Like venom coursing through the body: Researchers identify mechanism
driving COVID-19 mortality

Date:
August 24, 2021
Source:
University of Arizona
Summary:
Researchers have identified what may be the key molecular
mechanism responsible for COVID-19 mortality -- an enzyme related
to neurotoxins found in rattlesnake venom.



FULL STORY ==========================================================================
An enzyme with an elusive role in severe inflammation may be a key
mechanism driving COVID-19 severity and could provide a new therapeutic
target to reduce COVID-19 mortality, 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 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 eventually succumb to the virus.

sPLA2-IIA, which has similarities to 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 defense against bacterial infections, destroying microbial cell membranes.

When the activated enzyme circulates at high levels, it has the capacity
to "shred" 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's 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 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,"
said study 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.



========================================================================== Collaboration Amid Chaos "The idea to identify a potential prognostic
factor in COVID-19 patients originated from Dr. Chilton," Del Poeta
said. "He first contacted us last fall with the idea to analyze lipids
and metabolites in blood samples of COVID-19 patients." Del Poeta
and his team collected stored plasma samples and went to work analyzing
medical charts and tracking 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.

"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." The research team was 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 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 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," said Chilton, who has been
studying the enzyme for over three decades.

An Enzyme with a Bite The role of the sPLA2-IIA enzyme has been the
subject of study for half of a century and it is "possibly the most
examined member of the phospholipase family," Chilton explained.

Charles McCall, lead researcher from Wake Forest University on the study, refers to the enzyme as a "shredder" for its known prevalence in severe inflammation 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 ancestry
with a key enzyme found in snake venom.

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 said.

"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?" ========================================================================== Story Source: Materials provided by University_of_Arizona. Original
written by Rosemary Brandt. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Justin M. Snider, Jeehyun Karen You, Xia Wang, Ashley J. Snider,
Brian
Hallmark, Manja M. Zec, Michael C. Seeds, Susan Sergeant, Laurel
Johnstone, Qiuming Wang, Ryan Sprissler, Tara F. Carr, Karen
Lutrick, Sairam Parthasarathy, Christian Bime, Hao H. Zhang, Chiara
Luberto, Richard R. Kew, Yusuf A. Hannun, Stefano Guerra, Charles
E. McCall, Guang Yao, Maurizio Del Poeta, Floyd H. Chilton. Group
IIA secreted phospholipase A2 is associated with the pathobiology
leading to COVID-19 mortality. Journal of Clinical Investigation,
2021; DOI: 10.1172/ JCI149236 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210824135358.htm

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