دورية أكاديمية
Endogenous and Therapeutic 25-Hydroxycholesterols May Worsen Early SARS-CoV-2 Pathogenesis in Mice.
| العنوان: | Endogenous and Therapeutic 25-Hydroxycholesterols May Worsen Early SARS-CoV-2 Pathogenesis in Mice. |
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| المؤلفون: | Fessler MB; Immunity, Inflammation and Disease Laboratory., Madenspacher JH; Immunity, Inflammation and Disease Laboratory., Baker PJ; Inflammation and Innate Immunity Unit., Hilligan KL; Immunobiology Section, and., Bohrer AC; Inflammation and Innate Immunity Unit., Castro E; Inflammation and Innate Immunity Unit., Meacham J; Immunity, Inflammation and Disease Laboratory., Chen SH; Viral Vector Core Facility, Neurobiology Laboratory., Johnson RF; SARS-CoV-2 Virology Core, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland., McDonald JG; Department of Molecular Genetics and.; Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas; and., Martin NP; Viral Vector Core Facility, Neurobiology Laboratory., Tucker CJ; Fluorescence Microscopy and Imaging Center, Signal Transduction Laboratory, and., Mahapatra D; Integrated Laboratory Systems, LLC, Research Triangle Park, North Carolina., Cesta M; Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina., Mayer-Barber KD; Inflammation and Innate Immunity Unit. |
| المصدر: | American journal of respiratory cell and molecular biology [Am J Respir Cell Mol Biol] 2023 Dec; Vol. 69 (6), pp. 638-648. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Intramural; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Thoracic Society Country of Publication: United States NLM ID: 8917225 Publication Model: Print Cited Medium: Internet ISSN: 1535-4989 (Electronic) Linking ISSN: 10441549 NLM ISO Abbreviation: Am J Respir Cell Mol Biol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2000- : New York, NY : American Thoracic Society Original Publication: [New York, NY : The Association, [c1989- |
| مواضيع طبية MeSH: | Epstein-Barr Virus Infections* , COVID-19*, Humans ; Animals ; Mice ; SARS-CoV-2 ; Herpesvirus 4, Human ; Hydroxycholesterols/pharmacology ; Cholesterol ; Receptors, G-Protein-Coupled ; Antiviral Agents/pharmacology ; Cytokines ; Weight Loss |
| مستخلص: | 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 7α,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 Ch25h -/- and Gpr183 -/- mice infected with the β 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. |
| التعليقات: | Update of: bioRxiv. 2022 Sep 13;:. (PMID: 36263064) Comment in: Am J Respir Cell Mol Biol. 2023 Dec;69(6):610-611. (PMID: 37672661) |
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| معلومات مُعتمدة: | Z01 ES102005 United States ImNIH Intramural NIH HHS; ES103316 United States ES NIEHS NIH HHS; Z01 ES102005 United States ES NIEHS NIH HHS; 1P30DK127984 United States HL NHLBI NIH HHS; P30 DK127984 United States DK NIDDK NIH HHS; UL1 TR003163 United States TR NCATS NIH HHS; R21 AI129303 United States AI NIAID NIH HHS; P01 HL160487 United States HL NHLBI NIH HHS; 5P01HL160487 United States DK NIDDK NIH HHS |
| فهرسة مساهمة: | Keywords: 25-hydroxycholesterol; EBI2; SARS-CoV-2; cholesterol-25-hydroxylase; pneumonia |
| المشرفين على المادة: | 767JTD2N31 (25-hydroxycholesterol) 0 (NIBR189) 0 (Hydroxycholesterols) 97C5T2UQ7J (Cholesterol) 0 (Receptors, G-Protein-Coupled) 0 (Antiviral Agents) 0 (Cytokines) 0 (Gpr183 protein, mouse) |
| SCR Organism: | SARS-CoV-2 variants |
| تواريخ الأحداث: | Date Created: 20230814 Date Completed: 20231204 Latest Revision: 20231214 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC10704115 |
| DOI: | 10.1165/rcmb.2023-0007OC |
| PMID: | 37578898 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1535-4989 |
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| DOI: | 10.1165/rcmb.2023-0007OC |