The roles of Pellino-1 in the control of airway viral infection.

Lead Research Organisation: University of Sheffield
Department Name: Infection Immunity & Cardiovasc Disease

Abstract

Lung diseases are very common and cause huge suffering. People who have asthma, or the very common disease COPD (chronic obstructive pulmonary disease) are often ill and breathless. Sometimes acute attacks of breathlessness progress to the point that hospital care is needed, and in the worst cases death may result. COPD is becoming one of the leading causes of death worldwide. These are diseases that affect all ages: asthma affects children, adolescents, young adults, older adults and the elderly. COPD affects millions of people from adulthood.
The commonest cause of an acute attack of breathlessness in asthma or COPD is an infection. In asthma attacks, these are almost always caused by a virus. In acute attacks of COPD, a viral infection is again a very common initiator of the attack. The common cold is a small illness for most people, but for someone with asthma or COPD it may cause days or weeks of breathlessness that can be severe and frightening, and may progress to needing hospital care, care on the intensive care unit, or even death.
We've been working for a long time to understand how infections cause these acute attacks, and why they cause problems that are so much worse in people with asthma or COPD than they are in people without lung disease. We believe that we've found a new way of interrupting the upset caused by viruses in the lung, and want to explore this further.
The viruses that cause the common cold affect the cells lining the surface of the lung. When they do, they trigger a response in the lung cells that tries to control the virus. This response includes 'good' inflammation that stops the virus spreading through the lining of the lung, and 'bad' inflammation that causes damage to the lung. We've found that this response can be manipulated to reduce the bad inflammation, whilst preserving the good inflammatory response. If we could do this in patients, we could stop the virus from causing acute attacks of lung disease.
Our aims are to study a key checkpoint in the body's inflammatory response, and work out exactly how we can exploit this checkpoint to change the way the body responds to viruses. The checkpoint is regulated by a protein called Pellino-1. We will see exactly how Pellino-1 works in humans and mice, and through these studies we will work out what drugs we need to manipulate this checkpoint to stop people with asthma and COPD reacting badly to the common cold.

Technical Summary

Exacerbations of asthma and COPD are triggered by viral infections. We have shown that an E3 ubiquitin ligase, Pellino-1, regulates inflammatory responses to rhinoviruses.
Our hypothesis is that Pellino-1 is expressed in the human airway, regulated in disease and during viral infection, and its knockdown will reduce responses to airway viral infection with rhinovirus without impairing control of viral replication.
Objective 1: To examine Pellino-1 expression in tissues from patients with varying levels of severity of COPD, and patients with asthma. Data will be paralleled by a study of human viral infection, determining Pellino-1 expression in the nasal respiratory epithelium during an active viral infection.
Objective 2: To explore the roles of Pellino-1 in vivo. We have generated collaborations providing access to a Pellino-1 knockout mouse, and will establish models of rhinoviral infection. These models will allow us to determine how Pellino-1 regulates inflammation in a dynamic model of viral infection, complementing the static and dynamic expression studies in objective 1.
Objective 3: Explorations of how Pellino-1 regulates signalling in human cells. We will identify the binding partners of the Pellino-1 protein through a mass spec approach, and explore in detail how Pellino-1 regulates key aspects of responses to viruses, focusing on control of epithelial apoptosis and inflammatory signalling. Critical assays will be repeated in primary cells from patients with asthma and COPD, in order to determine whether disease modifies roles for Pellino-1.
These studies will allow us to further our understanding of the roles of Pellino-1 in the control of viral infections. Through a combined in vitro and in vivo approach, in which the human studies of tissue, virally-infected cells, and virally-infected patients parallel studies in the mouse, we will explore the biology of Pellino-1 and the pathways it regulates, in order to enable its therapeutic targeting.

Planned Impact

The pathways we are studying will be important for investigators in multiple fields, as they underpin key inflammatory control pathways in the innate immune system. We collaborate actively with researchers from multiple disciplines, and will look to share our knowledge widely and ensure it is rapidly applied outside the field of asthma, COPD and respiratory infection. IS already has established links with groups studying connective tissue disease, cardiac disease, and gastrointestinal disease. We will ensure our work is disseminated through general conferences as well as disease-specific conferences, and share our knowledge widely wherever possible.
We have active links and collaborations with numerous pharmaceutical companies, including GSK and MedImmune. We have already discussed Pellino-1 with them, and suggested that the pathways it targets may represent novel therapeutic opportunities for the control of inflammatory disease, including and going beyond lung disease. Through subsequent exploitation of the targets we are developing, we expect our work to create new treatment opportunities for a disease, COPD, which is becoming one of the most common killers across the whole world. Any therapeutic opportunities developed through our research has the chance to make a huge impact on patients, and generate major wealth-creating opportunities. We are already liaising with our commercial IP partners at Sheffield to determine how to protect ideas and targets as they emerge.
IS has recently cofounded Medical Humanities Sheffield (www.sheffield.ac.uk/mhs), a cross-discipline research and teaching institute that aims to bridge disciplines in order to find new ways to change the understanding and delivery of effective healthcare and health-related research. We will seek to spread the concepts of therapeutic targeting of viral infections, exploring through humanities based research strategies how to make these concepts and discoveries meaningful to patients and the wider public, and how to interpret scientific thinking through humanities-based approaches. We expect to welcome humanities students and researchers into our labs, and to establish new ways of sharing and communicating these data to change hopes, expectations, and outcomes of patients with airways disease. Activities exploring Pellino-1 from a broader viewpoint may include undergraduate writing projects, artistic interpretations of research outcomes, collaborative research engaging Humanities students in practical research and its ethical dimensions, and engagement with other University and community networks such as the Arts and Wellbeing Network (http://www.artsandwellbeingsheffield.co.uk/).
Our work will develop the career progression of the scientists employed on the project. Through Medical Humanities Sheffield, our scientists will have a unique exposure to different ways of thinking about health, illness, science, art and its communication. We will encourage our staff to consider ethical dimensions of their work, artistic interpretations of it, and the impact of the disease they are studying on the lives of the sufferers of these conditions. We will encourage collaboration between our staff and researchers in the humanities to create a unique interdisciplinary environment that develops humanities students and researchers with an understanding of science, and science researchers with a vision of how their work impacts on the wider community of patients, and how this may be communicated through alternative humanities-based approaches.

Publications

10 25 50
 
Description Collaboration with BridgeBio 
Organisation BridgeBio
PI Contribution They have a novel antagonist of Pellino-1 that they wish us to test in our viral systems. Our work has highlighted a role for Pellino-1 in control of viral infection which was previously unknown. This excellent opportunity will help us develop our work in control of viral infection, and will help them develop a novel application of their antagonist.
Collaborator Contribution They have a novel antagonist of Pellino-1 that they wish us to test in our viral systems. Our work has highlighted a role for Pellino-1 in control of viral infection which was previously unknown. This excellent opportunity will help us develop our work in control of viral infection, and will help them develop a novel application of their antagonist.
Impact New, no outputs yet
Start Year 2016
 
Description Collaboration with Paul Moynagh 
Organisation Maynooth University
Country Ireland 
Sector Academic/University 
PI Contribution Extensive shared interests led to a brief period of work by the postdoc in Paul's lab, and an ongoing plan to develop further grants in Pellino biology
Collaborator Contribution Shared ideas, period of time working in Paul's lab
Impact None yet
Start Year 2017
 
Description Collaboration with Professor Hussell 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborations to explore how Pellino 1 is regulating airways inflammation in response to viruses
Collaborator Contribution Prof Hussell's group are taking part in experiments with us to define how downregulation of Pellino-1 results in changes in response to viral infections. In particular, her group is helping us profile the immune infiltrate in the lung after viral infection.
Impact Experiments still underway
Start Year 2016
 
Description Pellino and A20 collaborations 
Organisation Maynooth University
Country Ireland 
Sector Academic/University 
PI Contribution Key collaboration to help establish IP for important associating proteins
Collaborator Contribution Brought insights into molecular biology of our protein
Impact None as yet
Start Year 2014
 
Description Pellino-1 mice 
Organisation University of Texas
Country United States 
Sector Academic/University 
PI Contribution Sharing of information regarding pellino-1
Collaborator Contribution Access to Pellino-1 knockout mice
Impact Supported new funding
Start Year 2013
 
Description Peter Bradding SAPS and Pellino collaboration 
Organisation University of Leicester
Department Respiratory Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Use of asthma cells to explore viral responses in asthma, and their potential modification by our new targeting strategies
Collaborator Contribution Donation of cells from patients with asthma to allow testing of new approaches in cells from people with disease
Impact Contributed to funding of HC Roscoe award
Start Year 2014