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Lipids, COVID-19, and host immunity

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which occurred in Wuhan, China in December 2019, infected more than 237 million people worldwide and killed more than 4.85 million people. bottom. This has led to intensive research into the etiology of coronavirus disease 2019 (COVID-19) to control clinical features and prevent disability and death.

New research published in Lipid Research Journal A team of researchers at the University of Pennsylvania is investigating the role of lipids in this disease.

Interaction between coronavirus Host lipids such as receptor binding and fusion, endoplasmic reticulum-derived membrane remodeling to form replicating organellas, and altered lipid metabolism to promote viral replication.

Background

Most viral respiratory illnesses in humans are caused by adenovirus or viruses with a ribonucleic acid (RNA) genome. In addition to SARS-CoV-2, this includes respiratory syncytial virus (RSV), influenza virus, parainfluenza virus, and rhinovirus.

These viruses primarily cause mild upper respiratory tract infections. However, in severe cases, the lower respiratory tract is involved. Because the host’s immune response is aimed at weakening the clinical characteristics of the infection, it activates antiviral resistance to induce disease resistance or reduce viral load. The result is to get rid of the infection.

The drawback of the antiviral immune response is the adverse effects caused by the activation of pro-inflammatory mediators. They cause a systemic hyperinflammatory phenomenon that causes severe tissue damage and can cause multisystemic dysfunction and acute respiratory distress syndrome (ARDS), which are characteristic of severe COVID-19 patients.

Host-resistant molecules are important to regulate this inflammatory signaling cascade and prevent serious harm to the host.

Lipid and viral entry

The virus invades the host cell through a lipid-rich cell membrane. During SARS-CoV-2 infection, the viral membrane attaches to the host cell membrane via virus-mediated fusion. Spike protein Following binding of the host to the angiotensin converting enzyme 2 (ACE2) cell receptor. The next step involves proteolytic cleavage of spikes at the interface between the two subunits.

However, the fusion step depends on the addition of palmitoyl groups to the peplomer. Similarly, for the virus to be infectious, the peplomer must be acylated by the host ZDHHC20 enzyme. This is to promote the membrane interaction between spikes and lipids.

The virus also binds to cholesterol in high-density lipoprotein (HDL) particles. To this end, HDL uptake by the HDL receptor scavenger receptor B type 1 (SR-B1) causes increased viral entry into ACE2-positive cells.

Multiple lipid molecules affect the fluidity and curvature of the membrane. For example, phosphatidylethanolamine and cholesterol increase fluidity and negative membrane curvature, allowing viral fusion to occur. The opposite happens with lysophospholipids.

Therefore, compounds capable of altering membrane lipid composition may increase the spectrum of activity while inhibiting infection by many viruses and reducing the likelihood of resistance. Current research describes the molecule LJ001, a photosensitizer that is activated by light to produce oxidative activity on unsaturated phospholipid substrates. This stiffens the membrane and prevents it from participating in viral fusion.

Membrane rigidity occurs in both host and viral membranes, but only the former can be repaired through the synthesis of new lipids. This compound may lead to the development of new types of antiviral agents through this activation mechanism.

Other classes of potential antiviral compounds include hard amphipathic fusion inhibitors (RAFIs) and nucleoside analogs that prevent negative curvature formation by being incorporated into the membrane.

Lipid raft is also important in promoting viral endocytosis because it is rich in cholesterol and glycosphingolipids that express high levels of cell surface receptors. Acidic and neutral sphingomyelinase can break down sphingomyelin in lipid rafts into ceramides, enhancing negative curvature and increasing fluidity.

Finally, lipids can alter the conformation of the virus or receptors on the host cell, inhibiting viral binding and subsequent infection. Peplomers bind tightly to linoleic acid and stabilize in a locked conformation, so they cannot bind to the ACE2 receptor. Therefore, omega-3 fatty acids of which linoleic acid is a member may inhibit viral infectivity.

Lipid and viral replication

Lipid molecules also hijack the lipid pathways of cells, making the appropriate oxidative substrates available for the viral replication process. It occurs through the recruitment of phosphatidylinositol 4 (PI4) -kinase IIIβ in cell membrane remodeling.

Positive sense RNA viruses may prevent the host’s antiviral response by using a membrane-bound replication organella (RO) to increase the efficiency of viral replication and mask viral particles from immune recognition. In the case of SARS-CoV-2, RO is derived from the endoplasmic reticulum and is mediated by viral nonstructural proteins.

Cytosol phospholipase A2α (cPLA2α) is also involved in this process and provides a target for reducing viral replication. Cholesterol biosynthesis is the key to SARS-CoV-2 infection, which contains several genes involved in the metabolism and transport of this lipid molecule.

Viral particles have also been found to localize with lipid droplets. This could mean that the latter provides a platform for replication. Therefore, the SREBP pathway may be a therapeutic pan-coronavirus target.

In vitro Screening of reused drugs shows that phospholipidosis is strongly associated with anti-SARS-CoV-2 activity. Further research is needed to assess the clinical value of these findings.

Lipids and inflammation

Inflammatory mediators are also lipids derived from eicosanoids. These include prostanoids, including prostaglandins (PG) and thromboxane (Tx) produced by cyclooxygenase (COX) -1 and -2. Leukotriene mediated by lipoxygenase (LOX) enzyme; also includes epoxyeicosatrienoic acid (EET) and 20-hydroxyeicosatetraenoic acid (20-HETE) formed by cytochrome P450 (CYP) enzyme.

Some of these derivatives are immunomodulators, but they can also inhibit viral replication and the host’s immune response.Others may lead to Cytokine storm Causes serious or serious COVID-19.

Mouse experiments have shown favorable responses to COX-2 inhibition, PGE2 inhibition, and PGD2 receptor DPr1 agonism or DPr2 inhibition. Other components of these pathways are also directly involved in viral respiratory infections through their effects on host immunity, or indirectly by facilitating a fibrotic response.

Drugs such as montelukast that affect the LOX pathway have been suggested to be useful in hospitalized COVID-19 patients by reducing the risk of progression. However, clinical trials to evaluate its usefulness are still underway.

Epoxyeicosatrienoic acid (EET) is a powerful anti-inflammatory drug that acts by activating the cytokine-induced nuclear factor κB (NF-κB) and inhibiting the adhesion of leukocytes to the walls of blood vessels. 20-HETE has the opposite effect. However, their role in the SARS-CoV-2 related immune response remains unclear.

COVID-19 lipidomics

COVID-19 is associated with the transition to fatty acid oxidation, as seen in patients with trauma or acquired immunodeficiency syndrome (AIDS). Therefore, this is likely to be a general change in metabolic response during serious illness, and recovery involves the return of HDL and low-density lipoprotein (LDL) to normal levels.

Sphingosine-1-phosphate (S1P) is reduced at COVID-19. This is probably due to reduced HDL levels. This is because the latter is a carrier molecule of S1P in blood. This reduction can lead to suppression of many biological processes involved in inflammation and tissue damage.

Increased phospholipase A2 activity is also seen in COVID-19, as indicated by decreased glycerophospholipids and increased lysophospholipid levels. Eicosanoid synthesis is also increased, and elevated PLA2 levels may be an early signal of severe COVID-19.

However, only long-term follow-up is required to determine if this applies to lipid changes in COVID-19 patients.

Conclusion

“”The essential role of lipids in the viral life cycle suggests that targeting these pathways may be a viable therapeutic strategy. Continuous lipid analysis in individuals with COVID-19 may identify specific lipid pathways that mediate heterogeneous responses to viral infections, serve as biomarkers of prognosis, or contribute to long-term sequelae... “

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