The main symptoms of Covid-19 are cough, fever and, above all, inflammation of the lung tissue. These symptoms arise because the Sars-CoV-2 coronavirus primarily affects cells in the airways and lungs. A study now gives more precise information about which cells these are. In it, researchers examined which cells in the respiratory tract form the docking sites and cofactors required by the coronavirus. It was shown that a cell type in the alveoli and progenitor cells for the bronchial mucous membrane provide the virus with the necessary entry points. In addition, men and older people apparently have more docking sites for the virus on these cells – this could explain their greater vulnerability.
For the coronavirus to enter our cells, it must first bind to a receptor on the surface of the human cells. It is already known from previous studies that this docking point is the so-called angiotensin converting enzyme 2 – ACE2 for short. This receptor has also been used by the closely related Sars corona virus for cell entry. To do this, the coronavirus flips its protruding coat protein, the spike protein, so that the binding site is exposed and can dock onto the ACE2 receptor. In addition, the virus likely needs one or more cofactors located on the cell membrane to help it enter the host cell. Analyzes show that ACE2 is present in the tissues of the lungs, kidney, heart and also the digestive tract, which could explain why Sars-CoV-2 can cause diarrhea and heart problems in some patients.
RNA detection in lung and bronchial tissue
So far, it has only been partially clarified which cell types carry the ACE2 receptor and the necessary cofactors. “We wanted to know exactly which cells are affected by the coronavirus,” explains senior author Christian Conrad from Charité Universitätsmedizin Berlin. To clarify this, the researchers used tissue samples from the lungs and bronchi of 16 patients who had undergone a biopsy or bronchoscopy because of suspected cancer. None of the patients had Covid-19 or were infected with the coronavirus. The researchers used RNA analysis to examine the samples for copies of the genes encoding the ACE2 receptor and the cofactor TMPRSS2. Through additional analyzes, they were also able to narrow down which of the cells in the tissues carry these factors and how many of them.
“We examined a total of almost 60,000 cells to determine whether they switched on the genes for the receptor and any cofactors, so that they can in principle be infected by the corona virus,” reports lead author Soeren Lukassen from the Charité and the Berlin Institute of Health. The analyzes showed that, above all, a cell type sitting in the alveoli forms the ACE2 receptor in the lung tissue. These so-called type 2 alveolocytes (AT2) cover around five percent of the inner surface in the alveoli and, above all, ensure that the exchange surface between blood vessels and air, which is important for breathing, remains moist with a special liquid. The AT2 cells showed the highest ACE2 expression in the lungs in terms of both the number and the percentage of positive cells, ”the researchers report. For the TMPRSS2 cofactor, which also occurs on other lung cells, they also found slightly increased values on the AT2 cells.
Cells of the alveoli and bronchial progenitor cells
The results for the bronchi were somewhat different: “The most striking result of this study was the detection of ACR2 expression in a population of precursor cells for the respiratory mucosa,” report Lukassen and his colleagues. These progenitor cells usually develop into the cells in the respiratory tract, which, with their cilia, ensure that mucus and bacteria are transported out of the lungs. The current analyzes show that it produces both the ACE2 receptor and the cofactor TMPRSS2 to a particularly high degree. These progenitor cells could therefore be particularly susceptible to Sars-CoV-2 infection, as the researchers explain. “These results show us that the virus is very targeted and relies on certain cells in the body to spread and multiply,” explains co-senior author Roland Eils from the Charité and the Berlin Institute of Health.
As an interesting secondary finding, the team also found that the density of the ACE2 receptor on the cells apparently increases with the age of the patient. In addition, this docking site appears to be more present on the cells of men than of women. “It was just a trend, but it could explain why more men than women are infected,” says Eils. “However, our case numbers are still far too small for a verifiable statement. We have to repeat this examination in larger patient cohorts. ”In the next step, the scientists now want to examine Covid-19 patients to determine whether they actually have these cells infected by the virus. “We want to understand why the infection is so harmless in some patients and why others are so seriously ill. We will also take a closer look at the immune cells in the affected tissue, ”explains Eils. “The better we understand the interactions between the virus and its host, the better we can develop counter strategies.”
Source: Soeren Lukassen (Charité Universitätsmedizin Berlin) et al., EMBO Journal, doi: 10.15252 / embj.20105114
You can read more about the corona virus and Covid-19 in our pandemic topic special