CM – A cell atlas of the COVID-19 pathology is being created as a result of the great collaboration


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April 30, 2021

by Stephanie M. McPherson, Broad Institute of MIT and Harvard

Scientists from several hospitals and research centers have shown what happens in individual cells of patients who have died of COVID-19. In a study published in Nature, the researchers describe how infected cells from multiple organs exhibited a series of molecular and genomic changes. They also saw signs of several unsuccessful attempts by the lungs to self-repair in response to respiratory failure, which is the leading cause of death in COVID-19 patients.

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« You really feel the tragedy of the disease when you see this result, » said Aviv Regev, co-senior author of the study and a member of the core institute at the Broad Institute of MIT and Harvard, when the study began. « The lungs are trying everything it can and still can’t repair themselves. This was a very emotional study. We are grateful to the patients and families who have volunteered to use tissues for the COVID-19 research to donate to improve understanding of this devastating disease.  » The researchers examined tissue obtained from autopsies of 17 people who had succumbed to COVID-19 and who were being cared for at Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, and Massachusetts General Hospital.

That Team studied how the SARS-CoV-2 virus affects the function of cells and their genetic programs. They used single-cell RNA sequencing data from tissue samples from 11 organ systems – including the lungs, heart, liver, and kidneys – to create a comprehensive « cellular atlas » of hundreds of thousands of individual cells showing how COVID-19 can lead to organ failure and death.

« We knew people were dying from COVID-related pneumonia and extrapulmonary complications, » said Alexandra-Chloé Villani, associate member of Broad, lead investigator at Mass General, assistant professor of medicine at Harvard Medical School, and co- Co lead author of the study. « Before this study, we had limited knowledge of the cellular and molecular mechanisms involved in the death of a patient. »

The study describes the results of a collaboration between researchers from the Broad Institute, the Mass General, the Ragon Institute of MGH, MIT and Harvard, MIT, Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Irving Medical Center, Columbia University, and other institutions. A team led by Columbia employees co-authored an accompanying study that will also be published in Nature.

The team’s cell atlas is freely available to other scientists. They also created a biobank with 420 samples from the autopsy samples that can be used for other COVID-19 studies. « We have created a fundamental resource that other researchers can use in the future to ask specific questions, » said Orit Rozenblatt-Rosen, co-senior author and institute scientist and scientific director of the Klarman Cell Observatory on Broad, when the study began . « We hope our results will enable people to find better therapeutics for COVID-19. »

To learn more about the cellular mechanisms underlying organ failure caused by COVID-19, the researchers knew they had to examine the organs themselves. For that they would need autopsy specimens.

Working with autopsy specimens is challenging under normal circumstances. To deal with samples that may contain a novel, highly contagious pathogen, the researchers developed new tissue collection and processing protocols that are compatible with the requirements for a Biosafety Level 3 laboratory.

« We wanted to make sure we can learn and share as much as possible to prevent future deaths while prioritizing the safety and wellbeing of everyone involved. This was no small feat given the COVID-related restrictions and uncertainties that come with it. It was amazing to see how Dozens of scientists and medical professionals from different institutes came together as a collaborative partnership to carefully design and coordinate our experimental and computational efforts, « said institute member and co-senior author Alex K. Shalek, who is also a member of the Ragon Institute and associate Professor f For chemistry, core member of the Institute for Medical Technology and Natural Sciences and extramural member of the Koch Institute for Integrative Cancer Research at MIT.

The team then profiled RNA from the individual cells and developed new methods for analyzing and annotating the large amounts of sequence data. They compared gene expression signatures from different cells: cells damaged by COVID-19 and uninfected cells from COVID-19 patients as well as cells from patients with other diseases and from healthy people.

The largest set of findings came from the lungs. The scientists were amazed at the extent of the changes in the genetic programs they found there. « The virus is causing chaos in the lungs and we are seeing it in the cells, » Regev said.

A major cause of lung damage in COVID-19 is the destruction of AT1 cells that allow breathing and gas transmission. The scientists found that after AT1 cells died, related lung cells called AT2 attempted to transform into AT1 cells through a process called transdifferentiation. However, this attempt stopped halfway, leaving the cells in an intermediate state that is common in patients with other lung conditions such as pulmonary fibrosis.

In a final attempt at self-repair, the lungs attempted to remove cells from higher airways that were found to be intrapulmonary basal-like Progenitor cells are known to convert into AT1 cells. This attempt at transdifferentiation has so far only been seen in mouse models.

The results suggest that lung failure in patients was caused by the inability of the lung cells to outperform the damage caused by the virus when the cells tried to close regenerate.

The paper also describes how the virus affects other tissues outside of the lungs. One surprising finding was that although the heart suffered considerable damage and showed evidence of altered genetic programs in many different cell types, very little viral RNA was present in the heart tissue itself. « Whether this means the virus has already been cleared or that the heart has collateral damage is an area for further research, » Regev said.

The researchers also looked at 27 different genes that previous genome-wide association studies with severe COVID-19 had have connected. They focused on a handful that were highly expressed in key cell types in the new study, particularly infected lungs. This finding helps narrow the list of potential genetic factors for serious illness and highlight the cell types that may be most relevant in severe COVID-19.

The team now plans to analyze the other autopsied tissues such as the brain, spleen and Complete the trachea to paint a more complete picture of COVID-19 pathology and provide a resource for future studies.

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