MICA: Phenotyping immune responses in asthma and respiratory infections - a systems approach to understanding changes from childhood to adulthood

Asthma, allergies and respiratory tract infections (RTIs) are the most common diseases in childhood and adulthood. Although they are inextricably linked, the immune mechanisms governing the relationships between the infection, allergy and increased risk of asthma development and asthma attacks are very poorly understood. Consequently, there have been few advances in treatments for asthma (and in particular asthma attacks) in the last 50 years. Severity and risk of these conditions varies substantially with age, with in particular large changes occurring through puberty - before puberty boys have increased risk/severity of asthma and RTIs, while after puberty females are at substantially greater risk.
Impaired immune responses to viruses are strongly implicated in increased susceptibility to virus infections in asthma, but the mechanisms behind these impaired responses are unknown. The mechanisms explaining increased susceptibility to bacterial infections in asthma are unknown.
We propose a novel approach aiming to understand the mechanisms of interplay between asthma, allergies and innate immune responses to viruses and bacteria. Building on knowledge we already have of a population of 1000 children, followed since birth to look for risk factors for asthma and allergies, we will collect new data (outlined below) and by using a systems approach to apply innovative computational statistical methods to the data we will study the interactions between host response to infections, allergens and asthma. This will give a better understanding of why children develop asthma, how this changes through puberty and we hope to identify new targets for possible drug therapies.

We will combine world-leading expertise in birth cohort/life course studies, respiratory infections, innate immunity, asthma and allergies and computational analysis
We will utilise novel analytical techniques to identify mechanisms related to increased susceptibility to RTIs causing increased susceptibility to asthma development and asthma attacks
We will investigate changes in the way the body handles infection from bacteria and viruses from childhood by taking blood cells from the body at age 8 years, through puberty (ages 11 & 14), to adulthood (age 18) and exposing them to these infectious agents and measuring the response
We will investigate how through puberty the body changes in the way it makes antibodies to allergens, by measuring IgE antibodies at the time points above
We will investigate how changes in gene sequences are associated with immunity to infection and to allergens.
We will analyse the data using novel computational techniques, recognising that these systems are highly complex and interact with each other, and do not operate in isolation
By studying mechanisms which are important regulators at a molecular level, we will identify potential targets for treatment or prevention of asthma development, asthma attacks and RTIs.
Potential therapeutic targets will be validated using molecular cell biology techniques in human primary cells and in vivo studies in which the applicants are well versed.

Asthma, allergies and respiratory tract infections (RTIs) are the most common acute and chronic diseases and their prevalence and severity vary greatly from childhood to adulthood, with large swings occurring through puberty. This study will combine world-leading expertise in infection and immunity, a population based birth cohort study and computational analysis to identify novel mechanisms related to increased susceptibility to asthma, allergies and RTIs. We will harness the power of systems biology to the rich clinical, immunological, genetic and environmental data sets, in hundreds of subjects, either already available in the Manchester Allergy and Asthma Study birth cohort, or in new datasets collected as part of this proposal to generate:
- complete clinical follow up and sampling of the cohort from birth to adulthood at 18yrs
- next generation sequencing of targeted relevant immune genes
- complex functional characterisation of immune responses to viral and bacterial infections, gene methylation studies and component resolved allergy diagnostics in blood collected in childhood (8yrs), early (11yrs) and late (14yrs) puberty and adulthood (18yrs)

Using a flexible probabilistic framework, we will extrapolate knowledge from generated/existing data and formulate new hypotheses that will lead to functional experiments testing these hypotheses in in vitro and in vivo models. Statistical inference and experimental data on the roles of specific molecules or pathways will iterate in the hypothesis generation/validation process. We will elucidate the development of functional antiviral and anti-bacterial immune responses and of epigenetic marks from childhood to adulthood and their relation to susceptibility to asthma, allergies and RTIs, and to underlying genetic polymorphisms. These approaches together will lead to identification of new targets for development of novel diagnostic and therapeutic approaches for treatment/prevention of asthma, allergies and RTIs

Why will this research have impact?
Asthma, allergies and respiratory tract infections (RTIs) are the most common acute and chronic diseases in childhood and adulthood, and they are inextricably linked. The immune mechanisms governing the relationships between the susceptibility to infection with increased risk of asthma development and asthma attacks are very poorly understood.
Severity and risk of these conditions varies substantially with age, with in particular large changes occurring through puberty. People with asthma have substantially increased risk and severity of both viral and bacterial RTIs. Impaired innate responses to viruses are strongly implicated in increased susceptibility to virus infections in asthma, but the mechanisms behind these impaired innate responses are unknown. The mechanisms explaining increased susceptibility to bacterial infections in asthma are unknown.
We aim to explore how immune responses to viruses and bacteria change over a 10 year time frame from childhood to adulthood, the influence of puberty on these responses, their relation to susceptibility to RTIs, asthma development and asthma exacerbations. In addition we will characterise the development of immune responses to allergens using component resolved diagnostics through puberty. We will investigate associations between the regulation of these responses and novel polymorphisms in ~100 genes implicated in their regulation, and by differences in and changes in DNA methylation between children, and over time from childhood to adulthood, and through puberty.
By studying mechanisms which are important regulators at a molecular level, we will identify potential targets for treatment or prevention of asthma development, asthma exacerbations and RTIs. Potential therapeutic targets will be validated using molecular cell biology techniques in human primary cells and in vivo studies in which the applicants are well versed. RS is well versed in drug development and formation of new companies focussed on drug development. The translation of our findings into new medicines has potential to have major impacts on human health.
Who will benefit from this research?
a) This knowledge will be of general interest to and benefit academic immunologists, microbiologists, virologists, allergists and respiratory physicians/scientists.
b) Patients with allergies and asthma: viral and bacterial infection of these patients represents as massive global unmet medical need. Respiratory tract infections are also strongly implicated in onset of these diseases - understanding how might lead to effective preventive approaches.
c) Patients vary enormously in their susceptibility to respiratory tract infections - understanding the immune basis for this, and how it changes with age, and through puberty may lead to diagnostic and therapeutic developments to help reduce the enormous burden of disease associated with RTIs.
d) This research will be of interest to Pharmaceutical and Biotechnology companies. There are 350 million asthmatics worldwide and it is estimated 50% of the health care costs associated with asthma are due to attacks caused by infection. This is important for healthcare providers and an opportunity for companies.
e) This proposed study brings together Imperial College, Manchester University and via RS, GSK and assembles a team of immunologists, virologists/microbiologists, clinicians, epidemiologists, geneticists, and bioinformaticians. It will create a network of scientists in Academia and Industry all benefiting and learning from one another. Partnerships such as these help to make the UK an attractive location to retain research activities and help expose academics to the process of translating basic science into products.