Innate interferons in epithelial defence against respiratory viruses

Lead Research Organisation: Newcastle University
Department Name: Translational and Clinical Res Institute

Abstract

Respiratory viruses are a major threat to human health and economic prosperity. Examples include influenza and the virus that causes coronavirus disease 19 (COVID-19), SARS-CoV-2. In order to develop medical interventions to combat these viruses, we need to better understand the normal immune response to viral infection in target cells, such as the cells that line the airways - the air passages of the lung. Through the careful study of patients with unusually severe COVID-19, it appears that certain immune factors play an important role in limiting disease at the earliest stages of infection in the airway.

These factors are known as 'interferons'. Interferons are produced by virally infected cells. They signal uninfected neighbours to adopt an 'antiviral state' that blocks viral spread. Two major types of interferons are made by airway cells, type I and type III interferons. Consequently, viruses have evolved several strategies to evade this response.

Type I and III interferons are distinct factors but share similar mechanisms of action. However, little is known about their individual functions or how they interact in humans. Understanding this will tell us how best to manipulate individual interferon types for clinical benefit. Our study of human patients with rare 'spelling errors' in their DNA (mutations) that affect the interferon pathways teach us valuable lessons.

Patients with mutations of the type I interferon system are vulnerable to severe COVID-19, suggesting that type I interferons play an essential role in protecting against serious consequences of viral infection. Interestingly, these individuals cope normally with most other respiratory viruses, such as influenza, as do those with specific lesions of the type III interferon system. However, patients with impairment of both type I and III interferon systems can develop severe disease due to many respiratory viruses. Based on these observations, I propose that type I and III interferons compensate for one another in the defence of the airway, but that in some cases there are gaps that viruses such as SARS-CoV-2 exploit.

I will use new cutting-edge laboratory models. We make use of stem cells that, in theory, are able to turn into any other type cell type in the human body. We have developed a way to turn them into cells that line the airway. We expose them to air, matching what happens in the airway. We then infect airway cells with different viruses, including SARS-CoV-2 - which causes COVID-19 - and influenza. We will measure the growth of the viruses and the damage that they cause to the airway cells. The reason for using stem cells to create these airway cells is that we can introduce 'spelling errors' into the DNA of the stem cell, preventing them from responding to interferons. By comparing the behaviour of the virus in these different airway cells, we will learn which interferons are important in controlling specific viruses.

We will also measure the immune response to these viruses using techniques to measure the responses of individual cells. This will help us to identify the way that interferons work and allow us to do more detailed experiments to confirm our findings. We will also investigate the impact of specialised immune cells, present normally in the airway, on this process. We think that they will aid the interferon response of airway cells. Finally, we will conduct experiments in a rodent model of viral infection to assess how these interferons operate in the airway in the intact organism.

Together, these results will explain how these immune factors work and give insight into the purpose of these apparently independent systems. It is possible that this is a deliberate strategy by the host to mitigate against viral evasion of interferons, or it may be that they work together, or are individually better against certain viruses. This information is relevant to the clinical use of interferons to treat or prevent viral disease.

Technical Summary

Respiratory viruses pose substantial threats to human health and economic prosperity, exemplified by the SARS-CoV-2 pandemic. This has highlighted the critical role played by innate interferons in limiting the severity of respiratory viral disease.

Type I (IFN-I) and type III interferons (IFN-III) are produced by virally infected cells, signalling their uninfected neighbours to adopt an 'antiviral state' that inhibits viral spread. However, it is difficult to distinguish the action of IFN-I from IFN-III in the airway epithelium, since they share overlapping signalling pathways. Consequently, little is known about their individual functions, especially in humans.

Patients with inborn errors of IFN-I signalling are vulnerable to SARS-CoV-2 but not apparently to other respiratory viruses. In contrast, patients deficient in STAT2, a transcription factor essential to both IFN-I and IFN-III pathways, are vulnerable to many respiratory viruses. These observations lead to the hypothesis that IFN-I and IFN-III generally compensate for one another in antiviral defence, however this compensation is incomplete in the case of SARS-CoV-2.

Exploiting cutting-edge experimental models to genetically manipulate innate interferon signalling pathways in airway epithelial cells (AECs), I will precisely dissect the roles of IFN-I/III in human epithelial defence, through four independent but complementary aims:

1: Define the relative importance of IFN-I and IFN-III in AECs by gene knockout.
2: Identify the molecular basis of differential antiviral activity of IFN-I/III.
3: Determine whether immune cells amplify IFN-I/III mediated protection of AECs.
4: Assess whether IFN-I/III responses of AECs are critical to antiviral protection in vivo.

Together, these approaches will deliver critical insight into the cellular and molecular architecture of the interferon system, informing the potential therapeutic role for IFN-I/III in respiratory viral disease.

Publications

10 25 50
 
Description New RSV vaccine recommended for NHS RSV immunisation programme
Geographic Reach National 
Policy Influence Type Citation in other policy documents
 
Description Cellular drivers of type I interferon-mediated neuropathology
Amount £1,240,987 (GBP)
Funding ID MR/Y001958/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 11/2023 
End 10/2027
 
Description ConquerRSV Study Group 
Organisation Moderna
Country United States 
Sector Private 
PI Contribution I serve as UK Chief Investigator for this phase III clinical trial programme and am a member of the publication steering group. I receive no personal renumeration for this work.
Collaborator Contribution Sponsorship and funding for the clinical trial.
Impact Clinical trial data indicate the vaccine to be efficacious. Licensure applications are in progress. The JCVI have indicated that it should be included in the national UK RSV Immunisation Programme.
Start Year 2022
 
Description Leukolabs Research Network 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution Participation in inaugural meeting
Collaborator Contribution Development of the network, funding support
Impact None to date
Start Year 2022
 
Description Member of Genomics England Clinical Interpretation Partnership (GeCIP) 
Organisation Genomics England
Country United Kingdom 
Sector Public 
PI Contribution Member of Genomics England's 100,000 genomes Immunology GeCIP
Collaborator Contribution Identified core diseases, begun patient enrolment
Impact ongoing project
Start Year 2015
 
Description Odyssey Study Group 
Organisation Moderna
Country United States 
Sector Private 
PI Contribution I am the Principal Investigator and my team provide clinical delivery of this phase I clinical trial.
Collaborator Contribution Sponsorship and funding.
Impact Nil to date
Start Year 2023
 
Description Oxford COVID Vaccine Trial Group 
Organisation University of Oxford
Department Jenner Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Principal Investigator for the Oxford COVID-19 Vaccine Trials - responsible for overseeing all aspects of clinical trial governance and delivery at site in addition to providing intellectual input to study design and involvement in writing reports.
Collaborator Contribution Sponsorship, oversight, trial design and management, monitoring etc.
Impact Multiple highly cited publications in high-impact journals Delivery of a licensed COVID-19 vaccine Influence on practice and policy - WHO and UK vaccination guidance
Start Year 2020
 
Description PITCH Consortium 
Organisation University of Liverpool
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input, patient recruitment, sample collection and analysis, immunological assay application, collection and analysis of data, preparation of manuscript(s).
Collaborator Contribution Intellectual input, governance, provision of reagents, sample collection and analysis, immunological assay development, collection and analysis of data, preparation of manuscript(s).
Impact Onward funding - from MRC/UKRI in collaboration with UKHSA and from MRC for PITCH (COVID-19 Partnership Award) Papers - Cell, Lancet Microbe, Journal of American Society of Nephrology, Frontiers in Immunology (2 others submitted) Engagement - media interview(s) Impact - citations in Green Book (UK Vaccine Guidance document) (see relevant sections)
Start Year 2020
 
Description PITCH Consortium 
Organisation University of Oxford
Department Nuffield Department of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input, patient recruitment, sample collection and analysis, immunological assay application, collection and analysis of data, preparation of manuscript(s).
Collaborator Contribution Intellectual input, governance, provision of reagents, sample collection and analysis, immunological assay development, collection and analysis of data, preparation of manuscript(s).
Impact Onward funding - from MRC/UKRI in collaboration with UKHSA and from MRC for PITCH (COVID-19 Partnership Award) Papers - Cell, Lancet Microbe, Journal of American Society of Nephrology, Frontiers in Immunology (2 others submitted) Engagement - media interview(s) Impact - citations in Green Book (UK Vaccine Guidance document) (see relevant sections)
Start Year 2020
 
Description PITCH Consortium 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input, patient recruitment, sample collection and analysis, immunological assay application, collection and analysis of data, preparation of manuscript(s).
Collaborator Contribution Intellectual input, governance, provision of reagents, sample collection and analysis, immunological assay development, collection and analysis of data, preparation of manuscript(s).
Impact Onward funding - from MRC/UKRI in collaboration with UKHSA and from MRC for PITCH (COVID-19 Partnership Award) Papers - Cell, Lancet Microbe, Journal of American Society of Nephrology, Frontiers in Immunology (2 others submitted) Engagement - media interview(s) Impact - citations in Green Book (UK Vaccine Guidance document) (see relevant sections)
Start Year 2020
 
Description Recovery Collaborative Group 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Delivery of the UK Recovery Study - participant recruitment, delivery of study, management of participants and data
Collaborator Contribution Study sponsorship, monitoring, protocol design etc.
Impact Publications (see list) Delivery of new treatments for COVID-19 Influence on global clinical practice and policy
Start Year 2020
 
Description UKHSA SIREN Collaboration 
Organisation UK Health Security Agency
Country United Kingdom 
Sector Public 
PI Contribution We developed and maintained a cohort of health care workers, arranged regular blood draws and oversaw isolation and storage of biological samples, in addition to research assays (ELISpot, multiparametric and spectral flow cytometry, tetramer staining and T cell memory phenotyping). We presented and analysed data and figures and co-wrote the resulting scientific reports. We
Collaborator Contribution Partners
Impact There are 3 publications arising from this collaboration and a further two publications have been submitted for publication. Others are in preparation. Work from this partnership (also co-funded by consortium awards to PITCH and UK-CIC) was cited in Chapter 14 of the UK Green Book of vaccination guidance, influencing UK and International policy around of COVID-19 vaccine intervals.
Start Year 2021
 
Description Genetics Matters Public Engagement Event 
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 Well attended, lots of engaged interaction. No specific outcomes as yet
Year(s) Of Engagement Activity 2024