SARS-CoV-2 hijacks the body’s metabolism, amplifying the severity of COVID-19

A review article published in a magazine Signaling and targeted therapyscientists discuss host metabolic alterations caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their impact on disease severity.

study: Metabolic changes during SARS-CoV-2 infection and potential therapeutic targets for coronavirus infection. Image credit: NIAID

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the 2019 coronavirus disease (COVID-19) pandemic, is an enveloped, positive-sense, single-stranded RNA virus that belongs to the human beta-coronavirus family. is. Viruses enter host cells by interacting with the host cell membrane receptor angiotensin-converting enzyme 2 (ACE2) via their surface. glycoprotein, spike protein.

Host metabolism plays an important role in regulating various physiological processes during viral replication. Conversely, many viruses can modulate host metabolism to support their life cycle within host cells and evade host immune responses.

Studies have shown that viruses can alter host lipid metabolism to create replication compartments. Lipid accumulation in the lungs has been observed in patients with COVID-19. Changes in lipid patterns induced by SARS-CoV-2 have been found to be associated with disease severity.

Type 2 diabetes has been identified as one of the significant risk factors for severe COVID-19 infection and mortality. Increased glycolysis has been observed in all immune cells of COVID-19 patients. These observations highlight the link between SARS-CoV-2 infection and altered glucose metabolism.

SARS-CoV-2 entry into host cells

Interaction between the spike protein and ACE2 through the spike S1 domain leads to cleavage of the spike protein at the S2 site by the host transmembrane protease TMPRSS2. Following this, the viral envelope and the host lipid bilayer fuse and the viral particle is released inside the host cell.

Lipid rafts are microdomains containing lipid molecules such as cholesterol and sphingolipids. Evidence suggests that lipid rafts located in the host cell membrane play a key role in the SARS-CoV-2 entry process by providing a platform for membrane receptors. Lipid rafts can also support cell-to-cell viral infection by promoting the formation of syncytia. Disruption of lipid rafts induced by cholesterol transport from the membrane to the endoplasmic reticulum (ER) has been shown to reduce entry into SARS-CoV-2 host cells.

The SARS-CoV-2 spike protein can directly bind to cholesterol and receptor-bound high-density lipoprotein (HDL). Spike proteins have been shown to trap lipid components from cell membranes by binding to HDL and altering its function.

Similar to membrane cholesterol, intracellular cholesterol also participates in viral entry. A genetic screen with a CRISPR library identified specific genes related to cholesterol metabolism that are essential for SARS-CoV-2 infection.

Various sphingolipids, especially ceramide and sphingosine, play important roles in SARS-CoV-2 entry into host cells. Ceramide is either converted from sphingomyelin by acid sphingomyelinase (ASM) or synthesized de novo from palmitoyl-CoA and serine. Ceramide has been found to facilitate SARS-CoV-2 entry by forming ceramide-rich microdomains in which ACE2 clusters. Several ASM inhibitors have been shown to prevent SARS-CoV-2 entry by altering surface ceramide levels.

Sphingosine is derived from ceramide, catalyzed by ceramidase, or sphingosine 1-phosphate (S1P), catalyzed by S1P phosphatase. In contrast to ceremide, sphingosine has been found to bind to ACE2 and prevent viral entry by blocking the interaction of spike with ACE2. S1P, a downstream product of sphingosine, has also been found to ameliorate clinical symptoms of COVID-19 by protecting the endothelial barrier.

Modification of the SARS-CoV-2 spike protein

Evidence indicates that the SARS-CoV-2 entry process can be regulated by lipid-mediated post-translational modifications of spike proteins. Binding of linoleic acid to the spike protein has been shown to lock the protein into a closed conformation and inhibit viral entry.

In contrast, covalent attachment of fatty acids to the spike protein (palmitoylation) has been found to facilitate viral entry by stabilizing the spike protein homotrimer. Palmitoylation of spike proteins is a conserved process across all disciplines. coronavirus.

In type 2 diabetes, high blood glucose levels have been found to increase ACE2 expression and promote viral entry. In addition, spike protein glycosylation (covalent attachment of sugar moieties) has been found to significantly regulate the viral entry process.

Replication of SARS-CoV-2

In addition to viral entry, host lipids regulate SARS-CoV-2 replication. Studies have shown that glycerophospholipid metabolism promotes viral replication by causing the formation of double-membrane vesicles.

Recent evidence indicates that SARS-CoV-2 utilizes host lipid droplets to meet the energy needs of replication. TMEM41B, an ER-localized protein responsible for lipid mobilization from lipid droplets, has been identified as an essential host factor for SARS-CoV-2 replication.

Like many other viruses, SARS-CoV-2 induces the ‘Warburg effect’ (shift from glucose metabolism to aerobic glycolysis) to promote replication. Glycolysis provides the energy and building blocks for nucleotide synthesis, a prerequisite for viral replication.

One-carbon metabolism also facilitates SARS-CoV-2 replication by providing material for RNA capping necessary to prevent RNA degradation by the innate immune response and promote translation of viral proteins.

SARS-CoV-2 assembly

Host lipids play an important role in the assembly of SARS-CoV-2. Studies have shown that viral membrane proteins use several lipid components to induce membrane curvature. Similarly, palmitoylation has been found to support viral assembly by stabilizing envelope proteins and maintaining their functional structure.

drug reuse

Considering the important involvement of host metabolism in SARS-CoV-2 infection, several lipid- and glucose-regulating agents such as statins, ASM inhibitors, non-steroidal anti-inflammatory drugs, montelukast, omega-3 fatty acids, 2-deoxy drug is used. -D-glucose and metformin are being repurposed for the management of COVID-19. These drugs are currently in clinical research for the treatment of COVID-19 patients.