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An enzyme that can tear cell membranes to shreds may contribute to organ damage that ends up killing some people with severe COVID-19, according to a new study.
The enzyme, called “secreted group IIA phospholipase A2” (sPLA2-IIA), normally protects the body against invaders, such as bacteria, by grabbing specific fats in the membranes of microbes and tearing them apart, said lead author Floyd Chilton, biochemist and director of the Precision Nutrition and Wellness Initiative at the University of Arizona. Human cells also contain these fats, but unlike bacteria, human cells carry these fat molecules on the inner wall of their cell membranes, rather than on the outer surface.
This arrangement typically hides sPLA2-IIA molecules and prevents the enzyme from attacking human cells, but it’s not a foolproof system, Chilton said.
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Cells need energy to maintain the structure of their cell membranes, but when cells begin to die from infection or stress, the fatty molecules targeted by sPLA2-IIA can be exposed, leaving the cells humans vulnerable to attack. In addition, damaged cells release their mitochondria, the so-called powerhouse of the cell; mitochondria resemble bacteria in terms of membrane structure, so sPLA2-IIA rushes to shred floating mitochondria into pieces and spill their contents throughout the body, Chilton said. This, in turn, can call the immune system in action and unleashed a wave of intense inflammation, according to a 2020 report in the newspaper EMBO reports.
“Once that starts to happen, you go down a slippery slope,” Chilton told Live Science.
New research from Chilton and his colleagues suggests that this disastrous chain of events may play out in patients with serious COVID-19 infections – although we need more research to be sure. So far, the study shows only a strong correlation between sPLA2-IIA and the risk of severe illness and death from COVID-19; he cannot prove that the enzyme directly causes the damage seen, Chilton said.
In the study, published Tuesday, August 24 in the Clinical investigation journal, the researchers analyzed blood samples from 127 patients hospitalized between January and July 2020. Of these patients, 30 died from COVID-19; 30 experienced a severe case but survived; and 30 patients suffered mild COVID-19 infections, meaning they did not need supplemental oxygen. The remaining 37 people did not have COVID-19 and served as a comparison group.
The team measured the levels of more than 1,000 enzymes and metabolites in patients’ blood plasma, then used a computer algorithm to see what patterns emerged. Surprisingly, they found that circulating levels of sPLA2-IIA reflected the severity of the patients’ illness, “particularly in patients who died from COVID-19.” In other words, a person’s sPLA2-IIA levels indicate whether or not they died from a COVID-19 infection.
For background, the plasma of healthy people contains relatively low concentrations of sPLA2-IIA – at most a few nanograms per 0.03 ounces (1 milliliter) of blood, the authors wrote in the study. “SPLA2 is normally very low, increases due to the viral trigger and decreases again when the inflammation subsides,” Frans Kuypers, director of the Red Blood Cell Laboratory at the University of California at San Francisco, who was not involved. in the study. Live Science said in an email.
Studies suggest only in severe inflammatory conditions such as sepsis, sPLA2-IIA levels can reach hundreds of nanograms per milliliter. And in the new study, some of the patients who died from COVID-19 showed sPLA2-IIA levels as high as 1,020 nanograms per milliliter (ng / ml) of blood, the team reported.
Overall, patients who died from COVID-19 had sPLA2-IIA levels five times higher than those who had a severe case but survived; and those who died had sPLA2-IIA levels nearly 10 times higher than those with mild COVID-19 infections or non-COVID-related illnesses.
In addition to sPLA2-IIA, a marker of kidney function called “blood urea nitrogen” (BUN) was also linked to the severity of patients’ disease, the team found. BUN, a waste of protein digestion, is normally filtered from the blood by the kidneys, but when the kidneys are damaged, BUN builds up quickly. As COVID-19 infection damages the kidneys, high levels of sPLA2-IIA likely further damage the organ, thereby increasing circulating BUN levels, Chilton said.
The researchers then created an index to predict the risk of COVID-19 mortality based on both BUN and sPLA2-IIA levels. They tested the index on a group of 154 patients, distinct from their original study cohort, who had been hospitalized between January and November 2020; these patients had mild, severe or fatal COVID-19. The team found that they could predict “with reasonably high accuracy” which patients had died from COVID-19 based on their levels of sPLA2-IIA and BUN, and that they could also identify those who had the disease. serious but who survived.
Again, the current study only identifies a correlation between sPLA2-IIA and severe COVID-19, but the results suggest that the enzyme can often be a critical factor in fatal cases, Chilton said.
“Their discovery underscores the importance of this good guy [sPLA2-IIA] is bad, ”Kuypers told Live Science. That said, the current study has some limitations, namely that the sample size is quite small and the team was unable to track sPLA2-IIA levels over time, he noted. . For the future, an ideal The study would include a large number of patients whose levels of sPLA2-IIA are checked daily.This would provide clearer evidence as to patients with high concentrations of the enzyme, how the enzyme causes damage and whether treatments reduce that damage, Kuypers said.
As for possible treatments, drugs that work against sPLA2-IIA already exist, although none have made it through clinical trials. Especially as new variants of SARS-CoV-2 emerge, it is important to identify drugs that can protect against death, regardless of the version of the drug. virus a person catches. In that regard, targeting sPLA2-IIA may be a good idea, but we need trials to be sure, Chilton said.
Such a test is already underway. According to ClinicalTrials.gov, researchers are currently recruiting people with severe COVID-19 for a trial of varespladib, a potent inhibitor of sPLA2 enzymes.
Originally posted on Live Science.
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