Researchers, involving experts at Newcastle University, have found distinct phases where waves of immune responses give way to lung fibrosis – scarring of the lungs – in severe cases of the disease.

As part of the UK Coronavirus Immunology Consortium (UK-CIC), researchers from Newcastle, Wellcome Sanger Institute, Imperial College London, and Harvard University used a combination of cell mapping technologies to build a comprehensive understanding of the cellular response and lung tissue changes instigated during Covid-19.

This study, published today in Nature Communications, is part of the international Human Cell Atlas initiative to map every cell type in the human body.

Identifying potential treatments

The research shows a new set of molecular markers that distinguish gradual stages of damage to alveoli in the lungs. The work opens the door to further analysis of cellular mechanisms underlying inflammatory responses in severe disease.

Andrew Fisher, Professor of Respiratory Transplant Medicine at Newcastle University and Honorary Consultant Chest Physician at The Newcastle upon Tyne Hospitals NHS Foundation Trust, led the Newcastle-based research for the study.

Professor Fisher said: “This is an excellent example of how collaboration across centres and across countries allows us to generate an in-depth understanding of how Covid-19 caused such catastrophic lung disease in some people.

“In Newcastle, we assembled one of the world’s largest collections of lung samples collected from patients who died from Covid-19 and with our collaborators have applied cutting-edge technology that reveals exactly how the immune system contributed to severe lung damage over time.

“Armed with this information, we will be better able to identify potential treatments to combat any future respiratory viral pandemics.”

With more than seven million deaths caused by Covid-19 worldwide, the SARS-CoV-2 virus continues to spread, with the most common cause of death being respiratory failure.

Alveoli are balloon-shaped air sacs in the lungs where the blood and lungs exchange oxygen and carbon dioxide during breathing. Lung damage from Covid-19 is known as diffuse alveolar damage (DAD).

DAD shows distinct pathological features as it worsens from early-stage to late-stage. Whilst previous studies document an expanded immune response in late DAD, knowledge of the cellular and molecular differences between early and late stages of alveolar damage has been limited.

It is important for researchers to understand these differences so therapies can be developed in order to prevent patients from developing severe Covid-19.

This collaborative work sought to characterise the cellular and molecular progression of DAD following Covid-19. In a new study, they combined single cell RNA sequencing data and spatial transcriptomics data from post-mortem lung tissue samples of Covid-19 patients.

The combination of these two methods allowed the researchers to identify the gene activity, molecular biomarkers and interactions between cells associated with early versus late-stage DAD.

In early-stage DAD, the researchers identified activity in genes associated with protective inflammatory responses, such as an increased expression of interleukin genes – proteins that regulate the immune response.

They also found upregulation of metallothionein-related genes, which are thought to protect cells from toxic high-metal content. Surprisingly, the researchers also saw different waves of macrophages, a key immune cell type in Covid-19, as DAD progressed from early to late stage.

In late-stage DAD, the researchers saw an increase of markers associated with lung fibrosis – a lung pathology that causes scarring and stiffness in lung tissue, making it difficult to breathe.

The team also noted changes in the regulation of several genes that are involved in fibrinolysis. Fibrinolysis is a normal process that involves the breaking down of blood clots.

They demonstrated the gene, SERPINE1 to be a key player in the dysfunction of fibrinolysis as seen in lung cells infected with Covid-19. They also found this gene is upregulated more in early DAD compared to late DAD and is promoted via signals from disease-associated macrophage populations.

Informing future studies

The researchers hope that a better understanding of the cellular and molecular mechanisms underlying progressive lung damage during Covid-19 will inform future studies and ultimately lead to therapies that benefit patients before they develop severe disease.

Dr Omer Ali Bayraktar, Group Leader at the Wellcome Sanger Institute, said: “When the most common death from Covid-19 is respiratory failure, we have a duty to investigate what causes the underlying lung damage and how we can intervene.

“Our study provides new in-depth detail on the dynamic nature of tissue damage in the lungs, which we hope influences change one day, whether that is for further research or the development of therapies, to help those who contract Covid-19.”

Dr Sam Barnett, co-first author and postdoctoral researcher at Imperial, added: “One of the hallmarks of severe disease is clotting in blood vessels of the lung.

“Here, we identified the factors and the specific cells driving this process, suggesting that there is an accumulation of blood clots due to a defect in mechanisms that break them down. This provides a potential target for resolving these blockages and restoring blood flow in the lung tissue.”

Reference: Jimmy Tsz Hang Lee et al. (2025) ‘Integrated histopathology, spatial and single cell transcriptomics resolve cellular drivers of early and late alveolar damage in COVID-19.’ Nature Communications. DOI: 10.1038/s41467-025-56473-x