Discovering the cellular landscape of the airways and the lung

Project Information

discovAIR

Grant agreement ID: 874656

DOI

10.3030/874656

Project closed

EC signature date 9 December 2019

Start date 1 January 2020

End date 30 June 2022

Funded under

• SOCIETAL CHALLENGES - Health, demographic change and well-being

Total cost

€ 4 958 682,50

EU contribution

€ 4 958 682,50

Coordinated by

ACADEMISCH ZIEKENHUIS GRONINGEN
Netherlands

Periodic Reporting for period 2 - discovAIR (Discovering the cellular landscape of the airways and the lung)

Reporting period: 2021-07-01 to 2022-06-30

Summary of the context and overall objectives of the project

Lung diseases are a leading cause of death worldwide, with incidence increasing. The recent COVID-19 pandemic underscores the impact of infectious lung diseases on medicine, society and the economy. If we could diagnose lung disease early, this would allow for intervention before a point of no return. To develop early diagnostic tests and design curative interventions, we need a more detailed understanding of healthy lung cells and the changes that occur in lung disease.

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The discovAIR project ran from January 2020 to June 2022, including a 6-month no-cost extension to deal with the delays caused by the COVID-19 pandemic. Given the focus of discovAIR on the Human Lung Cell Atlas (HLCA), and the fact that the pandemic hit Europe shortly after the start of the project, discovAIR partners have addressed society’s need for more detailed insight into the cellular and molecular mechanisms underlying COVID-19. Early on in the pandemic, discovAIR partners coordinated an international effort within the Lung Biological Network of the HCA consortium to analyse data from healthy people to understand how SARS-CoV-2 (the virus that causes COVID-19) enters the cells of our body. These analyses identified the upper airways (nasal cavity) as the main site of entrance and transmission of the virus. This discovery was shared widely using scientific and public news outlets. It had immediate consequences for appropriate use of personal protection such as facemasks. In addition, discovAIR partners have contributed to several studies on the mechanisms of disease in patients with COVID-19, some of which have already been published. Finally, discovAIR has used SARS-CoV-2 to see how specific lung cells respond to viral infection.

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The Human Lung Cell Atlas is the first of its kind within the efforts of the HCA consortium. Along with the HLCA as an interactive, open atlas, the discovAIR consortium also generated atlases for a range of lung diseases, many of which did not have such an atlas already. These include the description of how the different cell types in the lung change in disease, and how the cells interact in several long-term or infectious lung diseases. These important discovAIR results will allow scientists, physicians and diagnostic or pharmaceutical industry to chart how healthy cells change, either as a result of disease or to cause disease. The perturbation atlas will help untangle cause and effect in the altered cellular landscape of a diseased lung. This will help to identify new approaches to diagnose, prevent or treat them. By creating the HLCA, discovAIR has enabled the development of new, precise diagnosis or medicine to combat lung disease. The pioneering work completed within the HLCA will help the HCA consortium continue to develop the infrastructure and expertise needed to develop further tissue atlases for the other organs studied within this large international network.

discovAIR: towards the Human Lung Cell Atlas