CLARITY · Causative Link between respirAtory syncytial viRus and chronic lung diseases: Identifying Targets for therapY

Chronic respiratory diseases are non-communicable diseases for which infections by several respiratory viruses and human genetics constitute major risk factors. The molecular and physiological mechanisms of how these viral infections cause and contribute to non-communicable disease development are unknown. Respiratory syncytial virus (RSV) is a virus that infects nearly all infants before the age of 2 years and that is linked to asthma development. We propose an integrative approach to identify genetic risk factors and mechanisms underlying virus-induced asthma. Specifically, using two national cohorts (Estonian and Spanish), we will identify human genetic risk factors and RSV strains that contribute to severe bronchiolitis. We analyse how RSV perturbs intracellular networks to change cellular properties that trigger asthma development. We will use Artificial Intelligence (AI)-based techniques to integrate generated data with the current biological knowledge, to generate RSV-induced perturbation signatures and to identify drug-like compounds able to revert the effects of the RSV-induced perturbations. We will validate both mechanisms and candidate compounds in patient derived airway organoid models and, when promising, in a controlled human infection model trial. CLARITY will impact the understanding, prevention and possibly treatment of virus-triggered asthma. The results will enable development of a genetic risk score for long-term asthma development that enables personalised prevention campaigns, which will be developed jointly with patient groups. The molecular mechanisms discovered, and the drug-like compounds that revert the perturbation signatures, will enable development of mechanism-targeted drugs. Fundamentally, the mechanisms identified in this specific model for a strong viral contribution to non-communicable disease will likely represent general mechanisms of how viral infections cause onset and development of other non-communicable diseases.