Previously, we described the construction of our lists of genes that are up/down-regulated upon a “cytokine storm.” We also have a list of cytokines and cytokine receptors (dbase ID 118764101), composed of 178 different genes. Intersecting the “upregulated in a cytokine storm” list with the “cytokines and cytokine receptors” list, we only find 7 genes in common (ccl20, il1r1, il1r2, il18r1, il8, tnf, and pglyrp1); four receptors and just three actual cytokines. One cytokine, ccl5, was actually downregulated during a cytokine storm. One could be pedantic and claim that if it doesn’t involve cytokines, it’s not a cytokine storm. Or…we did a shoddy job of constructing lists that are supposed to exemplify cytokine storms.
However, you might find that our cytokine storm lists
actually do a fine job of capturing the events behind a deadly infection. How
might you know? Currently, our “Match Studies” tool is pre-loaded with the
up/down cytokine storm lists. Simply hitting “submit”, the output you’ll see
will be studies that match up with cytokine storms. Ignoring the studies from
which the lists are actually derived, we still see studies involving Kawasaki
disease, septic shock, pneumococcal disease, lupus, dengue infection, and more…the
cytokine storm lists match up quite nicely with the nastiest forms of immune
over-reaction.
Taking the validity of our lists for granted, we can ask, “How
might one reverse a cytokine storm?” Here, all you need to do is click the “Inverse
Correlations” box in the “Match Studies” tool. This will search for studies in
which the genes found in the “upregulated in cytokine storms” list are
downregulated, and the genes in the “downregulated in cytokine storms” list are
upregulated.
This is where we toot our own horn a bit. The current
standard of care for a Covid-19 cytokine storm is treatment with Tocilizumab.
Sure enough, a study involving Tocilizumab is rated the 10th best “reverser”
of cytokine storms, and second-best if one selects “Treatment”* under the “Experiment
Type” filter.
There are, however, other cytokine storm reversers that
appear more potent than Tocilizumab, at least by our rating system. Infliximab
ranks higher, and there is at least one study that has examined this antibody,
with interesting
results, for Covid-19 treatment. A study involving proprionic acid (for
Multiple Sclerosis) also evinced strong reversal of cytokine storm genes,
though we don’t see Covid-19-related research. Rosuvastatin is another
reverser, and a quick Google Scholar search shows that statin use may indeed be
associated with decreased Covid-19 mortality. The same goes for JAK inhibitors,
which rank highly as cytokine-storm reversers. The list goes on.
Actually, the single strongest reverser of a canonical
cytokine storm involved an antibiotic course. Note, however, that the study
involved treatment for mycobacterium-related ulcers over 90 days. One shouldn’t
expect that antibiotics would reverse a cytokine storm, especially over a short
time period. On the other hand, the history of drug-discovery is, of course,
rife with examples of the discovery of effective drugs with unexpected mechanisms
of action.
How about DIY cytokine-storm reversal? With the obligatory warning that preventative and acute treatments may be diametrically opposed, a notion very much lost on the general public, the answer may not be surprising: Vitamin D. Specifically, results obtained in a 100-subject 2017 study suggest that Vitamin D supplementation reverses the transcriptomics of cytokine storms. Note, however, that the study involved year-long courses of supplementation! Be that as it may, yet another vitamin D study showed a similar reversal. A study involving an agaricus mushroom supplement also reversed our cytokine storm genes**. For more results, check out our tools and have at it!
*We discriminate between “treatment” and “drug” experiments
in our database. A treatment would involve a protein, or another sort of large
molecule, while a drug would be small. Treatments might also involve a mixture
of molecules; a study in which serum was applied (vs withheld) to cell culture
would be an example.
**A little searching shows that some mushrooms, agaricus included, have high Vitamin D levels.
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