Cracking COVID19: the PLA2 clues

What are the keys to cracking COVID-19 and stopping this pandemic?

I provide evidence that the solution will involve Phospholipase A2 (PLA2), and I describe the panoramic jigsaw puzzle for which PLA2 is a critical centerpiece.

The COVID-19  numbers are grim: as I write this sentence, 79,506 people are reported to have lost their lives due to the virus, and the actual loss of life worldwide is presumed to be far higher than officially reported.  The same source shows that just under 1.4 million people are infected.  Behind every "1" added to make those large numbers, there is a face, a mind, and a life story, and the numbers continue to grow.  Everyone alive is affected by this pandemic, and a great many people are thinking about how to defeat the virus.

I believe that scientists and medical professionals will unlock the mysteries of COVID-19.  Maybe there are several valid strategies for stopping the SARS-CoV-2 virus.  Possibly everything we need to know is already available in databases of scientific research, but we have to pick out the right pieces and snap them together in just the right way.  I am skilled at pattern-matching.  I have read a great deal of scientific and medical research.  I propose that PLA2 is key.

Phospholipase is like a pair of scissors that cuts only molecules that fit a certain pattern--phospholipids.  I picture the targeted phospholipid molecule as an atomic squid with a phosphorus atom in the squid's head, and two long lipid arms that are chains of carbon and hydrogen atoms.  Those lipid arms are stuck onto the squid's head with a couple of oxygen atoms.  Drop a bunch of these squids in water, and they form a lipid bilayer, meaning that squids line up side by side to form two sheets, phosphorus-heads facing the water and lipid arms facing away from the water.  Because of the way their lipid arms are repelled by water, what results is two sheets of these squids sandwiched at the feet.  Your cell membranes are largely these bilayers of atomic squids.

Phospholipase A2 "scissors" cut off one arm of the squid at a very specific atomic bond where the arm connects to the squid, releasing a molecule named "lysolecithin" that acts as a detergent and can dissolve the membrane of a red blood cell.

For later discussion, it helps to know that the PLA2 scissors are power scissors.  Wikipedia sums up the chemistry nicely as follows:

"PLA2 is regulated by phosphorylation and calcium concentrations. PLA2 is phosphorylated by a MAPK at Serine-505. When phosphorylation is coupled with an influx of calcium ions, PLA2 becomes stimulated and can translocate to the membrane to begin catalysis."

An excellent, longer version is fascinating.

How do I picture it? To operate, the PLA2 scissors require a phosphorus battery, and to phosphorylate the scissors, you need one of those special tiny screwdrivers to jam the phosphorus into the battery compartment and close it up, and the screwdriver is a Calcium atom minus a couple of electrons.  Ca++.

So far we have power scissors that cut off a squid's arm, and the severed arm goes around wrecking red blood cells and causing other destruction.  We know the scissors need power to activate.  Where do the scissors get their phosphorus battery?

I am about to take you on a shortcut.  I found the logic shortcut because I took a long, slow, and circuitous route that gave me the answers in a very non-linear and inefficient way, and only after I assembled the right pieces did I recognize the shortcut when I saw it right there on Wikipedia.

"Phosphorylation of PLA2 may be a result of ligand binding to receptors including:"

   5-HT2 receptors

   mGLUR1

   IFN-gamma receptor

I speculate that these receptors are important to answering questions such as 

• Why does SARS-CoV-2 affect older people more often and more severely than younger people?
• Why do certain drugs/molecules inhibit SARS-CoV-2? (e.g. hydroxychloroquine)
• Why do people ache (head, muscles, etc.) when they get COVID-19?
• Why do people experience mood changes due to the virus and/or due to treatments aimed at the virus?

That first one--what is different between old and young people?  For influenza, we are relentlessly told that children are more vulnerable because "their immune systems are relatively naive."  If that is the case, then you would think COVID-19 would afflict children as often and as severe as influenza, but COVID-19 injures children far less often than it does adults.  If a "naive immune system" is not to blame for severity of viral infection, then what's going on?

In a tweet October 2019 regarding influenza, I asked, "What if age-related serotonin receptor changes are key?"

I also referred to this 1992 research (that does not mention virus,) that reports 5HT2 expression is highest in kids and declines with age, with some differences between sexes:

"Among the ages sampled, the highest levels of 5HT2 receptor binding were found in 6-year-olds. A sharp decline in receptor binding occured during adolescence, with levels reduced by half between ages 13 and 17. This pattern is similar to the one we have observed in brain 5HT2 receptors postmortem. There were no significant sex differences in 5HT2 receptors on platelets in newborn and young children. A trend towards higher binding in girls appears around the onset of menstruation in teenage girls (age 14 and up). These results demonstrate that platelet 5HT2 receptors can serve as a model for age dependent changes in 5HT2 receptors in the brain."

I may be oversimplifying things, but perhaps this insight could inspire a diagnostic that can predict a person's risk from catching SARS-CoV-2.  Is there a difference in 5HT2 receptor binding on platelets in people who get sickest versus people who show no symptoms of COVID-19 infection?  Kids do get sick and die from COVID-19; is there something different about their expression of 5HT2?  Likewise, many older adults are asymptomatic after SARS-CoV-2 exposure.  For their age group, do they have a higher-than-average expression of 5HT2 receptors in some type of cell that might reveal more about how the disease attacks?

Two of the other questions I posed earlier relate to serotonin receptors such as 5HT2.  

• Why do people ache (head, muscles, etc.) when they get COVID-19?
• Why do people experience mood changes due to the virus and/or due to treatments aimed at the virus?

Serotonin is extensively involved in our biology, including cognition, behavior and mood, pain perception (nociception,) immune system function, inflammation, blood clotting, cardiopulmonary function, taste, and smell.  If any of you are allergic to nuts, here's a nut to crack: serotonin production in drying seeds, which I found thanks to Wikipedia.  I wonder what enzymes and molecules remain after the nut baking process?

All serotonergic topics are worth exploring more fully.  For now I will stop with serotonin and zero in on our sense of smell, and I will tie that back to Phospholipase PLA2 (the squid scissors,) and to COVID-19.

I first started thinking about PLA2 and coronavirus on January 23rd when I searched for "phospholipase" and "coronavirus" and found the article 

   "A phospholipase linkage to SARS susceptibility".  

That excellent article led to a 2015 research paper ("Critical role of phospholipase A2 group IID in age-related susceptibility to severe acute respiratory syndrome–CoV infection") 

and via that, other papers worth a read, e.g. the 2018 "Inhibition of Cytosolic Phospholipase A 2 α Impairs an Early Step of Coronavirus Replication in Cell Culture":

"evidence to show that a cellular phospholipase, cPLA2α, which releases fatty acid from the sn-2 position of membrane-associated glycerophospholipids, is critically involved in coronavirus replication, most likely by producing lysophospholipids that are required to form the specialized membrane compartments in which viral RNA synthesis takes place. The importance of this enzyme in coronavirus replication and DMV formation is supported by several lines of evidence, including confocal and electron microscopy, viral replication, and lipidomics studies of coronavirus-infected cells treated with a highly specific cPLA2α inhibitor."

PLA2 kept coming up.

On February 19th I tweeted about a WSJ article mentioning chloroquine as a drug being tried against COVID-19.  I looked up chloroquine and saw that it inhibited PLA2.

Then in response to a March 3rd tweet mentioning chloroquine, I continued to search and think about PLA2.

March 20th the ENT UK and British Rhinological Society tweeted that COVID-19 patients were reporting loss of smell as a symptom of the sickness.

When I looked up anosmia, I saw that snake venom also can cause anosmia, and I knew already that venoms (snake, scorpion,) contain PLA2 enzymes.

I tweeted about how the virus biological effects had something in common with effects of snake bite, i.e. both the virus and a snakebite involve PLA2. 

I am convinced that PLA2 is a center piece of the COVID-19 puzzle.

This article presents a selection of information upon which I base that conclusion.

I look forward to writing more about 

• Phospholipase PLA2, and about how PLA2-inhibiting malaria drugs such as chloroquine and HCQ may help against COVID-19.  [Note: for safety's sake, use only under doctor supervision.]
• Mycobacteria (e.g. Tuberculosis, Chlamydia) treatments in the battle against this pandemic. 
• Molecular structures of promising drugs, metabolic pathways affected, and genetic and other reasons why people's outcomes may vary.

Thank you for reading, 

John C. Beach