New study paints the most detailed picture to date of SARS-CoV-2 infection in the lungs, revealing mechanisms that lead to fatal COVID-19, and may explain long-term complications and show in how COVID-19 differs from other infectious diseases.
Led by researchers at Columbia University Vagelos College of Physicians and Surgeons and Herbert Irving Comprehensive Cancer Center, the study found that in patients who died from the infection, COVID-19 triggered a harmful trifecta of uncontrolled inflammation , direct destruction and degradation of regeneration of lung cells involved in gas exchange and acceleration of pulmonary scars.
Although the study looked at the lungs of patients who died from the disease, it provides solid clues as to why survivors of severe COVID may experience long-term respiratory complications due to lung scarring.
“It’s a devastating disease, but the image we get of the COVID-19 lung is the first step towards identifying potential targets and therapies that disrupt some of the disease’s vicious circuitry. In particular, targeting the cells responsible for pulmonary fibrosis early on could perhaps prevent or improve long-term complications in survivors of severe COVID-19, ”says Benjamin Izar, MD, PhD, assistant professor of medicine, who led a group of more than 40 researchers to complete a series of analyzes that takes years over several months.
This study and a companion paper led by Harvard / MIT researchers, to which the Columbia researchers also contributed, were published in the journal Nature April 29.
Study Creates Atlas of Cells in COVID Lung
The new study is unique from other surveys in that it directly examines lung tissue (rather than sputum or bronchial washings) using single-cell molecular profiling that can identify every cell in a sample. tissue and record the activity of each cell, resulting in a cell atlas. in the COVID lung.
“A normal lung will have many of the same cells we find in COVID, but in different proportions and different activation states,” says Izar. “In order to understand how COVID-19 is different 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 died from COVID-19 and underwent a quick autopsy (hours after death) – during which the lungs and other tissue were collected and immediately frozen – and the lungs of non-COVID-19 patients. In collaboration with researchers at Cornell University, the researchers also compared their results to the lungs of patients with other respiratory diseases.
Medicines targeting IL-1beta may reduce inflammation
Compared to normal lungs, the lungs of patients with COVID were filled with immune cells called macrophages, according to the study.
Typically during infection, these cells chew on pathogens but also regulate the intensity of inflammation, which also helps in the fight.
“In COVID-19, we see an uncontrolled expansion and activation of macrophages, including alveolar macrophages and monocyte-derived macrophages,” says Izar. “They are completely out of balance and allow inflammation to accelerate without control. This results in a vicious cycle where more immune cells enter causing even more inflammation, which ultimately damages the lung tissue.”
An inflammatory cytokine in particular, IL-1beta, is produced at a high level by these macrophages.
“Unlike other cytokines such as IL-6, which appears to be universally prevalent in various pneumonias, IL-1beta production in macrophages is more pronounced in COVID-19 compared to other viral lung infections or bacterial, ”says Izar. “This is important because there are drugs available that lessen the effects of IL-1beta.”
Some of these drugs are already being tested in clinical trials in patients with COVID.
Severe COVID also prevents lung repair
In a typical infection, a virus damages lung cells, the immune system clears the pathogen and debris, and the lung regenerates.
But in COVID, the new study found that not only does the SARS-CoV-2 virus destroy alveolar epithelial cells important for gas exchange, the resulting inflammation also impairs the ability of the remaining cells to regenerate the damaged lung. . Although the lung still contains cells capable of making repairs, inflammation permanently traps them in an intermediate cellular state and leaves them unable to complete the final stages of differentiation necessary for replacement of the mature pulmonary epithelium.
“Among other things, IL-1b appears to be a culprit in inducing and maintaining this intermediate cellular state,” says Izar, “thus linking inflammation and impaired lung regeneration in COVID-19. This suggests that in addition to reduce inflammation, targeting IL-1beta may help loosen the brakes on cells necessary for lung repair. “
Prevent accelerated fibrosis
The researchers also found a large number of specific fibroblasts, called pathological fibroblasts, which create rapid scarring in the COVID-19 lungs. When fibroblast cells fill the lung with scar tissue, a process called fibrosis, the lung has less space for cells involved in gas exchange and is permanently damaged.
Given the importance of pathological fibroblasts in the disease, Izar’s team closely analyzed cells to discover potential drug targets. An algorithm called VIPER, previously developed by Andrea Califano, Dr, president of systems biology at Columbia University Vagelos College of Physicians and Surgeons, has identified several molecules in cells that play important roles and could be targeted by drugs. existing.
“This analysis predicted that inhibition of STAT signaling may mitigate some of the deleterious effects caused by pathological fibroblasts,” says Izar.
“Our hope is that by sharing this analysis and this huge data resource, other researchers and pharmaceutical companies can begin to test and develop these ideas and find treatments not only to treat critically ill patients, but also to reduce the risks. complications in people who survive severe COVID. 19. “
Team effort by several Columbia laboratories
“Putting this study together in such a short time was only possible with the help of several teams of researchers from Columbia,” says Izar.
During the first months of the pandemic, Columbia’s Department of Pathology and Cell Biology decided to quickly freeze many tissues from deceased COVID patients to preserve the molecular state of the cells. Hanina Hibshoosh, MD, director of the department’s tissue bank, initiated the collaboration with the Izar laboratory, which has expertise in performing single-cell analyzes with frozen tissue. Pathologist Anjali Saqi, MD, professor of pathology and cell biology, was also instrumental in obtaining and evaluating samples.
Jianwen Que, MD, PhD, professor of medicine, and his laboratory provided expertise in the identification and characterization of lung cells and their potential for regeneration. Fibrosis expert Robert Schwabe, MD, associate professor of medicine, was instrumental in dissecting the mechanisms by which COVID-19 propelled lung scars. “We are extremely grateful to all of the labs contributing to this effort and very fortunate to be at Columbia with all the necessary expertise at hand in a collaborative environment.”