Scientists are building more comprehensive tests for COVID-19

Novel coronavirus SARS-CoV-2 transmission electron microscope image of SARS-CoV-2 virus particles isolated from a patient. Image acquisition and color enhancement at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: National Institute for Allergy and Infectious Diseases, NIH

A new study paints the most detailed picture to date of SARS-CoV-2 infection in the lungs and shows mechanisms that lead to fatal COVID-19. It can explain long-term complications and show how COVID-19 differs from other infectious diseases.

Led by researchers from Columbia University’s Vagelos College of Physicians and Surgeons and the Herbert Irving Comprehensive Cancer Center, the study found that in patients who died from the infection, COVID-19 was a harmful trifecta of runaway inflammation, direct destruction and impaired regeneration of lung cells triggered involved in gas exchange and accelerated lung scarring.

Although the study looked at the lungs of patients who died from the disease, it provides solid evidence as to why survivors of severe COVID may have long-term respiratory complications due to lung scars.

“It’s a devastating disease, but the picture we’re getting of the COVID-19 lungs is the first step in identifying potential targets and therapies that disrupt some of the vicious cycles of the disease that may prevent long-term complications in survivors of severe COVID-19 or alleviate, “says Dr. med. Benjamin Izar, assistant professor of medicine who led a group of more than 40 researchers to conduct a series of studies over several months that usually take years to analyze.

This study and an accompanying paper from Harvard / MIT researchers, to which Columbia investigators contributed, were published in Nature on April 29th.

Study creates cell atlas in COVID Lung

The new study is unique in that it examines lung tissue (rather than sputum or bronchial washes) directly using single-cell molecular profiles that identify each cell in a tissue sample and record the activity of each cell, resulting in a cell atlas in the COVID lungs.

“A normal lung will have many of the same cells that we find in COVID, but in different proportions and different levels of activation,” says Izar. “To understand how COVID-19 differs from control lungs and other forms of infectious pneumonia, we had to examine thousands of cells one at a time.”

Izar’s team examined the lungs of 19 people who had died of COVID-19 who had undergone a rapid autopsy (within hours of death) – during the lung and other tissue collection, they were instantly frozen – and the lungs of Non-COVID-19 patients. Working with researchers from Cornell University, the researchers also compared their results with the lungs of patients with other respiratory diseases.

Drugs against IL-1beta can reduce inflammation

Compared to normal lungs, the COVID patients’ lungs were filled with immune cells called macrophages.

Typically, these cells chew pathogens during an infection, but they also regulate the intensity of the inflammation, which also helps in the fight.

“In COVID-19, we see expansion and uncontrolled activation of macrophages, including alveolar macrophages and monocyte-derived macrophages,” says Izar. “You’re completely out of whack and causing inflammation to rise in an uncontrolled manner. This creates a vicious circle in which more immune cells invade and cause even more inflammation that ultimately damages lung tissue.”

In particular, an inflammatory cytokine, IL-1beta, is produced by these macrophages at a high rate.

“Unlike other cytokines such as IL-6, which appear to be common in various pneumonias, IL-1beta production in macrophages is more pronounced in COVID-19 compared to other viral or bacterial lung infections,” says Izar. “This is important because there are drugs that block the effects of IL-1beta.”

Some of these drugs are already being tested in clinical trials with COVID patients.

Severe COVID also prevents lung repair

In a typical infection, a virus damages the lung cells, the immune system removes the pathogen and the deposits, and the lungs regenerate.

In the case of COVID, however, the new study found that the SARS-CoV-2 virus not only destroys the alveolar epithelial cells that are important for gas exchange, but that the resulting inflammation also affects the ability of the remaining cells to regenerate the damaged lungs. Although the lungs still contain cells that can make the repairs, inflammation permanently traps these cells in an intercellular state and leaves them unable to perform the final differentiation steps required to replace the mature lung epithelium.

“IL-1b appears to be one of the culprits in inducing and maintaining this intermediate cell state,” says Izar. 1beta can help slow down the cells needed for lung repair. “

Prevention of accelerated fibrosis

The researchers also found large numbers of specific fibroblast cells called pathological fibroblasts that cause rapid scarring in the COVID-19 lungs. When the fibroblast cells fill the lungs with scar tissue, known as fibrosis, the lungs have less room for cells involved in gas exchange and are permanently damaged.

Given the importance of pathological fibroblasts to the disease, Izar’s team carefully analyzed the cells to uncover potential drug targets. An algorithm called VIPER, previously developed by Andrea Califano, Dr., Chair of Systems Biology at Columbia University’s Vagelos College of Physicians and Surgeons, identified several molecules in cells that play important roles that existing drugs could target .

“This analysis predicted that inhibiting STAT signaling could mitigate some of the harmful effects caused by pathological fibroblasts,” says Izar.

“By sharing this analysis and the vast data resources, we hope that other researchers and pharmaceutical companies can begin to test and expand these ideas and find treatments to not only treat critically ill patients, but reduce complications in humans.” who have favourited severe COVID survival. 19. “

Teamwork from multiple Columbia Labs

“Bringing this study together in such a short time was only possible with the help of several research teams in Columbia,” says Izar.

In the early months of the pandemic, the Department of Pathology and Cell Biology in Colombia decided to flash freeze many tissues from deceased COVID patients in order to preserve the molecular condition of the cells. Hanina Hibshoosh, MD, director of the department’s tissue bank, initiated the collaboration with Izar’s laboratory, which has experience in performing single cell analysis on frozen tissue. The pathologist Anjali Saqi, professor of pathology and cell biology, also played a key role in the procurement and evaluation of the samples.

Jianwen Que, MD, Ph.D., Professor of Medicine, and his laboratory provided expertise in identifying and characterizing cells in the lungs and their regenerative potential. The fibrosis expert Dr. med. Robert Schwabe, Associate Professor of Medicine, was instrumental in analyzing the mechanisms by which COVID-19 caused lung scars. “We are incredibly grateful to all of the laboratories that have contributed to this endeavor, and we are very fortunate to be in Columbia in a collaborative environment with the necessary expertise.”

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More information:
Johannes C. Melms et al., A Molecular Unicellular Lung Atlas of Lethal COVID-19, Nature (2021). DOI: 10.1038 / s41586-021-03569-1 Provided by Irving Medical Center, Columbia University

Quote: New cell atlas of the COVID lung shows why SARS-CoV-2 is deadly and different (2021, April 29), accessed on April 29, 2021 from atlas-covid-lungs -reveals.html

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