Lipid rafts as viral entry routes and immune platforms: A double-edged sword in SARS-CoV-2 infection?

Abstract

Lipid rafts are nanoscopic compartments of cell membranes that serve a variety of biological functions. They play a crucial role in viral infections, as enveloped viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can exploit rafts to enter or quit target cells. On the other hand, lipid rafts contribute to the formation of immune synapses and their proper functioning is a prerequisite for adequate immune response and viral clearance. In this narrative review we dissect the panorama focusing on this singular aspect of cell biology in the context of SARS-CoV-2 infection and therapy. A lipid raft-mediated mechanism can be hypothesized for many drugs recommended or considered for the treatment of SARS-CoV-2 infection, such as glucocorticoids, antimalarials, immunosuppressants and antiviral agents. Furthermore, the additional use of lipid-lowering agents, like statins, may affect the lipid composition of membrane rafts and thus influence the processes occurring in these compartments. The combination of drugs acting on lipid rafts may be successful in the treatment of more severe forms of the disease and should be reserved for further investigation.

Keywords: Anticoagulant drugs; Antiviral drugs; COVID-19; Immunosuppressive drugs; Lipid rafts; Lipid-lowering drugs; Monoclonal antibodies; SARS-CoV-2.

Fig. 1

Lipid rafts composition and biological function. Lipid rafts are small compartments of cell membranes rich in sterols and other saturated lipids. These microdomains are highly dynamic and can exchange lipid content with adjacent nonraft membrane domains (double-headed arrow). Lipid rafts include multiple globular proteins, such as kinases, and can assemble into larger platforms that are used for specific functions in the plasma membrane or in organelles. Abbreviations: CHO: cholesterol.

Fig. 2

Schematic representation of endocytosis. a. Clathrin-mediated endocytosis. This type of endocytosis usually occurs in nonraft domains of the plasma membrane. After binding of a ligand to its receptor, clathrin molecules and other proteolipid components are recruited to the plasma membrane. This process results in invagination of the plasma membrane and formation of a coated pit that is transported to the endosome. Prior to fusion with the endosome, the clathrin molecules dissociate and are recycled to the cytosol. b. Caveolae-mediated endocytosis. This type of endocytosis is thought to occur in lipid rafts. Once the receptors bind their ligand, the plasma membrane is invaginated thanks to the recruitment of caveolin molecules. The resulting vesicle, a caveola, can be transported to the endosome, but unlike clathrin-mediated endocytosis, caveolin molecules do not dissociate from the caveola membrane. The fusion of a caveola with an early endosome creates a caveosome in which the persistence of caveolin molecules appears to be critical for ligand sorting and ultimate fate. Abbreviations: CHO: cholesterol.

Fig. 3

The entry of SARS-CoV-2 into target cells. The figure summarizes the plausible mechanisms of virus entry exploiting caveolae-mediated endocytosis (a), envelope fusion (b) and clathrin-mediated endocytosis (c). In the first scenario (a), SARS-CoV-2 binds to ACE2 located in lipid rafts. This may induce the subsequent formation of a caveola. Dynamin plays a central role in cutting the vesicle and enables its internalization. In the second scenario (b), the virus binds to ACE2 and TMPRSS2 on the plasma membrane of target cells, resulting in proteolytic priming and fusion of the envelope lipid bilayer with the cell membrane. In the third scenario (c), SARS-CoV-2 instead uses clathrin-mediated endocytosis to enter target cells. Following each of these entry mechanisms, SARS-CoV-2 can be transported to endosomes. The type of entry route, as well as the proteolipid composition of vesicles, may dictate a different processing pathway and is critical for viral clearance. Abbreviations: ACE2: angiotensin-converting enzyme 2; CHO: cholesterol; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TMPRSS2: transmembrane protease, serine 2.

Fig. 4

Potential mechanisms linking lipid rafts to the pathogenesis of COVID-19. In this scenario, SARS-CoV-2 may enter target cells via binding of ACE2, which is located in lipid rafts, or via caveolae-mediated endocytosis, which also occurs in raft compartments of the plasma membrane. The lipid and protein composition of rafts is critical for the subsequent transport of viruses to endosomes and lysosomes. The raft-associated protein cav-1 can inhibit eNOS in endothelial cells and the subsequent production of NO, which plays an important role in inflammation. Lipid rafts and cholesterol in the endosomal membrane may enhance TLR7 activity and promote nuclear translocation of NF-kB via the MYD88 pathway. This event leads to transcription of genes encoding the pro-inflammatory cytokines pro-IL-1β, IL-6, and TNF-α. Importantly, cav-1 may bind miR-138, which suppresses the NF-kB-mediated pathway. Moreover, lipid rafts in the mitochondrial membrane may contribute to autophagy and oxidative stress, both of which occur in infected cells. Lipid rafts in the plasma membrane of immune cells also harbor important protein complexes involved in the immune response, such as receptors for pathogens, antigens or cytokines or costimulatory molecules. Rafts also regulate the activity of TACE, a transmembrane enzyme that generates truncated forms of cytokine receptors. Cholesterol depletion in the immune synapse may profoundly alter the ability of cells to counteract SARS-CoV-2 infection and promote the improper generation of a dysfunctional immune response, characteristics of the most severe outcomes of COVID-19. Abbreviations: ACE2: angiotensin-converting enzyme 2; BCR: B cell receptor; cav-1: caveolin 1; CD28: Cluster of Differentiation 28; CHO: cholesterol; CKs: cytokines; eNOS: endothelial enzyme nitric oxide synthase; ER: endoplasmic reticulum; IkB: inhibitors-of-kappaB; IL-6: interleukin 6; IL6R: interleukin-6 receptor; miR: microRNA; MYD88: myeloid differentiation primary response 88; NFkB: nuclear factor kappa-light-chain-enhancer of activated B cells; NO: nitric oxide; P: phosphorylation; pro-IL1β: pro-interleukin 1 beta; T17: T helper 17 cell; TACE: tumor necrosis factor-alpha converting enzyme; TCR: T cell receptor; TLR7: Toll-like receptor; TNFR: tumor necrosis factor receptor; TNF-α: tumor necrosis factor alpha; Treg: Regulatory T cell.