Study shows that an enzyme involved in inflammatory response may be a key mechanism driving COVID-19 severity and could provide a new therapeutic target.
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A single enzyme shown to be a primary predictor of COVID-19 severity
Scientists from the University of Arizona, Stony Brook University, and Wake Forest University School of Medicine have reported findings that the enzyme phospholipase A2 group IIA, referred to as sPLA2-IIA, may be the most important factor in predicting which patients with severe COVID-19 eventually succumb to the virus.
The sPLA2-IIA enzyme is similar to one contained in rattlesnake neurotoxin as it can destroy cell membranes and is usually found in low concentrations in healthy individuals since it is a key defense against bacterial infection.
At high levels, the activated enzyme can shred membranes of vital organs, as Floyd Chilton, senior author on the paper and director of the University of Arizona Precision Nutrition and Wellness Initiative describes:
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 failures and death."
To better understand the role of this enzyme functions and its role in COVID-19 infection severity, researchers gathered blood samples from patients to quantify the concentration of sPLA2-IIA.
Findings can then be used to inform possible targets for preventative or post-infection treatments to prevent further mortality, yet the recent surge in cases in the USA, particularly of COVID-19 variants, has increased levels of urgency across clinical facilities.
Developing a diagnostic amid increasing urgency
Plasma samples and medical chart information were first collected from 127 patients hospitalized at Stony Brook University between January and July 2020 by Del Poeta and his team. A second cohort then included data from 154 patients from StonyBrook and Banner University Medical Centre in Tucson between January and November 2020.
Co-author Maurizio Del Poeta, a SUNY distinguished professor in the Department of Microbiology and Immunology in the Renaissance School of Medicine at Stony Brook University, says:
"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," Chilton said. "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."
Machine learning algorithms were then used to analyze data points of patients that considered age, body mass index, and pre-existing conditions as well as biochemical enzymes and patients' levels of lipid metabolites. This array of variables goes beyond the traditional clinical trial as it provides a biochemical profile of patients as well to support findings.
This profile was then used to develop a predictive decision tree that can inform and predict the risk of COVID-19 mortality of patients with specific symptoms and characteristics.
In this study, we were able to identify patterns of metabolites that were present in individuals who succumbed to the disease. The metabolites that surfaced revealed cell energy dysfunction and high levels of the sPLA2-IIA enzyme. The former was expected but not the latter."
Justin Snider, an assistant research professor in the University of Arizona Department of Nutrition
sPLA2-IIA associated with high COVID-19 mortality: mechanism and implications.
Healthy individuals typically have sPLA2-IIA enzyme levels around half a nanogram per milliliter (mL) of blood, but findings of the study showed that COVID-19 infection was lethal in 63% of patients who had severe COVID-19 and levels of sPLA2-IIA equal to or greater than 10 nanograms per mL of blood.
"Many patients who died from COVID-19 had some of the highest levels of this enzyme that have ever been reported," states Chilton.
This is of particular concern as the function of the sPLA2-IIA enzyme has been investigated for half of a century and it is “possibly the most examined member of the phospholipase family,” Chilton explained.
In past studies, the enzyme has been shown to destroys microbial cell membranes in bacterial infections, and shares similar genetic ancestry with a key enzyme found in snake venom. Charles McCall, the lead author of the study, describes the enzyme as a "shredder" for its effect in causing severe inflammation events, such as bacterial sepsis, as well as hemorrhagic and cardiac shock.
The protein "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," Chilton described.
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?”
Although the current study does not establish causal factors, further studies considering how this particular enzyme is activated will provide valuable information for potential treatments.
- Snider, J.M., You, J.K., Wang, X., Snider, A.J., Hallmark, B., Zec, M.M., Seeds, M.C., Sergeant, S., Johnstone, L., Wang, Q., Sprissler, R., Carr, T.F., Lutrick, K., Parthasarathy, S., Bime, C., Zhang, H.H., Luberto, C., Kew, R.R., Hannun, Y.A. and Guerra, S. (2021). Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality. The Journal of Clinical Investigation. [online] Available at: https://www.jci.org/articles/view/149236 [Accessed 25 Aug. 2021].