Long COVID and cortisol, an intriguing relationship

Marked differences in immune response profiles of long COVID (LC)-affected patients as compared to matched control subjects not suffering from LC have been recently described. Still of interest, lower cortisol levels have been additionally reported in LC-affected individuals (1).
Published in Microbiology

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Noteworthy, the SARS-CoV-2 betacoronavirus shows a high binding affinity to linoleic acid (LA), an essential free fatty acid, with this resulting in a diminished spike (S) protein interaction with the angiotensin-converting enzyme 2 (ACE2) viral receptor. Furthermore, LA supplementation synergizes with the antiviral drug remdesivir, thereby suppressing SARS-CoV-2 replication (2).
Such an intriguing virus-LA interaction mechanism could also provide biological plausibility for the favourable outcomes commonly observed in patients with severe COVID-19 disease, following corticosteroid (dexamethasone) administration. Natural and synthetic corticosteroids are known, in fact, to selectively inhibit the phospholipase-A2 enzyme, converting LA into linolenic acid, with this representing a critical step in the biosynthesis of prostaglandins and leukotrienes, both of which are key mediators in inflammatory reactions (3).
Therefore, given their lower cortisol levels (1), a reduced phosphospholipase-A2 inhibition could be reasonably expected to occur in LC-affected individuals, with this likely resulting in a stronger binding affinity of the SARS-CoV-2 S protein to the ACE2 receptor molecule, ultimately leading to increased viral replication and persistence in diseased host tissues.


1) Klein, J., Wood, J., Jaycox, J. et al. Distinguishing features of Long COVID identified through immune profiling. Nature (2023). https://doi.org/10.1038/s41586-023-06651-y.

2) Toelzer, C., Gupta, K., Yadav, S.K.N. et al. Freefatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein. Science 370: 725-730 (2020). DOI:10.1126/science.abd3255.

3) Robbins & Kumar Basic Pathology, 11th Edition. Inflammation Chapter. Elsevier - Health Sciences Division (2022).

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