Those who are seriously ill with Covid-19 often have to be artificially ventilated for a long time or are even temporarily dependent on a heart-lung machine. Researchers have now found a reason why the Sars-CoV-2 coronavirus causes particularly severe damage to the lungs compared to other viruses. Through autopsies, cell analyzes and laboratory experiments, they found that Sars-CoV-2 reprograms the scavenger cells of the immune system in such a way that they promote scarring of the lung tissue – similar to a severe form of pulmonary fibrosis. But studies of survivors show that some of the damage is repairable.
About five percent of people who become infected with Sars-CoV-2 develop acute respiratory distress syndrome (ARDS), in which their lungs are no longer able to absorb enough oxygen from the air. These patients often have to be artificially ventilated or connected to a heart-lung machine (ECMO) for many days. But even with optimal intensive medical treatment, only about every second patient with a severe Covid-19 course survives. How and why Sars-CoV-2 damages the lungs so severely, however, has been unclear so far.
Scarred lung tissue
A team led by Daniel Wendisch from Charité – Universitätsmedizin Berlin has now tracked down the disease mechanism. To do this, the researchers first examined the lungs of deceased Covid-19 patients using microscopic images. “We discovered enormous damage in almost everyone affected: the alveoli were largely destroyed, the walls significantly thickened. We also found extensive deposits of collagen, which is a major component of scar tissue. All of this is characteristic of severe fibrosis, ”describes co-author Peter Boor from RWTH Aachen University. “These observations indicate that we are dealing with a so-called fibroproliferative ARDS in Covid-19 lung failure, a particularly severe form of lung failure. That could explain why we have to ventilate those affected for so long. “
But what exactly is the reason for the severe scarring of the lungs? “With Covid-19, lung failure typically only develops in the second or third week after the onset of symptoms, when the viral load is actually falling again,” explains Wendisch’s colleague Leif Erik Sander. “This indicates that it is not uncontrolled virus replication that causes the lungs to fail, but that downstream reactions, for example of the immune system, play a role.” found in the lungs of seriously ill or deceased Covid 19 patients. The result: In those affected who developed lung failure, scavenger cells of the immune system, so-called macrophages, accumulated in the lungs. These are usually responsible for eliminating pathogens and cell waste, but also contribute to wound healing.
Sars-CoV-2 reprograms macrophages
“Surprisingly, the macrophages showed similar properties in severe Covid-19 as in a chronic form of lung scarring, idiopathic fibrosis,” says co-author Antoine-Emmanuel Saliba from the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg. In this incurable disease, the lungs inexorably scarring until they lose their organ function. The cause is unknown and of all forms of pulmonary fibrosis it has the worst prognosis. Similar to idiopathic fibrosis, the macrophages in severe Covid-19 stimulate certain cells of the connective tissue that are responsible for the formation of scar tissue and subsequently multiply.
In cell cultures with macrophage precursor cells from the blood of healthy people, the researchers showed how Sars-CoV-2 influences this process. When the researchers brought the immune cells in the laboratory into contact with Sars-CoV-2, they produced more messenger substances that promote scarring. “Sars-CoV-2 is at least one possible trigger for the misdirected reaction of the phagocytes,” explains co-author Matthias Selbach from the Max Delbrück Center for Molecular Medicine (MDC) in Berlin. “The virus does not seem to multiply in the immune cells, but reprograms them. Interestingly, we could not observe this effect when we stimulated the macrophages with an influenza virus. The influenza virus multiplied strongly in the immune cells. But it did not encourage them to promote the scarring process. “
Damage at least partially repairable
“Our data clearly show parallels between Covid-19 and chronic pulmonary fibrosis,” sums up Saliba. “That may explain why some risk factors for Covid-19 are also risk factors for idiopathic pulmonary fibrosis – for example underlying diseases, smoking, being male and being over 60 years of age.” But there is an important difference between the two diseases: “With Covid-19, the scarring is at least potentially repairable, ”says Saliba. CT images of recovered persons who previously had to be treated with a heart-lung machine showed that the body was able to at least partially dissolve the scarring over time.
The researchers now want to investigate more closely which cellular processes cause fibrosis to regress. “If we better understand the dissolution of scarred tissue, we will hopefully not only be able to help those affected by Covid 19 in the future, but also patients with previously incurable pulmonary fibrosis,” says Sander. “The important role of macrophages in both diseases also suggests that inhibiting the cells could help prevent scarring.”
Source: Daniel Wendisch (Charité – Universitätsmedizin Berlin) et al., Cell, doi: 10.1016 / j.cell.2021.11.033