A new study, published in The Journal of Clinical Investigation, has identified a snake venom-related enzyme that may be the key cause of COVID-19 related mortality. Their findings have revealed a brand-new target for potential therapeutic treatments.
The role of lipid metabolism in COVID-19
Up to 80% of individuals infected with SARS-CoV-2 are asymptomatic or develop mild to moderate symptoms. However, COVID-19 can be life-altering and ultimately fatal for the remaining 20%, with multiple organ failure often leading to mortality. Consequently, there is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19.
Recent studies have suggested that lipid metabolism plays a key role in determining an individual’s response to COVID-19 infection. There is evidence that SARS-CoV-2 modifies the levels of various lipids in host cells. This indicates that severe COVID-19 may be accompanied by phospholipases that cleave intact phospholipids from cellular membranes.
The team behind this study investigated this theory by using lipidomic methods to analyse blood samples. Samples were taken from individuals with no disease, mild COVID-19 and severe COVID-19 as well as deceased COVID-19 patients.
Identification of key enzyme
The analyses showed that deceased COVID-19 patients had the most significant changes to their lipid profile. In total, 181 unique molecules were identified in these patients, many of which were associated with phospholipid metabolism.
Further targeted lipidomics revealed that in comparison to survivors, deceased patients had elevated levels of a circulating, catalytically active enzyme called secreted phospholipase A2 Group IIA (sPLA2-IIA). Their sPLA2-IIA levels were 9.6-fold higher than in mild patients and 5-fold higher than in severe patients. In addition, high sPLA2-IIA levels were significantly associated with multiple organ dysfunction. This implies that sPLA2-IIA may drive the organ failure seen in fatal COVID-19 cases.
The study further demonstrated the importance of sPLA2-IIA through the use of a machine learning method. Out of 80 clinical indices, the algorithm identified sPLA2-IIA level as the key feature that differentiated survivors from non-survivors. This highlights a potential method for identifying COVID-19 patients at high risk of mortality.
sPLA2-IIA-caused membrane destruction
sPLA2-IIA is an extracellular enzyme that cleaves fatty acids and is normally present at low levels in healthy individuals. Previous studies have shown that activated sPLA2-IIA plays a key role in host defence against bacterial infections, due to its ability to destroy microbial cell membranes. The team behind this current study suggested that the membrane damaging ability of high sPLA2-IIA levels is what could be driving COVID-19 mortality.
“It’s a bell-shaped curve of disease resistance versus host tolerance,” senior author Floyd 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.”
Enzyme driving COVID-19 similar to snake venom toxin
Interestingly, previous research has also revealed that sPLA2-IIA shares a high sequence homology to the active enzyme in snake venom. It has been shown that sPLA2-IIA has the capacity to bind to receptors at neuromuscular junctions and potentially disable their function, just like the snake toxin. The researchers suggest that this functionality may contribute to the symptoms suffered by individuals with long COVID, an avenue that should be further explored in the future.
This study has identified sPLA2-IIA as a previously unrecognised mechanism underlying COVID-19 mortality. Further work on larger patient samples will be required to validate these findings, but the results presented here showcase a potential new target for future COVID-19 treatments.
Co-author Maurizio del Poeta said: “The study supports a new therapeutic target to reduce or even prevent COVID-19 mortality.”
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