#Research explores cellular changes as COVID-19 lung damage worsens

Researchers have uncovered changes in the cellular response throughout lung damage caused by SARS-CoV-2—the virus behind COVID-19. The team revealed distinct phases where waves of immune responses give way to lung fibrosis—scarring of the lungs—in severe COVID-19.

As part of the UK Coronavirus Immunology Consortium (UK-CIC), researchers from the Wellcome Sanger Institute, Imperial College London, Newcastle University 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 is part of the international Human Cell Atlas initiative to map every cell type in the human body.

The research, published in Nature Communications, 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.

With more than 7 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. Lung damage from COVID-19 is known as diffuse alveolar damage (DAD). Alveoli are balloon-shaped air sacs in the lungs where the blood and lungs exchange oxygen and carbon dioxide during breathing.

DAD shows distinct pathological features as it worsens from early-stage to late-stage. While 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.

In their 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 SARS-CoV-2. They also note this gene is upregulated more in early DAD compared to late DAD and is promoted via signals from disease-associated macrophage populations.

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.

“Our study allowed us to build a more thorough picture of how our lungs respond to the SARS-CoV-2 virus. We identified a group of new cell types that change between early and late stages of lung damage. We also identified sub-groups of immune cells, called macrophages, that start to accumulate in very early stages of infection, and how they shift to different groups as the disease worsens. Our results provide a more detailed understanding about a disease that affects people worldwide,” says Dr. Jimmy Tsz Hang Lee.

“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,” says Dr. Sam Barnett.

“The combination of single-cell data and spatial transcriptomic data allows you to immediately identify the genes and the molecular biomarkers that are enriched in early versus late stages of alveolar damage. The integrated method provides a detailed understanding of the molecular processes underlying COVID-19, which is a huge leap for understanding a virus that is still impacting millions of people,” says Dr. Martin Hemberg.