Periodic Reporting for period 1 - CLARITY (Causative Link between respirAtory syncytial viRus and chronic lung diseases: Identifying Targets for therapY)
Période du rapport: 2024-01-01 au 2025-06-30
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 noncommunicable 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. CLARITY applies 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 investigate how RSV perturbs intracellular networks to change cellular properties that trigger asthma development. We will use Artificial Intelligence (AI)-based approaches to integrate newly generated data with the current biological knowledge, to identify RSVinduced perturbation signatures and drug-like compounds capable to revert the eKects of the RSV-induced perturbations. Mechanisms and candidate compounds are validated in patient derived airway organoid models. Together with the RSV patient advisory board of the ReSViNET foundation, we disseminate our results and findings and thereby maximise scientific and societal impact of CLARITY.
During the first 18 months, CLARITY achieved all major planned milestones and made substantial scientific and operational progress. Analysis of human genetic data from the Estonian Biobank led to the identification of approximately 100 protein-coding variants reaching genome-wide significance, predominantly in genes involved in immune and epithelial functions. These findings provide a strong foundation for understanding genetic susceptibility to respiratory disease. Towards identifying and characterizing high risk RSV strains, all preparatory activities for the clinical studies were successfully completed, including ethical approvals. Two complementary studies were initiated: one focusing on young asthma patients with a history of severe RSV infection in infancy and available respiratory samples, and a second aiming to identify RSV strains with an increased capacity to promote asthma development through epidemiological analysis of seasonal RSV variants and long-term outcomes.Experimental studies investigating the role of RSV G and F proteins in bronchiolitis severity and asthma development are progressing as planned. A major early achievement was the generation of a comprehensive, high-quality RSV ORFeome comprising 213 expression-ready open reading frames representing 42 RSV clades. This unique resource enables systematic mapping of RSV–host protein interaction networks and represents a key milestone for downstream functional and systems-level analyses.Towards integration of all generated data, eKorts focused on establishing essential strategies and methodologies needed for later high-throughput analyses. Towards functional studies, major advances were made in setting up functional assays in Utrecht, to study RSV-induced changes in primary nasal organoid cultures. Organoid systems have been successfully established and optimised, and the development of transfection and co-culture strategies is well advanced. Following careful evaluation, organoid-based validation was selected as the primary strategy for testing candidate compounds. This decision ensures feasibility within the project timeframe while maintaining scientific rigor. All major activities remain on track. The next phase of the project will build directly on the foundations that are now established. The project will advance from preparatory and discovery phases into large-scale functional analyses, integration of genetic, virological, and clinical data, to progress towards organoid-based validation of key findings. These eKorts will accelerate the identification of RSV-related mechanisms underlying bronchiolitis severity and asthma development, supporting the translation of project results toward clinically relevant interventions.
CLARITY has established experimental and computational platforms that significantly advance the understanding of virus-triggered asthma. The development of a comprehensive RSV ORFeome and integrated systems-level approaches enables for the first time, systematic analysis of RSV-induced perturbation networks across viral strains and host genetic backgrounds.Combined with mechanistic network analyses, this work opens new avenues for personalised prevention strategies and for co-creation of prevention campaigns, with patient groups. To strengthen these eKorts by engagement with patient groups, we set up regular meetings with the RSV patient advisory board, created a CLARITY project EU LinkedIn site, a website and held a first webinar open to the public. As the project advances, the newly identified mechanisms and drug candidates are expected to pave the way for targeted preventive and therapeutic approaches. More broadly, these findings may reveal general principles of how viral infections can trigger or promote chronic non-communicable diseases.