Experimental viral challenge in bronchiectasis to study the immunopathogenesis of exacerbations
Lead Research Organisation:
Imperial College London
Department Name: Infectious Disease
Abstract
Bronchiectasis is a chronic lung condition that affects over 200,000 individuals in the UK. The disease is characterised by progressive susceptibility to symptomatic flare-ups (exacerbations). These episodes are a major cause of morbidity and mortality with limited treatment options. Historically, bacteria have been deemed responsible for most exacerbations leading to widespread treatment with prolonged antibiotics (which act to specifically counteract bacteria). However, bacteria are increasingly becoming resistant to many antibiotics and we urgently need new approaches.
We have recently found that, contrary to previous belief, a significant proportion of exacerbations (~40%) are associated with detection of viruses (most commonly rhinovirus) which may be an unrecognised trigger for bronchiectasis exacerbations. This was highlighted during the COVID-19 pandemic where there was a striking reduction in bronchiectasis exacerbation rates believed to be due to reduced social interactions between individuals which limited their exposure to circulating viruses. Despite this suggestive evidence, it remains unclear whether viruses can directly trigger exacerbations in bronchiectasis and the mechanisms that predispose these individuals to viral infections are unknown.
This project asks the following three questions:
1. Does deliberately infecting bronchiectasis subjects with rhinovirus lead to development of an exacerbation?
2. Does bronchiectasis reduce the immune system's ability to respond to and fight off viral infection?
3. What are the changes that occur in the lungs during a viral infection that lead to bronchiectasis exacerbation?
This research will be carried out by collaborating scientists at Imperial College, University of Dundee, University of Southampton and Nanyang Technological University (Singapore). We will administer rhinovirus into the nose of 36 subjects with bronchiectasis and 18 healthy control subjects to induce infection. We will record respiratory symptoms and also measure lung function daily following this, to determine whether rhinovirus infection causes a greater flare-up of symptoms in bronchiectasis compared to healthy individuals. We will take samples from the nose and also mucus coughed up by these individuals to measure concentrations of substances that are produced in the airways by the immune system to combat viral infections (substances called 'interferons' and others). We will additionally take cells from the lungs of these individuals using bronchoscopy (a test where a telescope is inserted into the airways to gain deep samples). We will culture these cells in the laboratory and infect them with rhinovirus before again measuring how much interferon and other substances they produce. This will determine if bronchiectasis is associated with a reduced ability of the immune system to respond to a viral infection.
We have previously successfully carried out similar rhinovirus infection studies in subjects with other chronic lung diseases (asthma and COPD) with an excellent safety profile. These studies allowed us to understand the importance of viruses in triggering exacerbations and the mechanisms involved. This project will establish a similar model for the first time in bronchiectasis and allow us to understand which are the key immune substances that are produced in lower quantities in these patients. This would then allow us to conduct future studies where we examine whether administering these substances directly into the lungs of patients with bronchiectasis (e.g. using an inhaler) could boost their immune response when exposed to viruses and thereby prevent exacerbations. The model we will develop would provide the perfect platform to test these types of approaches. In summary, this research will provide new scientific insight into an area of huge clinical importance and facilitate the development of exciting new therapies to reduce the burden of disease caused by bronchiectasis
We have recently found that, contrary to previous belief, a significant proportion of exacerbations (~40%) are associated with detection of viruses (most commonly rhinovirus) which may be an unrecognised trigger for bronchiectasis exacerbations. This was highlighted during the COVID-19 pandemic where there was a striking reduction in bronchiectasis exacerbation rates believed to be due to reduced social interactions between individuals which limited their exposure to circulating viruses. Despite this suggestive evidence, it remains unclear whether viruses can directly trigger exacerbations in bronchiectasis and the mechanisms that predispose these individuals to viral infections are unknown.
This project asks the following three questions:
1. Does deliberately infecting bronchiectasis subjects with rhinovirus lead to development of an exacerbation?
2. Does bronchiectasis reduce the immune system's ability to respond to and fight off viral infection?
3. What are the changes that occur in the lungs during a viral infection that lead to bronchiectasis exacerbation?
This research will be carried out by collaborating scientists at Imperial College, University of Dundee, University of Southampton and Nanyang Technological University (Singapore). We will administer rhinovirus into the nose of 36 subjects with bronchiectasis and 18 healthy control subjects to induce infection. We will record respiratory symptoms and also measure lung function daily following this, to determine whether rhinovirus infection causes a greater flare-up of symptoms in bronchiectasis compared to healthy individuals. We will take samples from the nose and also mucus coughed up by these individuals to measure concentrations of substances that are produced in the airways by the immune system to combat viral infections (substances called 'interferons' and others). We will additionally take cells from the lungs of these individuals using bronchoscopy (a test where a telescope is inserted into the airways to gain deep samples). We will culture these cells in the laboratory and infect them with rhinovirus before again measuring how much interferon and other substances they produce. This will determine if bronchiectasis is associated with a reduced ability of the immune system to respond to a viral infection.
We have previously successfully carried out similar rhinovirus infection studies in subjects with other chronic lung diseases (asthma and COPD) with an excellent safety profile. These studies allowed us to understand the importance of viruses in triggering exacerbations and the mechanisms involved. This project will establish a similar model for the first time in bronchiectasis and allow us to understand which are the key immune substances that are produced in lower quantities in these patients. This would then allow us to conduct future studies where we examine whether administering these substances directly into the lungs of patients with bronchiectasis (e.g. using an inhaler) could boost their immune response when exposed to viruses and thereby prevent exacerbations. The model we will develop would provide the perfect platform to test these types of approaches. In summary, this research will provide new scientific insight into an area of huge clinical importance and facilitate the development of exciting new therapies to reduce the burden of disease caused by bronchiectasis
Technical Summary
Bronchiectasis is a lung condition characterised by susceptibility to exacerbations, a major cause of morbidity and mortality. Contrary to previous belief that bacteria cause most exacerbations, we have recently found that viruses (commonly rhinoviruses (RV)) are detectable in ~40% of episodes. However, a causal role for viruses in bronchiectasis exacerbations remains unproven and underlying mechanisms driving susceptibility are unknown. We seek to set up a first-in-man experimental RV challenge model in bronchiectasis to gain insight into exacerbation pathogenesis and establish a platform to deliver future proof-of-concept therapeutic trials.
Our aims will be:
1).To establish causation between virus infection and bronchiectasis exacerbation.
2).To determine whether innate anti-viral immunity is impaired in bronchiectasis
3).To elucidate mechanisms dictating severity of virus-induced exacerbation in bronchiectasis.
We hypothesise that deficient innate immunity in bronchiectasis predisposes to increased immunopathology/clinical severity upon viral infection, leading to exacerbation.
Methodology: 36 individuals with bronchiectasis (18 Pseudomonas colonised and 18 non-colonised) and 18 healthy control subjects will be inoculated with RV-A16 with serial symptom monitoring. We will sample airway/peripheral cells at baseline (pre-infection) and measure ex vivo immune responses to RV and/or antiviral pathway agonists, to define if impaired anti-viral immunity occurs in bronchiectasis relative to health and determine key cells/signalling pathways involved. We will study in vivo viral replication and effects upon airway inflammation and microbial dynamics.
Expected outcomes: Our study will identify mechanistic drivers of exacerbations and thus reveal new druggable targets for future testing within the unique model system we will develop. This may subsequently lead to development of novel non-antibiotic immunomodulatory or antiviral exacerbation therapies.
Our aims will be:
1).To establish causation between virus infection and bronchiectasis exacerbation.
2).To determine whether innate anti-viral immunity is impaired in bronchiectasis
3).To elucidate mechanisms dictating severity of virus-induced exacerbation in bronchiectasis.
We hypothesise that deficient innate immunity in bronchiectasis predisposes to increased immunopathology/clinical severity upon viral infection, leading to exacerbation.
Methodology: 36 individuals with bronchiectasis (18 Pseudomonas colonised and 18 non-colonised) and 18 healthy control subjects will be inoculated with RV-A16 with serial symptom monitoring. We will sample airway/peripheral cells at baseline (pre-infection) and measure ex vivo immune responses to RV and/or antiviral pathway agonists, to define if impaired anti-viral immunity occurs in bronchiectasis relative to health and determine key cells/signalling pathways involved. We will study in vivo viral replication and effects upon airway inflammation and microbial dynamics.
Expected outcomes: Our study will identify mechanistic drivers of exacerbations and thus reveal new druggable targets for future testing within the unique model system we will develop. This may subsequently lead to development of novel non-antibiotic immunomodulatory or antiviral exacerbation therapies.
