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Phospholipase enzymes as potential biomarker for SARS
CoV-2 virus
D.V.D. Hemalika
Department of Chemistry, Faculty of Natural Sciences, The Open University of Sri Lanka
DOI: 10.29322/IJSRP.11.01.2021.p10919
http://dx.doi.org/10.29322/IJSRP.11.01.2021.p10919
Abstract-
Severe acute respiratory syndrome corona virus 2 (SARS CoV-2) is the responsible pathogenic RNA virus which is responsible for
current ongoing pandemic covid 19. This review provides an updated summary of the current knowledge of phospholipase enzymes
and its role on SARS CoV-2 virus, discussing the reported evidence as a potential bio marker and future directions that could be used
to develop PLAs as a therapeutic target for covid 19 pandemic.
Index terms- bio marker, covid 19, LpPLA2, SARS CoV-2, sPLA2, therapeutic target
1. INTRODUCTION
The covid 19 pandemic is a global health crisis which has grown exponentially to a disastrous scale. This is the greatest challenge we
have faced since world war two.
Corona virus disease 2019 (covid 19) is an infectious disease which is caused by novel SARS CoV-2 , Severe acute respiratory
syndrome. Considering the epidemiology of covid 19, WHO declared it as a global pandemic on 11th March 2020 [1]. Up to now
more than 79,100,000 reported covid 19 infected cases with around 1700000 deaths have been reported [2].
SARS CoV-2 is the seventh corona virus that infect human. Until 2020, six corona viruses were known to infect human namely 229E,
NL63 (genus Alpha-), OC43, HKU1, SARS-CoV, and MERS-CoV (Beta-)[3]. Among them in 2002 and 2012 we experienced severe
out breaks of SARS-CoV and MERS with high mortality [4].Those two viruses and SARS CoV- 2 are beta corona viruses which
infect lower respiratory tract and pneumonia in human. Corona viruses can cause common cold to more severe pneumonia condition
in human. However compared to SARS CoV and MERS, covid 19 shows less severe pathogenesis, but very rapid transmission whole
over the world [5].
This review summarizes the importance of phospholipase enzyme as therapeutic target for both noninfectious diseases and towards
that its possibility to use as a potential biomarker for the covid 19 current pandemic situation.
1. METHODOLGY
Information for this review were obtained from previous research findings regarding phospholipase enzymes, SARS CoV-2 virus, use
of phospholipase A2 (PLA2) as therapeutic targets for non-infectious diseases, role of PLA2 in corona viruses, studies of SARS CoV-
2 virus related to phospholipase enzyme from available literatures published in scientific databases such as Web of Science, Science
Direct, PubMed, JSTOR and Google Scholar. Primary search terms like, PLA2, Covid 19, SARS CoV-2, enzymes as therapeutic
targets are used to collect the information.
2. STRUCTURE OF SARS CoV-2
Pathogenic RNA viruses become most important group of zoonotic disease transmission among all pathogens. Biological diversity,
rapid inter transmission rates and epidemiology of recently developed Chikungunya(CHIKV) and Zika (ZIKV) viruses, Lassa fever,
Ebolavirus, Middle East respiratory syndrome (MERS), SARS, and Influenza A virus (IAV) are all RNA viruses [5]. Coronaviruses
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belong to the family coronaviridae, (subfamily Coronavirinae), which represent major group of viruses which responsible for
respiratory and neurological diseases [6].
Coronaviruses are single stranded positive sense RNA genome. Coronaviruses encode four major structural proteins, namely, spike
(S), membrane (M), envelope (E), and nucleocapsid (N) [5]. As its name implies this virus contain large, multifunctional
transmembrane S glycoprotein on the virion surface, make crown like appearance [7]. Those glycoproteins are responsible for the
viral attachment to the host cells. When we consider about our concern, SARS corona virus, in 2004 it is suggested that increasing
international wildlife trade in countries like China and Vietnam may played an important role in SARS outbreak in 2002 [8].
Unfortunately, same incident is repeat in Wuhan, China in 2019 and now the outcome SARS CoV-2 is unable to anticipate by modern
medical technologies even.
Using genome sequencing study of isolated viruses, it had been found that SAARS CoV- 2 is a new human infecting beta corona virus
[9]. Covid 19 is a zoonotic disease and based on phylogenetic studies bats might be the original host of covid 19 virus. It was also
found that Malayan pangolins (wild life mammal) are the intermediate host of SARS CoV-2 [10]. It had also been found that s
glycoprotein which is contribute for the receptor binding is almost similar in both pangolin CoV and SARS CoV-2 [10].
3. TREATMENT STRATEGIES FOR SARS CoV-2
Covid 19 emerged in china and now it is rapidly spread all over the world. This public health burden is now become supreme
challenge to whole universe. Therefore, strong investigations towards development of drugs and effective vaccines are highly needed
for the society.
Up to date scientists in all over the world are eager to find therapeutic targets for this disastrous virus and few treatment strategies are
identified and developed [11].
Severity and mortality of covid 19 patients are linked to excessive production of cytokines, called “cytokine storm” induce by the
virus. It leads to wide spread tissue damage, multiple organ failure and death, Therefore it is important to target the inflammatory
response as a therapeutic target for covid 19 virus [11].
In 2007, it had been shown another strategy that glycoproteins which is contain on the surface of the virus can be used as attractive
target to develop as antiviral agents against corona viruses [12].
Developing neutralizing antibodies that targeting S protein on covid 19 virus surface, using oligonucleotides against covid 19 virus,
Repurposing currently available antiviral medications [13] (viral polymerase and viral protease inhibitors [14]) against covid 19
viruses and development of vaccines (live vaccines with vector viruses, mRNA based vaccines, inactivated vaccines with viral
proteins) are still under ongoing clinical trials [15].
4. ENZYMES AS THERAPEUTIC TARGETS IN MEDICINE
Enzymes are biological macromolecules, which are essential for all life. Enzyme catalysis is vital for the vast majority of biological
reactions including synthesis of biomacromolecules (proteins, polysaccharides, and nucleic acids), intercellular communication and
immune responses [16].
Although enzymes are crucial for most essential life processes, dysregulated enzyme activity can lead to disease conditions. As a
result of these biological and pathophysiological implications, by modifying the action of enzymes, they become attractive targets for
drug discovery. This strategy has been applied in the development of a substantial amount of antibiotic and antiviral drugs that exist
today. In the year 2000, Hopkins and Groom reported that around 47% of drugs inhibit enzymes as their molecular targets. Nowadays
major pharmaceutical companies are seeking new drugs through selective enzyme inhibition since enzymes are susceptible to be
inhibited by small molecular weight drug-like molecules [17].
Viral enzymes also play a possible way to develop new anti-viral targets since each step of viral infection, viral enzymatic reactions
are involved [13].
5. ROLE OF LIPID METABOLISM IN VIRAL INFECTION
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Lipids have long been known as structural component in biological membranes of all living organisms. Lipids play a central role at
different stages in viral replication including cell entry and exit by viruses. Virus entry is a specific process which is depend on viral
surface proteins and host cell receptors[18]. Lipids also can function as host cell receptor for the viruses. Since lipids play a crucial
role in viral life cycle it is good to investigate whether the enzymes which related to lipid metabolism can be used as drug target for
viral infections.
Therefore, this lipid metabolic pathways become an important role in drug targets. Lipid related anti-viral strategies are promising
since lipoids play a crucial role in viral replication. Identification of host directed anti-viral that inhibit host factors is most promising.
It had been already reported that development of anti-viral drug for zika virus can drive through host directed anti-viral, since zika
virus having a different aspects of lipid metabolism to complete their life cycle [19].
Since SARS CoV -2 virus replication is occur within the host cell, virus first should be enter to the host via intracellular membranes
and create double membrane vesicles encoding with lipid bilayer and replicative organelles which are needed for the viral genome
amplification [18].
Not only lipid mediators that produce through lipid metabolic pathways, but also the enzymes which involved is used as promising
drug targets. Phospholipase enzymes may be considered as one such novel approach for fighting against SARS CoV-2 virus as well.
6. PHOSPHOLIPASES ENZYME
Phospholipases are a group of enzymes that lead to cleaving the various bonds in phospholipids, which are the major component of all
biological membranes in living organisms.
Phospholipases are categorized based on the bond cleavage in phospholipid substrates.
Figure 1: Site of action of various phospholipases on phospholipid. X = phospholipid common base (Choline, ethanol amine)
Based on the site of hydrolytic cleavage as depicted above, there are five types of phospholipases namely PLA1, PLA2, PLB, PLC,
and PLD. Up to date, phospholipase A2 (PLA2) is the most extensively studied group of phospholipases [20].
PLA2 enzymes vary in size, function, location, substrate specificity, and calcium requirement. Based on the structure, catalytic
mechanism, localization, and evolutionary relationships, PLA2s are subdivided into six subgroups as follows [21].
1. Cytosolic PLA2 - cPLA2
2. Secretory PLA2 - sPLA2 (Ca2+ dependent)
3. iPLA2 - Ca2+ independent PLA2
4. LyPLA2 - lysosomal PLA2
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5. PAFAH - PAF acetylhydrolase
6. AdPLA2 - adipose PLA2
Among them, sPLA2 is the first discovered group of PLA2 enzymes, which was discovered as a component of cobra venom [22].
PLA2 has been identified as one of the main components of animal venom. Elapidae and Viperidae family snakes having sPLA2
group IA, IIA or IIB as the main component in snake venom [23]. Snake venom PLA2s induce pathophysiological alterations in the
victim by hydrolyzing phospholipids in membranes [23].
Among all existing isoforms of phospholipase enzymes, sPLA2 mainly play a major role in developing drug target as inhibitors since
it involves in many inflammatory conditions [24].
Studies about this sPLA2 enzyme and its function, hold great importance since PLA2 catalyzes the release of arachidonic acid, which
is believed to be the rate-limiting event in the generation of pro-inflammatory lipid mediators (prostaglandins, leukotrienes, lipoxins)
and platelet-activating factor [25]. Release of these mediators initiates the pain, swelling, and other unpleasant symptoms we
experience as part of an inflammatory response [26].
Figure 2: Phospholipid hydrolysis by sPLA2
Therefore, the inhibition of these phospholipase enzymes will be the good therapeutic target, as it leads to inhibit the production of
inflammatory lipid mediators.
7.1 SPLA2 ACTIVITY IN VARIOUS DISEASE STATES
sPLA2 enzymes are responsible for a large variety of physiological functions as well in many disease conditions. They help to
maintain membrane structure and function by removing oxidized and damaged phospholipids under physiological conditions [22].
It is important to discuss the cause of pathological conditions that are initiated by sPLA2. Lysophospholipids and free fatty acids
(arachidonic acid) are the main products of hydrolysis of the phospholipid cell membrane. Arachidonic acid initiates the production of
numerous metabolites through cyclooxygenase or lipoxygenase enzymatic pathways, especially eicosanoids including prostaglandins
and leukotrienes, which mediate various pathological conditions [27].
Under pathological conditions, overexpression of sPLA2 activity can be observed in a variety of diseases. Especially increased
activity of sPLA2 is associated with inflammatory diseases such as arthritis and sepsis [28], different types of cancer [29] and
atherosclerosis [30].
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These studies have implicated a role of sPLA2 IIA known as inflammatory sPLA2, in disease pathogenesis, since it promotes the
production of inflammatory lipid mediators, mainly eicosanoids [31]. Moreover, it has been suggested that increased activity of
sPLA2-IIA can be used as a biomarker for the detection of sepsis and the presence of bacterial infection in adults [27]. The increased
sPLA2 activity has also been shown in the plasma or serum of patients with acute pancreatitis, septic shock, adult respiratory distress
syndrome and inflammatory bowel diseases including Chron’s disease and ulcerative colitis [22]. It had been shown that sPLA2 IIA ,
V, and X was overexpressed in transgenic mice with atherosclerosis [30]. A recent study had shown that an increase in the activity of
sPLA2 IIA was a significant risk factor in the occurrence of coronary artery disease.
sPLA2 IIA and sPLA2 X are the most studied sPLA2s in cancer so far [22]. It was determined that the sPLA2 X is expressed at high
levels in colon cancer by promoting cell proliferation and releasing various lipid mediators in other steps in progression and
development of cancer [33]. Several in-vitro studies had shown that human sPLA2 IIA activity is high in serum or in the tumor
microenvironment of patients with prostate, esophageal and lung cancer cells [35]. The previous study had suggested that plasma
sPLA2 IIA is a potential biomarker for lung cancer diagnosis since it is elevated in all most all lung cancer types [36]. sPLA2 IIA and
sPLA2 X are the most studied sPLA2s in cancer so far. Several in-vitro studies had shown that human sPLA2 IIA activity is high in
serum or in the tumor microenvironment of patients with prostate, esophageal and lung cancer cells [35]. It had been also reported that
sPLA2 group II is overexpressed in a variety of human breast, gastric and hepatocytic carcinomas and prostate cancers [37].
Above studies were evidenced that sPLA2s are considered as pro-inflammatory enzymes and their inhibition has long been
recognizing as a desirable therapeutic target.
7.2 PHOSPHOLIPASE ACTIVITY IN VIRAL INFECTIONS
Previous literature was cited that phospholipase enzyme act as key role of producing inflammatory lipid mediators in host during viral
infections.
It had been reported that dengue virus (DENV) of neuroblastoma cell lines leads to increase in the activity of the sPLA2 enzyme
leading to cell apoptosis. Increase in sPLA2 activity resulted in the increased production of prostaglandin E2 (PGE2), prostacyclin
(PGI2) , thromboxane and leukotriene, which could lead to the endothelial dysfunction leading to increased vascular permeability
[9],[38].
It was demonstrated that dengue shock syndrome (DSS) patients had higher sPLA2 levels than healthy individuals [39]. Another
study has shown that the sPLA2 activity was significantly higher in patients with DHF, especially in the very early phase of the
illness. The activity of sPLA2 diminished towards 120–132 hours of illness and was similar to the sPLA2 activity seen in patients
with DF [40].
Role of Phospholipace C (PLC) signaling had been reported for the bovine herpesvirus 1 infection which enhance the generation of
inflammatory mediator reactive oxygen species [41].
It had been also evidenced that PLA2 host enzyme and lysophosphatidylcholins are contributed to form west Nile virus replication
complex [42]. Moreover phospholipase D activity is stimulated by infection of influenza virus [43].
7.3 ROLE OF PLA2 IN LUNG INFECTIONS AND RELATED RESPIRATORY PROBLEMS
There are some evidence that elevated level of PLA2 is patients with lung infections and respiratory problems. Pulmonary surfactant
is important to maintain alveolar stability by lowering surface tension along the alveolar epithelium. Destruction of this surface
tension will results in lung injury (Acute Respiratory distress Syndrome ARDS) [44].
sPLA2 enzyme leads to hydrolyze phospholipid surfactant and destruction of surface tension. It had been found that inhibition of
sPLA2 activity play a protective role in lung injury by maintaining surfactant integrity [45]. It was also reported that various sPLA2
isoforms are produced in lungs by macrophages and epithelial cells [46].
Using multicenter translational study including several pediatric and neonatal intensive care units suggested that sPLA2 might be the
main cross road between inflammation and surfactant dysfunction in lungs [47].
Moreover it had been suggested that sPLA2 V and X participated to the lung injury by lipid mediator production and surfactant
hydrolysis [48].There are patients with severe asthma showed increasing sPLA2 activity [49].
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7. STUDIES RELATED TO PHOSPHOLIPASE ENZYMES AND CORONAVIRUSES
Studies related to PLA2 and covid 19 is already done by few scientists. As initial step it had been found that plasma sPLA2 level of
moderate and acute covid 19 patients significantly increase compare to the covid 19 negative patients. They also observed the
dramatic depletion of plasma phospholipids concentration with the elevation of sPLA2 [50]. That is may be due to hydrolysis of
phospholipids and formation of lyso phospholipids. Resultant lysophospholipds may stimulate the cytokine production and this
cytokine storm will lead the severity of SARS CoV-2.
This is further supported by recent finding that several circulating lipids and PLA2 activity can be used as potential biomarkers in the
pathogenesis of covid 19. It is mainly due to the down regulation of glycerophospholipids and upregulation of lysophospholipids
which produced by PLA2 activity [51]. It would suggest the strong influence of PLA2 in progression of pathogenesis of covid 19.
Previous reports were highlighted that cPLA2α is critically involved in RNA replication of some viruses. This enzyme also important
in corona virus replication by producing lysophospholipids that required to form double membrane vesicle formation, that is proven
by both electron microscopy studies and lipidomic studies [52],[18].
In another study, age dependent increase of PLA2 Group IID in lungs of mice had been shown that it is linked with more than 80 %
lethality of SARS CoV in mice than mice with lacking PLA2 Group IID [53].
There are some studies done to evaluate the relationship between mortality of covid 19 patients with gender, sex, BMI, cholesterol
level, Asthma and cardiovascular diseases. By analyzing the results of those studies, it was observed that PLA2 showed an important
biological link in that patients.
One study had clearly shown that increased BMI levels were associated with higher risk of contracting SARS CoV-2 [54]. Higher
BMI level is associated with increased sPLA2 activity in patients with stable asthma [49]. There is also an evidence that serum PLA2
level is higher in both asthma patients with and without attacks, when compared to the control group [56]. Therefore it can be
suggested sPLA2 activity is interrelated in the patients having higher BMI and asthma towards the susceptibility of severe covid 19
[49].
While both men and women have the same prevalence to SARS CoV-2 without any gender discrimination, men is more susceptible to
face more complications and death [55]. Study [49] was evidenced the inverse correlation of sPLA2 activity with vitamin c
concentration in covid 19 patients. Interestingly the vitamin C concentration in plasma is lower in males than females [49]. It also
links with the severity of covid 19 in males with the correlation of increasing sPLA2 activity and the decrease in vitamin C content.
LpPLA2 is a member of the GVII family of PLA2 enzymes. This enzyme was named for its ability to cleave the acetyl group from
the sn-2 position of PAF, as well as its association with lipoproteins [57] . It was well established that increasing LPPLA2 is a reliable
marker for the risk of cardiovascular events. It had been evidenced that LpPLA2 level upregulation is mainly found in non-
hospitalized covid 19 patients. This abnormal increase LpPLA2 was observed in covid 19 re-positive patients as well [58], [59], [60].
Those patients are not showed promising symptoms of pneumonia, however sometimes they first experienced cardiovascular
symptoms [61]. The limited medical care of these patients may follow up cardiovascular diseases.
Another study was revealed that Increasing rates of LpPLA2 were positively correlated with not only viral loads in patients with
COVID-19 but also severity of pneumonia in non-COVID-19 patients. Therefore it could be suggested that increased levels of Lp-
PLA2 in plasma could provide insights to higher mortality was seen in patients underlying comorbidities (e.g. hypertension, diabetes
mellitus, cardiovascular disease) [62].
Moreover proteomics studies of covid 19 infected host cell showed a potential link with inflammatory response supported by
increasing of PLA2 at 24h after virus infection [63].
Above studies revealed the contribution of phospholipase enzymes to SARS CoV-2 into some extent. However, it would be further
investigated beyond the current understanding.
8. CONCLUSION
This review summarizes the PLA2 and its role in SARS CoV-2 infection. The increasing of phospholipase enzyme is linked with
progression of disease from mild to severe and it is related with other associated complications like pneumonia, cardiovascular disease
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and towards the mortality. Therefore, this valuable information has unveiled potential antiviral targets that are now starting to be
explored.
Further understanding of interfacial activation mechanisms of PLA2s on lipid surface will also uncover the new therapeutic target.
Future studies with larger number of subjects is need to develop novel PLA2 inhibitors as therapeutic target for not only for covid 19,
but also other related diseases. Optimization of existing PLA2 inhibitors will also be a good approach to develop therapeutics for not
only infectious diseases but also for non-infectious disease.
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AUTHORS
First author – D.V.D. Hemalika, Ph.D, Faculty of Natural Sciences, The Open University of Sri Lanka
dvhem@ou.ac.lk
Correspondence Author - D.V.D. Hemalika, Ph.D, Faculty of Natural Sciences, The Open University of Sri Lanka
dvhem@ou.ac.lk, mobile no: +94711358415
