Already in the first days of the pandemic, the ability of Covid-19 to devastate the lungs and end the lives of many of those infected was evident. Until now, however, we did not have the details of that destruction; a map that an international team of researchers led by Manel Esteller, a scientist at the Sant Pau Research Institute in Barcelona, has been able to prepare. The resolution is published in the journal Nature Communications.
Their work, Esteller assures, provides the most detailed cellular mapping to date of the effects of the deadly Covid on the human lung. A definition that has been achieved thanks to the use of spatial transcriptomics techniques that make it possible to identify, while maintaining the architecture of the tissue, which genes are on or off throughout the process and at each point in the lung.
The scientist emphasizes that it is the first work that allows drawing a map of cellular arrangement and genetic activity while maintaining lung tissue in its natural state. In previous research, it was common to have to fragment the tissue to analyze it. However, this time, scientists were able to observe which genes were activated in a precise location in the lung, preserving the actual architecture of the tissue as the disease left it. "It is, in some ways, like replacing a blurry aerial photograph of a city with a detailed, street-by-street satellite map that shows exactly which neighborhoods are thriving and which are crumbling," the researchers say in a statement.
Scientists studied lung samples from 19 patients who died from Covid and compared them with healthy control lungs. This analysis not only revealed, step by step, how the infectious disease is capable of transforming healthy lung tissue into scar tissue, but also uncovered therapeutic options that may be useful to stop this destruction.
The first thing the map shows is the progressive collapse of the oxygen exchange system that Covid causes in the lungs in severe cases. Thus, the cells that allow oxygen to pass from the air to the blood gradually die as the disease progresses.
In addition, the cartography also shows the progressive transformation of healthy lung tissue into scar tissue.
"There is an increase in fibrosis around the bronchioles, which makes respiratory movements difficult" and colonizes the tissue, explains Esteller, who also highlights that, during the process, some cells of the immune system essential for the response, such as NK cells, a first line of defense against viral infections, decrease, which reinforces the hypothesis that a failure in the deployment of these cells contributes to the lethality of the disease.
At the same time that these 'good' cells were lost, the researcher points out, the team also observed an increase in myeloid cells, related to chronic inflammation.
Scientists have also located a molecular pathway that drives fibrosis progression.
In these cases of progressive destruction, the lung attempts to heal itself, but often fails to do so, a process that the study has also broken down.
"In these patients who did not overcome Covid, we see how the progenitor or stem cells (AT2 cells) that should regenerate or create cells of the functional alveoli, those responsible for oxygen exchange, were left halfway and could not originate them," says Esteller, who recalls that some previous research by his team had previously elucidated why this happened in some people and not in others. "The epigenetic and genetic profiles of each individual give a certain propensity to repair lung damage better or worse," he clarifies.
Many of the identified patterns of damage are specific to Covid, the researcher points out. By comparing their data with lung samples from cases of non-Covid-related pneumonia and idiopathic pulmonary fibrosis, the team demonstrated that the trace of destruction observed constitutes a distinctive signature of Covid and "not a common characteristic of any severe lung injury," they emphasize.
On the other hand, the work has also identified several drugs that could be useful to treat the active disease and prevent its progression. "Among them are fibrosis inhibitors directed against TGF-B1: drugs against the inflammasome (NLRP3 blockers); and inhibitors of myeloid cells that are more "belligerent" in the excessive immune response (such as MYB blockers)," says Esteller.
Knowing the molecular pathways and cell types involved in lung destruction associated with Covid allows us to be better prepared for future pandemics, predicts Esteller.
Because although the study reflects "that the cellular and molecular alterations observed in people who died from Covid are different from other pneumonias or fibrosis," it also shows "that there are common factors."
