University of Pennsylvania Study Shows That Lipids Pay A Critical Role In SARS-CoV-2 Replication And Human Immune Response

A new study by researchers from the University of Pennsylvania showed that that lipids pay a critical role in SARS-CoV-2 replication and human immune response.

 
According to the study abstract, “Lipids play essential roles in the viral life cycle. The lipid composition of cell membranes can influence viral entry by mediating fusion or affecting receptor conformation. Upon infection, viruses can reprogram cellular metabolism to remodel lipid membranes and fuel the production of new virions. Further, several classes of lipid mediators, including eicosanoids and sphingolipids, can regulate the host immune response to viral infection.”
 
The study team summarize the existing literature on the mechanisms through which these lipid mediators may regulate viral burden in COVID-19. They also defined the gaps in knowledge and identify the core areas in which lipids offer therapeutic promise for SARS-CoV-2.
 
The study findings were published in the peer review Journal of Lipid Research. https://www.jlr.org/article/S0022-2275(21)00111-5/fulltext
 
The SARS-CoV-2 coronavirus that emerged in Wuhan, China, in mid-December 2019, has infected over 238 million worldwide and caused the deaths of over 4.86 million individuals globally. This has led to intensive research into the pathogenesis of the COVID-19 disease in order to control the clinical features and prevent disability and death.
 
This new study examined the role played by lipids in this disease.
 
Typically, most viral respiratory illnesses 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), the influenza virus, the parainfluenza virus, and rhinoviruses.
 
Often these viruses mostly cause a mild upper respiratory infection.
 
However  in severe cases, the lower respiratory tract is involved. Host immune responses are targeted at muting the clinical features of the infection, thus inducing disease tolerance or reducing the viral load by activating antiviral resistance. The outcome is to clear the infection.
 
Unfortunately, the downside of the antiviral immune response is the adverse effects caused by the activation of pro-inflammatory mediators.
 
These may trigger systemic hyper-inflammatory phenomena commonly known as cytokine storms that cause severe tissue damage, resulting in multi-system dysfunction and acute respiratory distress syndrome (ARDS) that is characteristic of critically ill COVID-19 patients.
 
Hence human host tolerance molecules are crucial to modulating this inflammatory signaling cascade and thus preventing severe harm to the host.
 
Various viruses enter the human host cell via their cell membranes, which are rich in lipids.
 
During SARS-CoV-2 infection, the viral membrane attaches to the host cell membrane via fusion that is mediated by the viral spike protein following its binding to the host angiotensin-converting enzyme 2 (ACE2) cell receptor. The next step involves proteolytic cleavage of the spike at the interface between the two subunits.
 
Importantly however the fusion step depends on the addition of a palmitoyl group to the spike protein.
 
Simila rly, the spike protein must be acylated by the host ZDHHC20 enzyme for the virus to be infective, as this promotes spike-lipid membrane interactions.
 
It has been also found that this virus also binds cholesterol within high-density lipoprotein (HDL) particles. To this end, the HDL uptake by the HDL receptor scavenger receptor B type 1 (SR-B1) causes increased viral entry in ACE2-positive cells.
 
It is also known that multiple lipid molecules affect the fluidity and curvature of the membrane. For instance, phosphatidylethanolamine and cholesterol increase fluidity and negative membrane curvature, allowing viral fusion to occur.
 
However, the opposite occurs with lysophospholipids.
 
Hence, compounds capable of altering the membrane lipid composition may inhibit infection by a number of viruses, increasing the spectrum of activity while reducing the possibility of resistance.
 
The study also discusses the molecule LJ001, which is a photosensitizer that is activated by light to generate oxidative activity on unsaturated phospholipid substrates, thus making the membrane rigid and unable to participate in the viral fusion.
 
Although membrane rigidity occurs in both host and viral membranes, only the former is capable of repair via the synthesis of new lipids. This compound may lead to the development of new types of antivirals through this mechanism of activity.
 
The study also found that other classes of potential antiviral compounds include rigid amphipathic fusion inhibitors (RAFIs) and nucleoside analogs that prevent negative curvature formation by incorporation into the membranes.
 
It was also noted that lipid rafts are also important in facilitating viral endocytosis, as they are rich in cholesterol and glycosphingolipids, which express high levels of cell surface receptors. Acidic and neutral sphingomyelinases can break sphingomyelin in lipid rafts down to ceramide, thus enhancing negative curvature and increasing fluidity.
 
Lastly the study findings also showed that lipids can alter the conformation of the receptors on the virus or host cells to inhibit viral binding and subsequent infection. The spike protein binds linoleic acid tightly, 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 member, can thus inhibit viral infectivity.
 
Thailand Medical News had already covered the studies showing that Resolvins from omega fatty acids could prevent SARS-CoV-2 cytokines storms in May 2020. https://www.thailandmedical.news/news/breaking-covid-19-supplements-us-study-finds-that-resolvins-from-omega-3-fatty-acids-could-prevent-covid-19-cytokine-storms
 
https://www.thailandmedical.news/news/covid-19-supplements-yale-study-shows-lipidomic-changes-that-mark-covid-19-disease-severity-resolvins-from-omega-3-fatty-acids-could-help
 
However, Thailand Medical News only covered a study on the potential aspects of omega fatty acids as an antiviral against the SARS-CoV-2 virus only in June 2021. https://www.thailandmedical.news/news/covid-19-supplements-elovanoids-from-omega-3-found-to-block-sars-cov-2-cell-entry-and-protects-lung-cells-
 
According the University of Pennsylvania study lipid molecules also hijack the cellular lipid pathways so as to ensure adequate oxidative substrates are available for viral replication processes. This occurs via the recruitment of phosphatidylinositol 4 (PI4)-kinase IIIβ in remodeling cell membranes.
 
It was also found that positive-sense RNA viruses use membrane-bound replication organelles (ROs) to increase the efficiency of viral replication and perhaps prevent the host antiviral response by masking the viral particles from immune recognition. For SARS-CoV-2, ROs come from the endoplasmic reticulum, mediated via viral non-structural proteins.
 
The study also found that cytosolic phospholipase A2α (cPLA2α) is also involved in this process and offers a target for reducing viral replication. Cholesterol biosynthesis is key to SARS-CoV-2 infection, including several genes that take part in the metabolism and transport of this lipid molecule.
 
Also, viral particles were found to localize along with lipid droplets, which could mean that the latter offer a platform for replication. The SREBP pathway could thus be a therapeutic pan-coronavirus target.
 
Interestingly, In vitro screening of repurposed drugs shows that phospholipidosis is strongly linked to anti-SARS-CoV-2 activity. Further research is required to assess the clinical value of these findings.
 
It is also known that inflammatory mediators are also lipids that are derived from eicosanoids.These include prostanoids, comprising prostaglandins (PGs) and thromboxane (Tx), which are produced by cyclooxygenases (COXs)-1 and -2; leukotrienes via the lipoxygenase (LOX) enzymes; as well as epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE) that are formed by cytochrome P450 (CYP) enzymes.
 
Although some of these derivatives are immunomodulators, they may also inhibit viral replication and the host immune response. Others could lead to a cytokine storm that triggers severe or critical COVID-19.
 
Animal model experiments involving mice indicated a favorable response to COX-2 inhibition, PGE2 inhibition, and PGD2 receptor DPr1 agonism or DPr2 inhibition. Other components of these pathways are also directly implicated in viral respiratory infections through their effect on host immunity or indirectly by promoting a fibrotic response.
 
Interestingly drugs like montelukast, which affects the LOX pathway, are suggested to be useful in hospitalized COVID-19 patients by reducing the risk of progression. However, clinical trials are still underway to assess their utility.
 
Also Epoxyeicosatrienoic acids (EETs) are powerful anti-inflammatory drugs that act by inhibiting cytokine-induced nuclear factor κB (NF-κB) activation and leukocyte adhesion to the vascular wall. 20-HETE has the opposite effect; however, their role in SARS-CoV-2-related immune responses is not yet clear.
 
It has also been found that COVID-19 is associated with a shift to fatty acid oxidation, as shown in patients with trauma or acquired immunodeficiency syndrome (AIDS). Thus, this is likely a common alteration in the metabolic response during a critical illness, and recovery is accompanied by the return of HDL and low-density lipoproteins (LDL) to the normal levels.
 
The study findings also showed that sphingosine-1-phosphate (S1P) is reduced in COVID-19, perhaps because of the decreased HDL levels since the latter is the carrier molecule for S1P in blood. This reduction could lead to the dampening of many biological processes involved in inflammation and tissue damage.
 
Importantly increased phospholipase A2 activity is also seen in COVID-19, as shown by the reduced glycerophospholipid and increased lysophospholipid levels. Eicosanoid synthesis is also increased, and elevated PLA2 levels may be an early signal of severe COVID-19.
 
The study team however stressed that only long-term follow-up will determine if this is true of lipid alterations in COVID-19 patients.

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