A common cold virus can trigger a life-threatening asthma attack by hijacking the body’s allergic responses—and this alliance aims to find out exactly how. Asthma attacks are most often caused by rhinovirus infections, yet the molecular chain of events that turns a mild respiratory virus into a severe airway crisis remains poorly understood. The same virus also appears to help set the stage for asthma in early life by breaking down the immune system’s natural tolerance to allergens. This project will map the genes and molecules activated in lung cells during rhinovirus infection, and test whether those same signals are amplified in people with pre-existing allergies. By studying both human lung cells and a mouse model where virus infection reverses allergen tolerance, the team will identify which molecular pathways drive the dangerous interplay between allergy and infection. If successful, this work will reveal new drug targets for preventing asthma attacks or even stopping asthma from developing in the first place. Because the research is fundamental—focused on basic mechanisms of immune regulation and viral gene expression—it will not produce a treatment immediately. But understanding how a virus dismantles immune tolerance could eventually lead to therapies that block that process, reducing the burden of a disease that affects millions.
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We apply to form an Alliance between GSK and the MRC & Asthma UK Centre in Allergic Mechanisms of Asthma to discover and develop new approaches for prevention/treatment of asthma and asthma attacks. We will integrate research in areas of major strength for the Centre with the strengths in asthma drug discovery at GSK. The overall aim is to investigate mechanisms of interplay between allergy and virus infection in development of asthma and in acute asthma attacks. The major cause of asthma attacks are human rhinovirus (RV) infections, these are also related to development of asthma when they occur in early life. We will investigate gene expression and how expression is regulated in lung cells during RV infection to identify molecules/pathways induced by RV infection that are implicated in promoting allergic responses. We will determine whether RV induction/modification of these molecules/processes are related to pre-existing allergic responses, virus load and clinical severity of asthma exacerbation. A major cause of asthma is failure of development of immunological tolerance to allergens. We have shown that tolerance can be reversed by a virus infection, but the mechanisms are unknown. We will purify lung cells from the virus-induced breakdown of tolerance model to identify genes implicated in tolerance breakdown and determine whether these are replicated in lung cells in the human. Finally we will determine whether blocking or inducing molecules implicated in virus induced worsening of allergic responses/breakdown of tolerance, determines severity of RV induced allergic airway inflammation. Accomplishment of these aims will identify targets for development of novel therapies for asthma and asthma attacks.
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