Coronavirus-induced host cubic membranes and lipid-related antiviral therapies: A focus on bioactive plasmalogens

Deng Y and Angelova A. (2021) Coronavirus-induced host cubic membranes and lipid-related antiviral therapies: A focus on bioactive plasmalogens. Frontiers in Cell and Developmental Biology

Rhizomelic chondrodysplasia punctata (RCDP) is a disorder caused by a plasmalogen deficiency through the inability to synthesize this class of lipids and results in a severe form of dwarfism and cognitive defects. One of the most common symptoms experienced by individuals with RCDP is recurrent respiratory illnesses and this is the leading cause of death for RCDP patients. For this reason, coronavirus disease-19 (COVID-19) could pose a significant risk in this population. Coronaviruses are a class of related RNA viruses that cause respiratory tract infections in humans which can range from mild to severe, possibly even causing death. There are seven known coronaviruses able to infect humans, including the newest one, SARS-CoV-2, that causes COVID-19. Viruses commonly use endocytosis and fusion of their viral membrane with the cellular membrane to enter the host cell. Lipid composition plays a vital role in these processes, as well as in the protection against viral infection. Under stress conditions, bilayer lipid membranes can undergo rearrangement and form 3D cubic membranes, characterized by periodic structures of lipid bilayers organized into cubic lattice networks. Deng and Angelova investigated the role of plasmalogens, a class of lipids that contain a vinyl ether bond at sn-1, in viral entry, lipid-modulated host immune responses, and viral-induced host membrane rearrangements through a review of the available literature.

Attachment and entry of SARS-CoV-2 into a host cell depends on the lipid composition of the viral envelope and the host membrane, and its infection causes changes in the host lipid membrane composition and organization. Cubic membranes (CM) are the result of lipid rearrangement and a 3D non-lamellar assembly of folded membrane complexes induced by multiple viral infections. CM conformation is proposed to act as an antioxidant defense system and it is theorized that CM encourages the return of host homeostasis and mitigation of oxidative damage, promoting cell survival. Plasmalogens have been found to play a role in the amount of CM that forms in response to viral infection where a pre-treatment of plasmalogens was able to increase the abundance of CM after viral exposure in an ameba cell model. As the first step in infection is the virus crossing the plasma membrane, it is unsurprising that the composition of the membrane could be influential to the susceptibility of the host cell.

An essential part of the immune response are macrophages, a type of white blood cell that initiate inflammation and phagocytosis to clear pathogens. During phagocytosis, a macrophage rearranges its plasma membrane, which enables it to engulf, encapsulate, and digest the intruder. Plasmalogens have important roles in membrane structure and an association has been found between plasmalogen deficiency and reduced phagocytosis, while restoring plasmalogen levels also restored phagocytic activity and the number and size of lipid microdomains of macrophages.

SARS-CoV-2 infection also interferes with the ability of type 2 alveolar epithelium cells to make and secrete lung surfactant, a stabilizer for the respiratory surface of the mammalian lung. Lung surfactant minimizes surface tension where alveolus (small air containing compartment in the lungs where respiratory gases are exchanged with the pulmonary capillaries) meet air and liquid, facilitates breathing, and helps to avoid alveolar collapse. There is also known interaction between lung surfactant and phagocytic behaviour of alveolar macrophages, where the macrophages do not degrade the pathogens unless they are in the lung surfactant before phagocytosis. Lung surfactant contains a mixture of lipids classes including plasmalogens which seem to contribute to the stability and viscosity of the layer. As well, the antioxidant properties of the vinyl bond in plasmalogens help protect alveolar cells from oxidative stress.

Deng and Angelova have suggested that a plasmalogen deficiency in lung surfactant is present in patients with COVID-19. Populations more vulnerable to respiratory illnesses are at an increased risk for COVID-19 and the work described above helps explain why that is and the impact that plasmalogen deficiency may have on susceptibility and the ability to fight off the SARS-CoV-2 virus. The scientific community is working extensively on finding effective preventions and treatments for COVID-19 and it appears that a plasmalogen treatment could be beneficial in maintaining or improving the integrity of lung surfactant in patients with COVID-19 and the RCDP community.