Investigation of the therapeutic potential of oxysterols in SARS-CoV-2 infection

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We have completed a long series of studies to test the therapeutic potential of 25-hydroxycholesterol (25HC) in murine models of experimental SARS-CoV-2 pneumonia. First, we treated hACE2 transgenic mice with systemic (i.p.) 25HC or vehicle control prior to and during pulmonary infection with SARS-CoV-2. We found that 25HC, compared to vehicle, did not alter survival, weight loss, lung viral load, pulmonary histopathology, or the pulmonary immune response. Instead, we found a few indications that supplemental 25HC might be deleterious, specifically, an increase in airspace albumin concentration (a measure of lung injury) and increases in plasma levels of select cytokines. Consistent with this, we found that mice deleted for cholesterol-25-hydroxylase (Ch25h) had a response to pulmonary SARS-CoV-2 (B.1.351) infection similar to that of wild type mice. We also tested the downstream lipid, 7 alpha, 25-dihydroxycholesterol as it is produced through metabolism of 25HC and is thought to induce chemotactic migration of leukocytes through the G protein-coupled receptor, EBI2. We found that both Ebi2 KO mice and WT mice treated with an EBI2 antagonist had normal clearance of SARS-CoV-2 from their lungs. Consistent with these in vivo findings, we have also determined that 25HC does not inhibit SARS-CoV-2 infection of VEROE6 cells in culture. Taken together, we conclude that neither endogenous nor exogenous 25HC has a disease-modifying effect in experimental murine SARS-CoV-2 pneumonia. These findings were submitted to a print journal and received favorable reviews. At the time of this writing, we have nearly completed the requested revisions to the manuscript and expect to resubmit to the journal within 1-2 weeks (no later than August, 2023).