Lipids, COVID-19 and Host Immunity



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

A new study published in the Lipid Research Journal of a team of researchers from the University of Pennsylvania examines the role played by lipids in this disease.

Interactions between coronaviruses and host lipids, including receptor binding and fusion, remodeling of membranes derived from the endoplasmic reticulum to form replicating organelles, and alterations in lipid metabolism to promote viral replication.


Most viral respiratory diseases in humans are caused by adenoviruses or by viruses with a ribonucleic acid (RNA) genome. Besides SARS-CoV-2, this includes respiratory syncytial virus (RSV), influenza virus, parainfluenza virus, and rhinoviruses.

These viruses mainly cause a mild infection of the upper respiratory tract. In severe cases, however, the lower respiratory tract is involved. The host’s immune responses aim to attenuate the clinical features of the infection, thereby inducing tolerance to the disease or reducing the viral load by activating antiviral resistance. The result is to eliminate the infection.

The downside of the antiviral immune response is the side effects caused by the activation of pro-inflammatory mediators. These can trigger systemic hyper-inflammatory phenomena that cause severe tissue damage, resulting in multisystem dysfunction and acute respiratory distress syndrome (ARDS) which is characteristic of critically ill COVID-19 patients.

Host tolerance molecules are crucial in modulating this inflammatory signaling cascade and thus preventing serious damage to the host.

Lipids and viral entry

Viruses enter the host cell through their lipid-rich cell membranes. During infection with SARS-CoV-2, the viral membrane attaches to the membrane of the host cell via a fusion mediated by the viral spike protein after its binding to the cell receptor for the converting enzyme. host angiotensin 2 (ACE2). The next step involves the proteolytic cleavage of the tip at the interface between the two subunits.

The fusion step, however, depends on the addition of a palmitoyl group to the spike protein. Likewise, the spike protein must be acylated by the host enzyme ZDHHC20 for the virus to be infectious, as this promotes spike membrane-lipid interactions.

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

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

Thus, compounds capable of altering the membrane lipid composition can inhibit infection with a number of viruses, increasing the spectrum of activity while reducing the possibility of resistance. The present study focuses on the LJ001 molecule, which is a photosensitizer activated by light to generate oxidative activity on unsaturated phospholipid substrates, thereby rendering the membrane rigid and unable to participate in viral fusion.

While membrane stiffness occurs in both host and viral membranes, only the former is able to repair itself through the synthesis of new lipids. This compound can lead to the development of new types of antivirals thanks to this mechanism of activity.

Other classes of potential antiviral compounds include rigid amphipathic fusion inhibitors (RAFIs) and nucleoside analogs which prevent the formation of negative curvature by incorporation into membranes.

Lipid rafts are also important in facilitating viral endocytosis, as they are high in cholesterol and glycosphingolipids, which express high levels of cell surface receptors. Acid and neutral sphingomyelinases can break down sphingomyelin in ceramide lipid rafts, thereby improving negative curvature and increasing fluidity.

Finally, lipids can alter the conformation of receptors on the virus or host cells to inhibit viral binding and subsequent infection. The spike protein binds tightly to linoleic acid, stabilizing it in the locked conformation so that it cannot engage with the ACE2 receptor. Omega-3 fatty acids, of which linoleic acid is a part, can thus inhibit viral infectivity.

Lipids and viral replication

Lipid molecules also hijack cellular lipid pathways to ensure that adequate oxidative substrates are available for viral replication processes. This occurs via the recruitment of phosphatidylinositol 4 (PI4) -kinase IIIβ into the remodeling of cell membranes.

Positive-sense RNA viruses use membrane-bound replicating organelles (ROs) to increase the efficiency of viral replication and possibly prevent the host’s antiviral response by masking viral particles from immune recognition. For SARS-CoV-2, ORs originate from the endoplasmic reticulum, mediated by non-structural viral proteins.

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

It was also found that the viral particles localize with the lipid droplets, which could mean that the latter offer a replication platform. The SREBP pathway could thus be a therapeutic target for pan-coronavirus.

In vitro screening for reused drugs shows that phospholipidosis is strongly linked to 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), which are produced by cyclooxygenases (COX) -1 and -2; leukotrienes via lipoxygenase enzymes (LOX); as well as epoxyeicosatrienoic acids (EET) and 20-hydroxyeicosatetraenoic acid (20-HETE) which are formed by cytochrome P450 (CYP) enzymes.

Although some of these derivatives are immunomodulators, they can also inhibit viral replication and the host’s immune response. Others could lead to a cytokine storm that would trigger severe or critical COVID-19.

Experiments in mice indicate a favorable response to inhibition of COX-2, inhibition of PGE2 and agonism of the PGD2 receptor DPr1 or inhibition of DPr2. Other components of these pathways are also directly involved in viral respiratory infections through their effect on host immunity or indirectly by promoting a fibrotic response.

Drugs like montelukast, which affects the LOX pathway, are suggested to be helpful in hospitalized COVID-19 patients by reducing the risk of progression. However, clinical trials are still ongoing to assess their usefulness.

Epoxyicosatrienoic acids (EET) are potent anti-inflammatory drugs that work by inhibiting cytokine-induced nuclear factor κB (NF-κB) activation and leukocyte adhesion to the vessel wall. 20-HETE has the opposite effect; However, their role in the immune responses linked to SARS-CoV-2 is not yet clear.

Lipidomics in COVID-19

COVID-19 is associated with a switch to fatty acid oxidation, as seen in patients with trauma or acquired immunodeficiency syndrome (AIDS). It is therefore probably a common alteration in the metabolic response during severe illness, and recovery is accompanied by the return of HDL and low density lipoproteins (LDL) to normal levels.

Sphingosine-1-phosphate (S1P) is reduced in COVID-19, possibly due to decreased levels of HDL since HDL is the carrier molecule of S1P in the blood. This reduction could lead to the damping of many biological processes involved in inflammation and tissue damage.

Increased activity of phospholipase A2 is also observed in COVID-19, as shown by reduced levels of glycerophospholipid and increased lysophospholipids. The synthesis of eicosanoids is also increased, and high levels of PLA2 can be an early signal of severe COVID-19.

However, only long-term follow-up will determine whether this is true of lipid alterations in COVID-19 patients.


The integral role of lipids in the viral life cycle suggests that targeting these pathways may be a viable therapeutic strategy. Serial lipidomic assays in people with COVID-19 can identify specific lipid pathways that mediate the heterogeneous response to viral infection, serve as prognostic biomarkers, or contribute to long-term sequelae. “


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