine and leads the COVID-19 task force for UU and is an advisor to the Public Health Agency and Department of Health.  Prof Peace, consultant cardiologist, will advise on the clinical aspects of the project.  The team together have successfully supervised several PhD students in recent years.

AccessNI clearance required

Please note, the successful candidate will be required to obtain AccessNI clearance prior to registration due to the nature of the project.

Essential criteria

Applicants should hold, or expect to obtain, a First or Upper Second Class Honours Degree in a subject relevant to the proposed area of study.

We may also consider applications from those who hold equivalent qualifications, for example, a Lower Second Class Honours Degree plus a Master’s Degree with Distinction.

In exceptional circumstances, the University may consider a portfolio of evidence from applicants who have appropriate professional experience which is equivalent to the learning outcomes of an Honours degree in lieu of academic qualifications.

• Sound understanding of subject area as evidenced by a comprehensive research proposal
• Clearly defined research proposal detailing background, research questions, aims and methodology

Desirable Criteria

If the University receives a large number of applicants for the project, the following desirable criteria may be applied to shortlist applicants for interview.

• Completion of Masters at a level equivalent to commendation or distinction at Ulster
• Experience using research methods or other approaches relevant to the subject domain
• Sound understanding of subject area as evidenced by a comprehensive research proposal
• Work experience relevant to the proposed project
• Publications record appropriate to career stage
• Experience of presentation of research findings
• A comprehensive and articulate personal statement
• Relevant professional qualification and/or a Degree in a Health or Health related area

Funding and eligibility

The University offers the following levels of support:

Vice Chancellors Research Studentship (VCRS)

The following scholarship options are available to applicants worldwide:

• Full Award: (full-time tuition fees + £19,000 (tbc))
• Part Award: (full-time tuition fees + £9,500)
• Fees Only Award: (full-time tuition fees)

These scholarships will cover full-time PhD tuition fees for three years (subject to satisfactory academic performance) and will provide a £900 per annum research training support grant (RTSG) to help support the PhD researcher.

Applicants who already hold a doctoral degree or who have been registered on a programme of research leading to the award of a doctoral degree on a full-time basis for more than one year (or part-time equivalent) are NOT eligible to apply for an award.

Please note: you will automatically be entered into the competition for the Full Award, unless you state otherwise in your application.

Department for the Economy (DFE)

The scholarship will cover tuition fees at the Home rate and a maintenance allowance of £19,000 (tbc) per annum for three years (subject to satisfactory academic performance).

This scholarship also comes with £900 per annum for three years as a research training support grant (RTSG) allocation to help support the PhD researcher.

• Candidates with pre-settled or settled status under the EU Settlement Scheme, who also satisfy a three year residency requirement in the UK prior to the start of the course for which a Studentship is held MAY receive a Studentship covering fees and maintenance.
• Republic of Ireland (ROI) nationals who satisfy three years’ residency in the UK prior to the start of the course MAY receive a Studentship covering fees and maintenance (ROI nationals don’t need to have pre-settled or settled status under the EU Settlement Scheme to qualify).
• Other non-ROI EU applicants are ‘International’ are not eligible for this source of funding.
• Applicants who already hold a doctoral degree or who have been registered on a programme of research leading to the award of a doctoral degree on a full-time basis for more than one year (or part-time equivalent) are NOT eligible to apply for an award.

Due consideration should be given to financing your studies. Further information on cost of living