Why SARS-CoV-2 is so deadly and different in the lungs





One of the most intriguing aspects of SARS-CoV-2, the virus that causes Covid-19, is its infectivity and its lethality, especially in lung cells. Now, a study published in “Nature” has managed to reveal the mechanisms that make a Covid-19 lethal and can explain why long-term complications occur and also shows how it differs from other infectious diseases.

The study has seen that in patients who died from the infection, Covid-19 triggered a harmful career in which you are involved uncontrolled inflammation, direct destruction and impaired lung cell regeneration and gas exchange, and accelerated lung healing.

Although the work analyzed the lungs of patients who had died from the disease, it also provides strong clues as to why severe Covid survivors may experience long-term respiratory complications due to lung scarring.

Covid-19 is a devastating disease, but the Covid-19 lung imaging is the first step toward identifying potential targets and therapies that disrupt some of the disease’s vicious circuits. Specifically, targeting the cells responsible for pulmonary fibrosis early on could prevent or improve long-term complications in severe Covid-19 survivors, “says Benjamin Izar, from Columbia University and the Herbert Comprehensive Cancer Center. Irving (USA), who led a group of more than 40 researchers.

The new study is unique in that it directly examines lung tissue (rather than sputum or bronchial washes) using single-cell molecular profiles that can identify each cell in a tissue sample and record the activity of each cell, resulting in an atlas of cells in lungs Covid.

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“A normal lung will have many of the cells that we find in one with Covid, but in different proportions and activation states,” Izar explains. To understand how Covid-19 differs from control lungs and other forms of infectious pneumonia, we needed to look at thousands of cells, one by one.

Thus, this team examined the lungs of 19 people who died of Covid-19 and underwent a quick autopsy (a few hours after death), during which lungs and other tissues and were immediately frozen, and other lungs of patients without Covid-19.

In addition, they also compared their findings with the lungs of patients with other respiratory diseases.

The results showed that compared to normal lungs, those of the Covid patients were filled with immune cells called macrophages.

Usually during an infection, these cells chew on pathogens but also regulate the intensity of inflammation, which also helps in defense.

«In Covid-19 we have seen an uncontrolled expansion and activation of macrophages, including alveolar macrophages and derivatives of monocytes -explains Izar-. They are completely unbalanced and allow inflammation to rage out of control. This creates a vicious cycle in which more immune cells enter causing even more inflammation, ultimately damaging the lung tissue.

These macrophages produce a particular inflammatory cytokine, IL-1beta, at a high rate.

“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 or bacterial lung infections,” Izar notes. “This is important because there are drugs that reduce the effects of IL-1beta.”

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Some of these drugs are already being tested in clinical trials of COVID patients.

The SARS-CoV-2 virus not only destroys alveolar epithelial cells important for gas exchange, but the resulting inflammation also affects the ability of the remaining cells to regenerate the damaged lung.

In a typical infection, a virus damages lung cells, the immune system removes the pathogen and debris, and the lung regenerates.

But in Covid, the new study found that the SARS-CoV-2 virus not only destroys alveolar epithelial cells important for gas exchange, but the resulting inflammation also affects the ability of the remaining cells to regenerate the damaged lung. Although the lung still contains cells that can make the repairs, inflammation permanently traps these cells in an intermediate cellular state and leaves them unable to complete the final differentiation steps necessary for replacement of the mature lung epithelium.

‘Among others, IL-1b appears to be the culprit in inducing and maintaining this intermediate cellular state, thus linking inflammation and impaired lung regeneration in Covid-19. This suggests that, in addition to reducing inflammation, targeting IL-1beta can help unblock the cells necessary for lung repair, ”Izar says.

The researchers also found a large number of specific fibroblast cells, called pathological fibroblasts, that create rapid scars in the Covid-19 lungs.

When fibroblast cells fill the lung with scar tissue, a process called fibrosis, the lung has less room for cells involved in gas exchange and is permanently damaged.

Given the importance of pathological fibroblasts in disease, Izar’s team analyzed the cells for possible drug targets. A algorithm called VIPER identified several molecules in cells that play an important role and could be the target of existing drugs.

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‘This analysis predicted that inhibition of signaling STAT it could alleviate some of the deleterious effects caused by pathological fibroblasts, “says Izar.

“Our hope is that by sharing this analysis and a massive data resource, other researchers and pharmaceutical companies can begin to test and expand these ideas and find treatments not only to treat critically ill patients, but also to reduce complications in the people who survive a serious Covid ».

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