The Sars-CoV-2 coronavirus causes severe pneumonia that can lead to death. A first atlas of the lung cells affected by Covid-19 now shows what exactly the virus does in the lungs. According to this, in unfavorable cases the virus not only causes the direct destruction of lung cells, but also causes an excessive inflammatory reaction that hinders the regeneration of the cells. In addition, increased scar tissue forms in the lungs. This could also explain long-term complications in survivors. The findings could be the first step on the way to new therapies.
The most common cause of deaths as a result of Covid 19 disease is serious pneumonia, which can lead to respiratory failure. Even patients who survive a severe course of the disease often have decreased lung function even months later. It is undisputed that Sars-CoV-2 damages the lungs. However, it has so far been unclear how and where exactly it causes damage and which mechanisms play a role in it. This information is relevant to find starting points, to intervene in the destructive processes and to interrupt them.
Autopsies of the lungs of deceased patients
To find answers to these questions, a team led by Johannes Melms from Columbia University Irving Medical Center in New York has now examined the lungs of 19 deceased Covid 19 patients and compared them with the lungs of other donors. The researchers focused on the activity of individual cells and cell types and thus obtained a detailed atlas of the changes that Sars-CoV-19 triggers in the lungs. “A normal lung contains many of the same cells that we find in Covid-19 lungs, but in different proportions and different activation states,” explains Melm’s colleague Benjamin Izar. “To understand how Covid-19 differs from both a control lung and other forms of infectious pneumonia, we had to look at thousands of cells individually.”
The researchers found that there were a particularly large number of macrophages in Covid-19 lungs. These immune cells are involved in the inflammatory response and actually serve to fight the virus. “With Covid-19, the macrophages are completely out of balance and cause the inflammation to increase in an uncontrolled manner,” describes Izar. “This leads to a vicious circle in which even more immune cells are added and cause even more inflammation, which ultimately damages the lung tissue.”
Inflammation and scarring damage lung tissue
In addition, the researchers found that the cells in lungs damaged by Covid-19 are apparently less able to regenerate than usual. It is true that there are enough cells that could carry out the repair. Instead of completely differentiating themselves into the new cells required, however, these progenitor cells remain in an intermediate state. One of the reasons for this is apparently an inflammation-promoting cellular messenger substance called interleukin-1beta, which the macrophages release. According to the studies, the release of IL-1beta is more pronounced in Covid 19 disease than in other viral or bacterial lung infections. “This finding is important because there are drugs that dampen the effects of IL-1beta,” says Izar. Some of these drugs are already being tested in clinical trials with COVID patients. “In addition to reducing inflammation, the targeted suppression of IL-1beta could help enable cells to regenerate lung tissue again,” says Izar.
Another finding of the investigations: A certain type of pathological fibroblasts accumulated in Covid-19 lungs. These connective tissue cells promote rapid scarring. Once the lungs have scarred, i.e. what is known as pulmonary fibrosis, there is less space for healthy lung cells, which are responsible for gas exchange. The lungs are permanently damaged. From the researchers’ point of view, this explains why many patients suffer from long-term lung problems after suffering from Covid 19.
Starting points for new therapies
Using computer analysis, the researchers looked for targets for drugs to counteract this problem. In doing so, they identified several molecules and signaling pathways in the cells that could possibly be suitable for mitigating the harmful effects of the pathological fibroblasts. “We hope that other research groups and pharmaceutical companies can use this data to find ways not only to provide acute treatment for seriously ill Covid-19 patients, but also to reduce long-term complications,” says Izar.
Overall, from the researchers’ point of view, the analyzes show how devastating the virus can be on the lungs. “But the picture we get of the Covid-19 lungs is the first step towards identifying potential targets and therapies that will disrupt some of the vicious cycles of the disease,” says Izar with conviction. The study is supplemented by another publication in the journal Nature, for which researchers led by Toni Delorey from the Broad Institute in Cambridge examined the heart, kidney and liver of deceased Covid-19 patients in addition to the lungs. Their findings confirm the results of Melms and colleagues and at the same time expand them with a view to a possible multi-organ failure due to Covid-19.
Source: Johannes Melms (Columbia University Irving Medical Center, New York) et al., Nature, doi: 10.1038 / s41586-021-03569-1