Some of our enzymes have a bite. They can be helpful if they sink their fangs into the membranes of disease-causing bacteria. Sometimes, however, they tear into the membranes of our own cells, causing excess inflammation. Consider an enzyme called secreted phospholipase A2 group IIA (sPLA2-IIA). It has long been known to play a critical role in defense against bacterial infections. But according to a new study, sPLA2-IIA can contribute to multiple organ failure and death in COVID-19 patients.

This finding emerged from a lipidomics analysis of plasma samples taken from patients with mild or severe COVID-19, and from patients who ultimately succumbed to COVID-19. Higher plasma sPLA2-IIA levels were found in deceased patients vs. those in patients with severe or mild COVID-19.

Additional details appeared August 24 in the Journal of Clinical Investigation, in an article titled, “Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality.” The article’s senior author, Floyd H. Chilton, PhD, a professor of nutritional science at the University of Arizona, noted that when sPLA2-IIA becomes an activated enzyme and circulates at high levels, it has the capacity to “shred” the membranes of vital organs.

“It’s a bell-shaped curve of disease resistance versus host tolerance,” Chilton explained. “In other words, this enzyme is trying to kill the virus, but at a certain point it is released in such high amounts that things head in a really bad direction, destroying the patient’s cell membranes and thereby contributing to multiple organ failure and death.”

Previous research has shown that the enzyme destroys microbial cell membranes in bacterial infections, and that it has a genetic ancestry similar to that of a key enzyme found in snake venom. The protein, Chilton elaborated, “shares a high sequence homology to the active enzyme in rattlesnake venom.”

One of the study’s co-authors, Charles E. McCall, MD, a professor of molecular medicine at Wake Forest University, noted that sPLA2-IIA is known to be prevalent in severe inflammation events, such as bacterial sepsis, as well as in hemorrhagic and cardiac shock.

In the current study, untargeted/targeted lipidomics and focused biochemistry were performed on 127 plasma samples, and metabolites associated with sPLA2-IIA activity and mitochondrial dysfunction were found to circulate at high levels in severe COVID-19 patients.

“Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2-IIA, with a median value 9.6-fold higher than mild patients and 5.0-fold higher than severe COVID-19 survivors,” the article’s authors reported. “Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction).”

The study was limited to small cohorts, Chilton admitted, but he added that they reflected a dedicated effort to track multiple clinical parameters under difficult circumstances. “As opposed to most studies that are well planned out over the course of years,” he pointed out, “this was happening in real time on the ICU floor.”

Study co-author Maurizio Del Poeta, MD, a professor of microbiology and immunology at Stony Brook University, led a team of scientists that collected stored plasma samples, analyzed medical charts, and tracked down critical clinical data from 127 patients hospitalized at Stony Brook University between January and July 2020. A second independent cohort included a mix of 154 patient samples collected from Stony Brook and Banner University Medical Center in Tucson between January and November 2020.

The researchers were able to analyze thousands of patient data points using machine learning algorithms. Beyond traditional risk factors such as age, body mass index, and preexisting conditions, the researchers also focused on biochemical enzymes, as well as patients’ levels of lipid metabolites.

“In this study, we were able to identify patterns of metabolites that were present in individuals who succumbed to the disease,” said lead study author Justin Snider, PhD, an assistant research professor at the University of Arizona. “The metabolites that surfaced revealed cell energy dysfunction and high levels of the sPLA2-IIA enzyme. The former was expected but not the latter.”

Using the same machine learning methods, the researchers developed a decision tree to predict COVID-19 mortality. Most healthy individuals have circulating levels of the sPLA2-IIA enzyme hovering around half a nanogram per milliliter. According to the study, COVID-19 was lethal in 63% of patients who had severe COVID-19 and levels of sPLA2-IIA equal to or greater than 10 nanograms per milliliter.

“Many patients who died from COVID-19 had some of the highest levels of this enzyme that have ever been reported,” Chilton observed.

The current study presents findings indicating that circulating levels of sPLA2-IIA could be the most important factor in predicting which patients with severe COVID-19 eventually succumb to the virus. The findings also suggest therapeutic possibilities. “With clinically tested inhibitors available,” the study’s authors concluded, “this study supports sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.”

An additional possibility was raised by Chilton: “Like venom coursing through the body, sPLA2-IIA has the capacity to bind to receptors at neuromuscular junctions and potentially disable the function of these muscles. Roughly a third of people develop long COVID, and many of them were active individuals who now can’t walk 100 yards. The question we are investigating now is: If this enzyme is still relatively high and active, could it be responsible for part of the long COVID outcomes that we’re seeing?”

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