Coronavirus Infection and Cholesterol Metabolism

Abstract

Host cholesterol metabolism remodeling is significantly associated with the spread of human pathogenic coronaviruses, suggesting virus-host relationships could be affected by cholesterol-modifying drugs. Cholesterol has an important role in coronavirus entry, membrane fusion, and pathological syncytia formation, therefore cholesterol metabolic mechanisms may be promising drug targets for coronavirus infections. Moreover, cholesterol and its metabolizing enzymes or corresponding natural products exert antiviral effects which are closely associated with individual viral steps during coronavirus replication. Furthermore, the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 infections are associated with clinically significant low cholesterol levels, suggesting cholesterol could function as a potential marker for monitoring viral infection status. Therefore, weaponizing cholesterol dysregulation against viral infection could be an effective antiviral strategy. In this review, we comprehensively review the literature to clarify how coronaviruses exploit host cholesterol metabolism to accommodate viral replication requirements and interfere with host immune responses. We also focus on targeting cholesterol homeostasis to interfere with critical steps during coronavirus infection.

Keywords: cholesterol; coronavirus; immune response; metabolism dysregulation; therapy.

Figure 1

Disrupting cholesterol homeostasis interferes with critical steps during coronavirus infection. Cholesterol is important for coronavirus attachment (A), endocytosis (B), membrane fusion (C), translation/replication (D), and maturation/release (E). 25HC, 25-hydroxycholesterol; MβCD, methyl-beta-cyclodextrin; LE/MVB, late Endosomes/Multivesicular Bodies; IFITM3, interferon-induced transmembrane protein-3; U18666a, an intra-cellular cholesterol transport inhibitor; DMVs, double-membrane vesicles; OSBP, oxysterol-binding protein; VAP-A, vesicle-membrane-protein-associated protein A; Oxy210, semi-synthetic oxysterols; Oxy232, semi-synthetic oxysterols; AM580, a selective retinoic acid receptor-α agonist.

Figure 2

Overview of mevalonate pathway and coronavirus infection. (A) Cholesterol metabolizing enzymes and metabolites act against viral infectivity. Red type represents cholesterol metabolizing enzymes or corresponding natural products which may be used as drug targets or directly to exert antiviral effects. (a) HMG-CoA reductase regulates cholesterol biosynthesis and is targeted by statins. (b, c, d) The sterol metabolic network participates in interferon (IFN) antiviral responses. (e, f) SARS-CoV-2 propagation in cultured cells is inhibited by various cholesterol molecules and semi-synthetic oxysterols. The detailed steps of the cholesterol synthesis pathway can be found in (–182). (B) Cholesterol metabolism reprogramming and antiviral responses after viral infection. (a) Cholesterol promotes pathological syncytial formation during SARS-COV-2 infection. (b) Serum TC, TG, and non-esterified polyunsaturated fatty acid levels are remodeled in COVID-19 patients. (c, d) SARS-CoV-2 infection increases glucose entry into the TCA cycle via increased pyruvate carboxylase expression and reduced oxidative glutamine metabolism, while maintaining reductive carboxylation. (f) SREBP-dependent lipidomic reprogramming is a broad-spectrum antiviral target, AM580 strongly inhibits coronavirus replication by interacting with SREBP-2. (e, h, g, i, j) COVID-19-activated SREBP-2 disturbs cholesterol biosynthesis, leading to a cytokine storm. Importantly, SREBP-2 activity is regulated by crosstalk between cholesterol consumption and NF-κB expression via several inflammatory response processes induced by SARS-CoV-2 infection. Red arrows represent upregulation and blue arrows represent downregulation. Acetyl-CoA, Acetyl-Coenzyme A; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; EBP, Δ(7)-isomerase; DHCR24, 3-β-hydroxysteroid-Δ-24-reductase; SC5DL, Sterol C5-desaturase; DHCR7, 7-dehydrocholesterol reductase; CH25H, cholesterol-25-hydroxylase; 25HC, 25-hydroxycholesterol; 27HC, 27-hydroxycholesterol; IFNβ, Interferon-β; TC, Total cholesterol; HDL-C, High-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, Triglyceride; ATP, Adenosine triphosphate; SREBP-2, Sterol regulatory element-binding protein 2; AM580, a selective RARα agonist; HMGCR, 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase; NF-κB, Nuclear transcription factor-κB.