Mechanism Driving COVID-19 Mortality Identified

Researchers have identified what may be the major molecular mechanism responsible for mortality from COVID-19 — an enzyme linked to neurotoxins found in rattlesnake venom.

An enzyme with an elusive role in severe inflammation may be a key mechanism driving the severity of COVID-19 and could be a new therapeutic target to reduce mortality from COVID-19, according to a study published in the Journal of Clinical Investigation.

Researchers from the University of Arizona, in collaboration with Stony Brook University and Wake Forest University School of Medicine, analyzed blood samples from two COVID-19 patient cohorts and found that the circulation of the enzyme — secreted phospholipase A2 group IIA or sPLA2-IIA — may be the most important factor in predicting which patients with severe COVID-19 will eventually succumb to the virus.

sPLA2-IIA, which shares similarities with an active enzyme in rattlesnake venom, is found in low concentrations in healthy individuals and has long been known to play a critical role in defending against bacterial infections, destroying microbial cell membranes.

When the activated enzyme is circulating at high levels, it has the capacity to “shredder the membranes of vital organs,” said Floyd (Ski) Chilton, senior author on the paper and director of the UArizona Precision Nutrition and Wellness Initiative, housed in the university college. of Agriculture and Life Sciences.

“It’s a bell-shaped curve of disease resistance versus host tolerance,” Chilton said. “In other words, this enzyme tries to kill the virus, but at some point it’s released in such large amounts that it goes the wrong way, destroying the patient’s cell membranes and thereby contributing to multiple organ failure and death. ”

Together with available clinically tested sPLA2-IIA inhibitors, “the study supports a novel therapeutic target to reduce or even prevent death from COVID-19,” said study co-author Maurizio Del Poeta, a leading SUNY professor. in the Department of Microbiology and Immunology in the Renaissance School of Medicine at Stony Brook University.

Collaboration in the midst of chaos

“The idea of ​​identifying a possible prognostic factor in COVID-19 patients comes from Dr. Chilton,” Del Poeta said. “He first contacted us last fall with the idea of ​​analyzing lipids and metabolites in blood samples from COVID-19 patients.”

Del Poeta and his team collected stored plasma samples and set to work analyzing medical charts and tracking 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.

“Although these are small cohorts, it was a heroic effort to get them and all the associated clinical parameters from each patient under these circumstances,” Chilton said. “Unlike most studies that are well planned over the years, this happened in real time on the IC floor.”

The research team was able to analyze thousands of patient data points using machine learning algorithms. In addition to traditional risk factors such as age, body mass index and pre-existing conditions, the team 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, an assistant research professor in the UArizona Department of Nutrition. “The metabolites that emerged revealed a dysfunction of cell energy and high levels of the sPLA2-IIA enzyme. The former was expected, the latter was not.”

Using the same machine learning methods, the researchers developed a decision tree to predict mortality from COVID-19. Most healthy individuals have circulating levels of the sPLA2-IIA enzyme around half a nanogram per milliliter. According to the study, COVID-19 was fatal in 63% of patients with 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 ever reported,” said Chilton, who has studied the enzyme for more than three decades.

An enzyme with a bite

The role of the sPLA2-IIA enzyme has been the subject of study for half a century, and it is “possibly the most researched member of the phospholipase family,” explains Chilton.

Charles McCall, Wake Forest University principal investigator for the study, refers to the enzyme as a “shredder” because of its known prevalence in severe inflammatory events, such as bacterial sepsis, as well as hemorrhagic and cardiac shock.

Previous research has shown how the enzyme destroys microbial cell membranes in bacterial infections, as well as its similar genetic ancestors to a key enzyme found in snake venom.

The protein “shares high sequence homology with the active enzyme in rattlesnake venom and, like venom that flows through the body, it has the ability to bind to receptors on neuromuscular junctions and potentially disable the function of these muscles,” Chilton said. .

“About a third of people develop long-term COVID, and many of them were active individuals who are now unable to walk 100 meters. The question we’re investigating now is, if this enzyme is still relatively high and active, could it be responsible for some of the long COVID results we’re seeing?”

Reference: “Group IIA secreted phospholipase A2 is associated with the pathobiology leading to mortality from COVID-19” Aug 24, 2021, Journal of Clinical Investigation.
DOI: 10.1172 / JCI149236