Coronavirus-Induced Host Cubic Membranes and Lipid-Related Antiviral Therapies: A Focus on Bioactive Plasmalogens

Abstract

Coronaviruses have lipid envelopes required for their activity. The fact that coronavirus infection provokes the formation of cubic membranes (CM) (denoted also as convoluted membranes) in host cells has not been rationalized in the development of antiviral therapies yet. In this context, the role of bioactive plasmalogens (vinyl ether glycerophospholipids) is not completely understood. These lipid species display a propensity for non-lamellar phase formation, facilitating membrane fusion, and modulate the activity of membrane-bound proteins such as enzymes and receptors. At the organism level, plasmalogen deficiency is associated with cardiometabolic disorders including obesity and type 2 diabetes in humans. A straight link is perceived with the susceptibility of such patients to SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) infection, the severity of illness, and the related difficulty in treatment. Based on correlations between the coronavirus-induced modifications of lipid metabolism in host cells, plasmalogen deficiency in the lung surfactant of COVID-19 patients, and the alterations of lipid membrane structural organization and composition including the induction of CM, we emphasize the key role of plasmalogens in the coronavirus (SARS-CoV-2, SARS-CoV, or MERS-CoV) entry and replication in host cells. Considering that plasmalogen-enriched lung surfactant formulations may improve the respiratory process in severe infected individuals, plasmalogens can be suggested as an anti-viral prophylactic, a lipid biomarker in SARS-CoV and SARS-CoV-2 infections, and a potential anti-viral therapeutic component of lung surfactant development for COVID-19 patients.

Keywords: COVID-19; TEM; coronavirus; cubic membrane; plasmalogen; virus-host interaction.

FIGURE 1

Coronavirus replication cycle highlighting areas where membrane interaction takes place (ER, Endoplasmic reticulum; DMV, Double-membrane vesicles; ERGIC, Endoplasmic reticulum Golgi intermediate compartments). SARS-CoV-2 viral particles consist of four proteins: S (“Spike”), M (“Membrane”), E (“Envelope”), and N (“Nucleocapsid”). The pathway of membrane interactions involves: (1) Viral internalization through binding of the viral spike (S) protein to the membrane protein receptor as human angiotensin-converting enzyme 2 (ACE2). The coronavirus particle enters the host cell by receptor-mediated endocytosis followed by RNA release and translation into virus polyproteins, which encode for non-structural proteins (NSPs). (2) NSPs stimulate the production of DMV compartments and the formation of replication transcription complexes (RTC). Translation of the structural proteins (M, E, and S) occurs in the ER membrane organelles. (3) Coronavirus assembly occurs in the intermediate compartment between the ER and ERGIC. The protein cargos migrate through Golgi stacks resulting in new virus particles that are embedded in vesicles (4). These vesicles can further fuse with the plasma membrane and egress. Reprinted from Alsaadi and Jones (2019) with permission.

FIGURE 2

Drug targeting strategies in viral infection exploiting the role of lipid metabolism. The scheme of the life cycle of SARS-COV-2 indicates the locations where lipid-modifying drugs may act as broad-spectrum antiviral compounds to inhibit viral entry, membrane fusion, endocytosis or host cholesterol and fatty acid biosynthesis. Reprinted from Abu-Farha et al. (2020) with permission.

FIGURE 3

Top panel: Cubic membrane topology represented by a mathematical model of the lipid bilayer organized on a 3D cubic lattice (A) and 2D-projected transmission electron microscopy (TEM) image of cubic membranes found in the mitochondria of 10-day starved ameba Chaos cells (B). Scale bar: 500 nm. Reprinted from Deng and Almsherqi (2015) with permission. Bottom panel: TEM images of interconnected convoluted membrane structures (CM) induced by MERS-CoV infection in mammal Huh7 cells (left) and SARS-CoV and HCoV-229E coronavirus induced convoluted membranes (CM), double-membrane vesicles (DMV), and double-membrane spherules (middle and right). Scale bars: 250 nm. Reprinted from Snijder et al. (2020) with permission.

FIGURE 4

Top panel: General chemical structure and multiple biological functions of bioactive plasmalogens. Bottom panel: Chemical structures of exemplary ether phospholipids (plasmalogens) involving arachidonic acid (AA) and docosahexaenoic acid (DHA) chains, e.g., 1-(1Z-hexadecenyl)-2-arachidonoyl-sn-glycero-3- phosphoethanolamine [C16(Plasm)-20:4 PE] and 1-(1Z-hexadecenyl)-2-docosahexaenoyl-sn-glycero-3-phosphoethanolamine [C16(Plasm)-22:6 PE].

FIGURE 5

Multiple examples of coronavirus-induced cubic membrane (CM) formation in the host cells. (A) SARS-CoV, 3d post-infection (p.i.) Vero-E6 cell with virus particles egress (Goldsmith et al., 2004) (B) MERS-CoV nsp3-6, 24h post-transfection, Huh-7 cell (Oudshoorn et al., 2017). (C) MHV-59, 8h p.i. HeLa-CEACAM1a cell (Ulasli et al., 2010); (D) SARS-CoV (nsp3 + nsp4), 24h post-transfection, 293T cell (Oudshoorn et al., 2017).

FIGURE 6

Two pathways of plasmalogen turnover, remodeling and degradation: (1) Through phospholipase A2 (PLA2) and (2) through oxidative stress. Plasmalogens are one of the primary targets of HOCl due to sensitivity of the vinyl-ether bonds to oxidation. X denotes the polar head group, which is typically ethanolamine or choline. R1 denotes the carbon chain at the sn-1 position, and R2 at the sn-2 position. Reprinted from Braverman and Moser (2012) with permission.

FIGURE 7

Essential fatty acids in inflammation and potential “lipid storm” in severe COVID-19 patients. Scheme of eicosanoid and related bioactive lipid mediators production due to metabolic pathways of fatty acid alteration (eicosanoid related precursors). Reprinted from Zurrier (1991) with permission.

FIGURE 8

Lipid (eicosanoid) storm may occur before the cytokine storm in SARS-CoV-2 infection. Eicosanoids are bioactive lipid mediators derived from oxygenated polyunsaturated fatty acids (PUFAs). Reprinted from Hammock et al. (2020) with permission.

FIGURE 9

Severe infections trigger inflammatory responses, ER stress and mitochondrial organelle dysfunction through lipid-mediated and cytokine peptide-mediated mechanisms. Reprinted from Hotamisligil (2006) with permission.

FIGURE 10

Life cycle of surfactant produced in the lung with an indication of the tubular myelin, lamellar bodies (LB), and alveolar macrophages (AM). Pulmonary surfactant is a surface-active lipo-protein complex produced by type II alveolar cells. Reprinted from Ramanathan (2006) with permission.

FIGURE 11

Composition of individual phosphatidylethanolamine PE-based plasmalogen (PE-P) lipid species during postnatal development of mouse lung. High contents of 20:4, 22:6, 22:5, and 22:4 plasmalogen (PE-P) derivatives are detected. PE P-16:0 (sn-1) plasmalogens are present in higher amounts in all 4 groups of ethanolamine plasmalogens, whereas PE P-18:0 and PE P-18:1 account for smaller amounts. Values are represented as nmol/mg wet weight. Reprinted from Karnati et al. (2018) with permission. Statistical significance (*^, **^, ***): p-values <0.05 (significant), < 0.01, < 0.001 (highly significant).

FIGURE 12

Exogenous lung surfactant delivery suggested as a therapy to reduce inflammation and restore pulmonary barrier in severe COVID-19 associated acute respiratory distress syndrome (ARDS). Reprinted from Mirastschijski et al. (2020) with permission.