Periodic Reporting for period 2 - discovAIR (Discovering the cellular landscape of the airways and the lung)
Okres sprawozdawczy: 2021-07-01 do 2022-06-30
Take for instance the pulmonary ionocyte, a recently discovered cell-type present in the airway wall. It has high levels of the gene that is changed to cause cystic fibrosis. Until 2 years ago, no one knew this cell even existed, and therefore we could not explore its role in cystic fibrosis. Clearly, we need a much more detailed map of the lung cells, their characteristics and how they interact. We need to understand how these cells vary between young and old people, males and females and people from different regions or ancestries. Finally, we need to know how changes to the cells in the lung disrupt the normal physiology and cause disease. Such a map of all lung cells, that could be used as a reference tool for the healthy human lung, is called the Human Lung Cell Atlas.
The main objective of discovAIR was to establish the first draft of the Human Lung Cell Atlas. In the last 30 months, discovAIR partners have worked relentlessly to achieve their goals. Despite the COVID-19 pandemic, the discovAIR consortium launched the first draft of the Human Lung Cell Atlas in March 2022, during the European Respiratory Society Lung Science Conference. This atlas is the first of its kind, not only for lungs, but for any major organ in the human body. As such, it represents an enormous leap forward in the study of the human lung in health and disease.
We created new ways to analyse datasets generated in discovAIR. For instance, discovAIR has developed a pipeline for combining and visualising data from different studies. This pipeline was first piloted to look into how age, BMI or smoking affects our genes, making it easier for SARS-CoV-2 to enter the body. This helped to understand why some groups were more likely to develop COVID-19. Building on these efforts, discovAIR partners have developed a way of combining lung datasets using all genes rather than a small selection of genes. This expertise was critical to deliver the first draft of the HLCA. The successful launch of the HLCA was presented and assessed as one of the key HCA successes to date at the annual general meeting (June 2022, Vienna). It has put the HLCA as frontrunner of the various tissue atlases within the international HCA consortium.
To achieve full impact for the HLCA, it has been made available through several open platforms, such as FastGenomics (developed by discovAIR partner Commasoft), Cellxgene from the Chan Zuckerberg Initiative and the Single Cell Expression Atlas hosted at the European Bioinformatics Institute. The atlas can be freely explored or downloaded. Research groups in the community lacking the infrastructure to do this can use option on the FastGenomics platform to perform these analyses online. The discovAIR consortium has further enabled wide use of the HLCA as a reference for label transfer by Azimuth or CellTypist, two frequently-used open platforms for annotating cells according to published references. At this moment, the HLCA is considered the gold standard for cell type annotation in lung tissue datasets. The HLCA was presented at the American Thoracic Society meeting in May 2022 and will be presented at the European Respiratory Society meeting in September 2022, thereby reaching a large proportion of the respiratory community across the globe.
The discovAIR consortium has also created disease atlases for asthma, chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension, idiopathic pulmonary fibrosis, and COVID-19. These show the changes in how cells behave in different diseases. The discovAIR consortium has also generated the first perturbation atlas for lung diseases. This uses cells from healthy people or people with lung disease. It monitors how cells change when stimulated with proteins that signal to cells or with environmental triggers such as house-dust mite, SARS-CoV-2 or respiratory syncytial virus. Finally, we mapped the cell types and the changing cell states that we observed in the HLCA, the disease atlas, and the perturbation atlas onto a model of the lung. This allowed discovAIR to define local cellular neighbourhoods in healthy lung tissue, and the changes in these cells between healthy and diseased lungs.