Researchers’ Tissue Analysis Shows How COVID-19 Affects Infected Cells

Since the COVID-19 pandemic began a little more than a year ago, scientists have sequenced the virus’ genome, developed vaccines to prevent its spread, and tested a range of drugs to help treat the often deadly infection. Yet much remains unknown about how SARS-CoV-2, the virus that causes COVID-19, drives illness in the body.

Now a large collaboration of scientists from several hospitals and research centers, including Beth Israel Deaconess Medical Center (BIDMC), has shown what happens in individual cells of patients who died of COVID-19. In a study recently published in Nature, the researchers described how infected cells from multiple organs exhibit a range of molecular and genomic changes. Using single-cell RNA sequencing data from tissue samples taken from 11 organ systems, including the lungs, heart, liver and kidneys, the scientists built a comprehensive “cell atlas” — available for free online — of hundreds of thousands of individual cells showing how COVID-19 can lead to organ failure and death. They also created a 420-specimen biobank from autopsy samples that can be used for other COVID-19 studies.

“Capturing the effects of COVID-19 on each cell population across human tissues can empower our understanding and help generate targeted therapeutics,” said co-corresponding author Ioannis Vlachos, PhD, Co-Director of the Bioinformatics Program of the Cancer Research Institute at BIDMC, and a member of the Broad Institute of MIT and Harvard. “Our researchers, trainees, pathologists, residents, core facilities staff, administrators and clinicians worked around the clock during the first wave of the pandemic to make this study possible. It was a gigantic effort and a clear testament to how interdisciplinary research, new technologies and team science can overcome barriers.”

Vlachos and colleagues from the Broad Institute, Massachusetts General Hospital, the Ragon Institute of MGH, MIT and Harvard, MIT, Brigham and Women’s Hospital, Columbia University Irving Medical Center, and other institutions studied tissue obtained at autopsies of 17 individuals who succumbed to COVID-19 and were cared for at BIDMC, Brigham and Women’s Hospital or Massachusetts General Hospital.

To investigate how the SARS-CoV-2 virus interferes with the function of cells and their genetic programs, the team profiled RNA from individual cells and developed new methods to analyze and annotate the large amounts of sequence data. They compared gene expression signatures from different cells: COVID-19-damaged cells and uninfected cells from the COVID-19 patients, as well as cells from patients with other diseases and from healthy individuals.

“Using powerful new technologies, we were able to create a highly granular cellular and transcriptional atlas of the effects of COVID-19 in the human tissue,” said Vlachos, who is also an assistant professor of Pathology at Harvard Medical School. “These new technologies offer us the ability to capture highly localized phenomena and understand the effects of pathologies on each individual cell, tissue organization, and cell-to-cell communication.”

The most extensive suite of findings were from the lungs, in which the scientists saw signs of multiple, unsuccessful attempts of the lungs to repair themselves in response to respiratory failure, which is the leading cause of death in COVID-19 patients.

The researchers also looked at 27 different genes that previous studies have linked to severe COVID-19. They zeroed in on a handful that were highly expressed in key cell types, particularly those in infected lungs. This finding helps narrow down the list of potential genetic factors for severe disease and highlights the cell types that may be most relevant in severe COVID-19.

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

“All our datasets, tools, methods and analyses are provided openly to the community,” Vlachos said. “The true enablers of these scientific findings are the patients and their families. We are humbled by their support for this effort and we went above and beyond to maximize its significance.”

Co-authors from BIDMC included; Yered H. Pita-Juárez, Pourya Naderi, Yury V. Popov, Sebastian Niezen, Linus T.-Y. Tsai, Olga R. Brook, Adam Essene, Jonathan Hecht, Deepti Pant, Winston Hide, Stefan Riedel, Gyongyi Szabo, Robert Rogers and Z. Gordon Jiang.

Please see the publication for a complete list of contributors and competing interests.

Support for this research was provided in part the Manton Foundation, Klarman Family Foundation, Howard Hughes Medical Institute, the Chan Zuckerberg Initiative, and the Human Tumor Atlas Network trans-network projects SARDANA (Shared Repositories, Data, Analysis and Access), DARPA, and the US Food and Drug Administration.

Editor's note: This was adapted from a press release issued by the Broad Institute.