Covid-19: Pyroptosis, a Fiery Falling

A rush is on to understand what underpins the progression of Covid-19 from a mild flu-like presentation, to out-of-control pneumonia, and ultimately, system-wide collapse. We know some factors (comorbidities) that tend to increase the risk of severe consequences of Covid-19, such as age, gender, high blood pressure, and even ABO blood type. In addition, severe Covid-19 presents with its own constellation of abnormal biomarkers (lab results) that appear to correlate with the disease process, and may help point the way to better, more targeted, approaches to therapy.

One such biomarker is lactate dehydrogenase (LDH), an enzyme found in almost all body tissues. LDH plays an important role in cellular respiration; the process by which sugar (in the form of glucose) from food is converted into usable energy by the cells of the body. Although LDH is abundant in tissue cells, blood levels of the enzyme are normally low. However, when tissues are damaged by injury or disease, they release more LDH into the bloodstream. This has been observed for a wide variety of illnesses, including liver disease, heart attack, anemia, muscle trauma, bone fractures, cancers, and infections such as meningitis, encephalitis, and HIV.

This preprint (not peer-reviewed) study showed that LDH is a powerful predictive factor for early recognition of lung injury and severe COVID-19 cases. This association was also reported in a separate study as well.

This prompted virologist Akiko Iwasaki to hypothesize that the increase in blood LDH levels was the result of pyroptosis; a form of cell death that leads to the rupture of the cell’s plasma membrane. LDH has been shown to be a reliable way to monitor pyroptosis; it is not released by other methods of cell death, such as cell suicide (apoptosis) or macrophage activation. To find LDH outside the cell requires pyroptosis and subsequent rupture of the cell membrane.

Inflammasomes, again.

Pyroptosis translates to ‘fiery falling’ (the Greek pyro refers to fire and ptosis means falling). The name was coined by in 2001, by Dr. Brad T. Cookson, to describe the bursting of pro-inflammatory chemical signals from the dying cell. Pyroptosis acts as a defense mechanism against infection by inducing pathological inflammation. Like most forms of innate immunity, these mechanisms are quite old on an evolutionary scale, and we share it organisms with far simpler immune systems than ours.

In an earlier post on the possible benefits of melatonin, I briefly described inflammasomes, multi-protein complexes triggered by a variety of danger signals, and whose assembly leads to the processing and secretion of the pro-inflammatory cytokines. The best characterized inflammasome complex, NLRP3, is part of the innate immune response that occurs during lung infection, including influenza A virus, syncytial virus, and bacteria. Unlike the more sophisticated cytotoxic (immune cells that kill) and humoral (antibodies that clump or tag) immunities, innate defenses rely on recognizing molecular patterns known to be associated with bad microbes. These patterns trigger toll-like receptors (TLRs) that then activate a variety of inflammatory cascades in response, including the NLRP3 inflammasome. Pyroptosis is a unique consequence of inflammasome activation. Very few other processes produce it.

Take home message:

Elevated LDH is a unique sign that pryoptosis is occurring.

Pyroptosis indicates that inflammasomes are being activated and things are going to get bad.

A rising LDH should prompt rapid utilization of inflammasome-blocking agents.

Besides the aforementioned melatonin, many drugs and natural products have been shown to possess the ability to inhibit inflammasome production, albeit with varying degrees of evidence. A quick look at PubMed provided these:

Using the Opus 23 database of natural products to identify agents that regulate NLRP3 gene expression, we find:

Naturopathic Agents Known to Influence Expression of NLRP3
AGENT ARTICLE ACTION SUBJECT
1,3-butanediol Link ANTAGONIST ANIMAL
Aloe Vera Link ANTAGONIST
Astragalus (Astragalus membranaceus) Link ANTAGONIST ANIMAL
Cinnamon (Cinnamomum spp.) Link ANTAGONIST ANIMAL
Cinnamon essential oil Link ANTAGONIST ANIMAL
Curcumin Link ANTAGONIST IN-VITRO
Daphnetin Link ANTAGONIST ANIMAL
Feverfew (Tanacetum parthenium) Link ANTAGONIST
Gypenosides (from Gynostemma pentaphyllum) Link ANTAGONIST ANIMAL
Huperzine A Link ANTAGONIST ANIMAL
Jack Fruit Link AGONIST IN-VITRO
Lupeol Link ANTAGONIST ANIMAL
Melatonin Link ANTAGONIST ANIMAL
Melatonin Link ANTAGONIST ANIMAL
Melatonin Link ANTAGONIST ANIMAL
Ozone therapy Link ANTAGONIST ANIMAL
Parthenolide (in Feverfew) Link ANTAGONIST
Sunlight Link AGONIST IN-VITRO
Triptolide Link ANTAGONIST ANIMAL
Ursolic acid Link ANTAGONIST ANIMAL
Wheat Germ Agglutinin (WGA) Link AGONIST ANIMAL

In our current situation, we’re looking for things that block (antagonize) NLRP3. Inversely, agents that enhance (agonize) NLRP3 are likely to contribute to inflammasome activity. These results would seem to indicate that munching that whole wheat sandwich while trying to get a few rays in the backyard might not be the best way to keep inflammasome activity under control.

3 comments on “Covid-19: Pyroptosis, a Fiery Falling”

  1. M, Reply

    While surfing ‘here and there’ on the net, I saw an article which claimed that possibly the parasitic drug, Ivermectin, had potential to kill the Covid 19 virus within 48 hours.
    just wondering if this drug has any relevance for combating the spread of the disease.

  2. Eberhardt Kalmar Huhn Reply

    Ivermectin is a medication used to treat parasitic infestations. Viruses are not parasites.

    • Peter D'Adamo Reply

      Many drugs can be repurposed from one use to another. One man’s low-dose biologic is another one’s chemotherapy. Although in this case the evidence is on the weak side.

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