TY - JOUR
T1 - Endogenous and Therapeutic 25-Hydroxycholesterols May Worsen Early SARS-CoV-2 Pathogenesis in Mice
AU - Fessler, Michael B.
AU - Madenspacher, Jennifer H.
AU - Baker, Paul J.
AU - Hilligan, Kerry L.
AU - Bohrer, Andrea C.
AU - Castro, Ehydel
AU - Meacham, Julie
AU - Chen, Shih Heng
AU - Johnson, Reed F.
AU - McDonald, Jeffrey G.
AU - Martin, Negin P.
AU - Tucker, Charles J.
AU - Mahapatra, Debabrata
AU - Cesta, Mark
AU - Mayer-Barber, Katrin D.
N1 - Publisher Copyright:
© 2023 by the American Thoracic Society.
PY - 2023/12
Y1 - 2023/12
N2 - Oxysterols (i.e., oxidized cholesterol species) have complex roles in biology. 25-Hydroxycholesterol (25HC), a product of the activity of cholesterol-25-hydroxylase (CH25H) on cholesterol, has recently been shown to be broadly antiviral, suggesting therapeutic potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, 25HC can also amplify inflammation and be converted by CYP7B1 (cytochrome P450 family 7 subfamily B member 1) to 7a,25-dihydroxycholesterol, a lipid with chemoattractant activity, via the G protein–coupled receptor EBI2 (Epstein-Barr virus–induced gene 2)/GPR183 (G protein–coupled receptor 183). Here, using in vitro studies and two different murine models of SARS-CoV-2 infection, we investigate the effects of these two oxysterols on SARS-CoV-2 pneumonia. We show that although 25HC and enantiomeric-25HC are antiviral in vitro against human endemic coronavirus-229E, they did not inhibit SARS-CoV-2; nor did supplemental 25HC reduce pulmonary SARS-CoV-2 titers in the K18-human ACE2 (angiotensin-converting enzyme 2) mouse model in vivo. Treatment with 25HC also did not alter immune cell influx into the airway, airspace cytokines, lung pathology, weight loss, symptoms, or survival but was associated with increased airspace albumin, an indicator of microvascular injury, and increased plasma proinflammatory cytokines. Conversely, mice treated with the EBI2/GPR183 inhibitor NIBR189 displayed a modest increase in lung viral load only at late time points but no change in weight loss. Consistent with these findings, although Ch25h and 25HC were upregulated in the lungs of SARS-CoV-2–infected wild-type mice, lung viral titers and weight loss in Ch25h2/2 and Gpr1832/2 mice infected with the b variant were similar to those in control animals. Taken together, endogenous 25HCs do not significantly regulate early SARS-CoV-2 replication or pathogenesis, and supplemental 25HC may have proinjury rather than therapeutic effects in SARS-CoV-2 pneumonia.
AB - Oxysterols (i.e., oxidized cholesterol species) have complex roles in biology. 25-Hydroxycholesterol (25HC), a product of the activity of cholesterol-25-hydroxylase (CH25H) on cholesterol, has recently been shown to be broadly antiviral, suggesting therapeutic potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, 25HC can also amplify inflammation and be converted by CYP7B1 (cytochrome P450 family 7 subfamily B member 1) to 7a,25-dihydroxycholesterol, a lipid with chemoattractant activity, via the G protein–coupled receptor EBI2 (Epstein-Barr virus–induced gene 2)/GPR183 (G protein–coupled receptor 183). Here, using in vitro studies and two different murine models of SARS-CoV-2 infection, we investigate the effects of these two oxysterols on SARS-CoV-2 pneumonia. We show that although 25HC and enantiomeric-25HC are antiviral in vitro against human endemic coronavirus-229E, they did not inhibit SARS-CoV-2; nor did supplemental 25HC reduce pulmonary SARS-CoV-2 titers in the K18-human ACE2 (angiotensin-converting enzyme 2) mouse model in vivo. Treatment with 25HC also did not alter immune cell influx into the airway, airspace cytokines, lung pathology, weight loss, symptoms, or survival but was associated with increased airspace albumin, an indicator of microvascular injury, and increased plasma proinflammatory cytokines. Conversely, mice treated with the EBI2/GPR183 inhibitor NIBR189 displayed a modest increase in lung viral load only at late time points but no change in weight loss. Consistent with these findings, although Ch25h and 25HC were upregulated in the lungs of SARS-CoV-2–infected wild-type mice, lung viral titers and weight loss in Ch25h2/2 and Gpr1832/2 mice infected with the b variant were similar to those in control animals. Taken together, endogenous 25HCs do not significantly regulate early SARS-CoV-2 replication or pathogenesis, and supplemental 25HC may have proinjury rather than therapeutic effects in SARS-CoV-2 pneumonia.
KW - 25-hydroxycholesterol
KW - EBI2
KW - SARS-CoV-2
KW - cholesterol-25-hydroxylase
KW - pneumonia
UR - http://www.scopus.com/inward/record.url?scp=85178650592&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85178650592&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2023-0007OC
DO - 10.1165/rcmb.2023-0007OC
M3 - Article
C2 - 37578898
AN - SCOPUS:85178650592
SN - 1044-1549
VL - 69
SP - 638
EP - 648
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 6
ER -