Researchers have identified what they believe to be the key driver behind COVID-19 severity and mortality – an enzyme that, if targeted therapeutically, could potentially help treat the disease.
According to a new study in The Journal of Clinical Investigation, the culprit is an enzyme that plays a role in severe inflammation in the body, and that’s related to the neurotoxins found in deadly rattlesnake venom.
The researchers, from the University of Arizona, in collaboration with Stony Brook University and Wake Forest University, all in the US, analysed blood samples from two cohorts of COVID patients and found that circulation of this enzyme – secreted phospholipase A2 group IIA, known more succinctly as sPLA2-IIA – may be the biggest predictor of whether a patient will die from the disease.
sPLA2-IIA is found in low concentrations in the healthy human body, and can defend it against bacterial infections by destroying the cell membranes of microbes. But, when the enzyme circulates at high levels, it can “shred” the membranes of vital organs, according to Floyd ‘Ski’ Chilton, senior author on the paper.
“[It] shares a high sequence homology to the active enzyme in rattlesnake venom and, like venom coursing through the body, it has the capacity to bind to receptors at neuromuscular junctions and potentially disable the function of these muscles,” says Chilton
“It’s a bell-shaped curve of disease resistance versus host tolerance. 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.”
Together with available clinically tested sPLA2-IIA inhibitors, “the study supports a new therapeutic target to reduce or even prevent COVID-19 mortality,” says study co-author Maurizio Del Poeta, a professor in the Department of Microbiology and Immunology in the Renaissance School of Medicine at Stony Brook University.
“The idea to identify a potential prognostic factor in COVID-19 patients originated from Dr Chilton. He first contacted us last fall with the idea to analyse lipids and metabolites in blood samples of COVID-19 patients.”
Del Poeta and his team collected plasma samples, analysed medical charts and tracked down clinical data from 127 patients hospitalised at Stony Brook University between January and July 2020. A second independent cohort included 154 patient samples collected from Stony Brook and Banner University Medical Center in Tucson between January and November 2020.
“These are small cohorts, admittedly, but it was a heroic effort to get them and all associated clinical parameters from each patient under these circumstances,” says Chilton. “As opposed to most studies that are well planned out over the course of years, this was happening in real time on the ICU floor.”
The researchers used machine-learning algorithms to analyse thousands of data points, factoring in typical risk factors, including age, body mass index and pre-existing conditions, as well as more unusual factors such as biochemical enzymes and lipid metabolite levels.
Co-author Justin Snider, of the University of Arizona, says the role of sPLA2-IIA enzyme was an unexpected revelation. “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 team then developed a decision tree to predict COVID-19 mortality. They found that while most healthy individuals have around half a nanogram of the enzyme per millilitre circulating in their bloodstream, COVID-19 was particularly lethal among patients who had high levels of the enzyme, equal to or greater than 10 nanograms per millilitre.
“Many patients who died from COVID-19 had some of the highest levels of this enzyme that have ever been reported,” says Chilton, who has been studying the enzyme for more than 30 years.
Now, the team hopes to focus its efforts on identifying whether the enzyme is responsible for the existence of long COVID.
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