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.

Niclosamide reverses SARS-CoV-2 control of lipophagy

“…A virus subjugates host lipid molecules as a vehicle for entry, intracellular transport, virus replication, assembly of infectious viral particles, and egress (Miyanari et al, 2007). Ether lipids have been identified as an important lipid class for efficient membrane trafficking, endocytosis, transcytosis, and internalization of particles (Thai et al, 2001;Deng and Angelova, 2021). Deficiency of ether lipids in several model systems affects plasma membrane function, as well as structural changes in the ER and Golgi cisternae (Bazill and Dexter, 1990;Gorgas et al, 2006).…”

“…The search for highly safe drugs for prophylaxis against COVID-19 remains elusive and controversial, but these data may suggest a role for niclosamide for future outbreaks given its broad antiviral activities. Considering the potential link between plasmalogens and the observed cytokine and lipid storms (Deng and Angelova, 2021) in severe COVID-19 patients, NIC may offer to a two-pronged treatment approach, i.e., reduce virus abundance and provide a check on an uncontrolled inflammatory response induced by SARS-CoV-2.…”

“…Of note, we observed significant increases in PG, PS and PI, but not a significant change in PC or PE phospholipids. This differential regulation of phospholipids could suggest formation of membranes for the viral envelope as most mammalian cells are high in PC and PE phospholipids (Deng and Angelova, 2021). The significant decrease in TGs and CEs is likely related to virus utilization of lipid droplets to make viral particles needed for replication.…”

Potential Therapeutic Applications of Pulmonary Surfactant Lipids in the Host Defence Against Respiratory Viral Infections

“…Interestingly, PS in the poxvirus envelope promotes viral infectivity ( 31 ), possibly through apoptotic cell mimicry ( 32 ). Plasmalogen pre-conditioning may be potentially used as anti-viral therapeutic and prophylaxis strategy to treat SARS-CoV-2, influenza, human cytomegalovirus (HCMV) and West Nile Virus (WNV) infections ( 33 ). The potential anti-viral mechanism of plasmalogen may include influencing viral entry host cells via non-receptor microdomain mediated endocytosis pathways; modulating lipid-modulated host innate immune response and virus-induced host membrane rearrangements, especially cubic membrane (CM) formation ( 33 ).…”

Endomembrane systems are reorganized by ORF3a and Membrane (M) of SARS-CoV-2

“…ORF3a-APEX2 expression significantly increased cubic membrane (CM, also denoted as convoluted membrane) structure formation; moreover, these CM structures were generated in ORF3a-GFP expressing cells shown by CLEM imaging (Figure 3C, S5C). Notably, CM structures also form in coronavirus-infected cells (Deng and Angelova, 2021;Snijder et al, 2020), and they are considered as neoorganelles for the assembly of viral proteins (Uchil and Satchidanandam, 2003). Additionally, in ORF3a-GFP expressed HeLa cells, structure of double membrane vesicle (DMV, red arrows in Figure 3C) was discovered near ER and mitochondria.…”