Basic Biochemistry

Course code: GEB201

Department of Genetic Engineering and Biotechnology

Effects of COVID-19 Infection on cellular metabolism

Submitted to;
Dr. Suraia Nusrin
Chairperson, Assistant Professor,
Department of GEB

Submitted by;
Subarna Hoque Ria
ID: 2020-1-77-020
 Effects of COVID-19 Infection on cellular metabolism

Abstract:
Clinical remedies for infectious illness epidemics often focus on effective pathogen
elimination. However the recently discovered COVID-19 pandemic, serves as a reminder that
infectious diseases are complex, multisystem problems that require a good knowledge to enhance
survival. Metabolic processes are integrally linked to the mechanisms of disease pathogenesis
and the ensuing pathophysiology, as well as the host defence response to infection, in COVID-19
and all other infectious diseases. In this assignment, I tried discussing the link between cellular
metabolism and COVID-19 Infection, through drawing analogies between the pathophysiology
of these metabolic abnormalities and COVID-19 disease progression.

Introduction:
The novel human coronavirus disease 2019 also called COVID-19 was first reported in
Wuhan, China, in 2019, and subsequently spread globally to become the fifth documented
pandemic since the 1918 flu pandemic. By September 2021, almost two years after COVID-19
was first identified, there had been over 200 million confirmed cases and over 4.6 million lives
lost to the disease.

Metabolism appears to be a key regulator of COVID-19 susceptibility, recovery, and survival.

During infection, changes in host metabolism occur in the slightest degree levels, from cellular,
tissue to organs & physiological, because infectious illnesses and host metabolic processes are
inevitably linked. The virus hijacks the host cell machinery to facilitate viral replication and
enhance pathogenesis, and these modifications are most visible at the cellular level for COVID-
19. During infections, host metabolic responses at the tissue, organ, and physiological levels
occur and a few of those reactions reflects the host’s adaptive mechanisms to defend against the
infection.

Covid-19 effect on glucose metabolism:

SARS-CoV-2 is the virus that causes Covid-19 infection. It enters through the door of
angiotensin converting enzyme 2 (ACE2), which is expressed in key metabolic tissues. As a
result, the novel virus induces pleiotropic changes in glucose metabolism. Even though SARS-
CoV-2 infection is not predominantly a metabolic disease, COVID-19 progression has been
identified to be dependent on metabolic pathways. COVID-19 and other critical circumstances
increase the energy needs. SARS-CoV-2 needs to rewire cellular metabolism in order to produce
macromolecules necessary for replication, assembly, and survival. Extracellular acidification is
increased by viral proteins, indicating that it regulates glucose metabolism directly in addition to
modulating transcription. SARS-CoV-2 causes a shift in cellular metabolism from oxidative
phosphorylation to glycolysis, resulting in lower ATP production. Glycolysis and the
tricarboxylic acid cycle are two metabolic processes that produce adenosine triphosphate (ATP).
The disruption of glucose metabolism may play a key role in the spread of respiratory pathogenic
viruses. In a study, the use of oxygen supplementation at the onset of COVID-19 was suggested
as a way to restore the imbalanced glucose aerobic metabolism (Mahrooz et al., 2021).

Recent study shows that pyruvate produced from glucose during Glycolysis was fermented to
lactate in COVID-19 patients under anaerobic conditions, resulting in the creation of limited
amounts of ATP. SARS-CoV-2 viral replication in infected cells, on the contrary, consumes a lot
of cellular ATP. Lactate failed to be processed through gluconeogenesis as this state persisted,
resulting in increasing blood lactate concentrations in COVID-19 patients. On the other hand,
Under aerobic conditions, glucose can also be oxidized via the pentose phosphate pathway,
which results in the production of NADPH. It is essential to maintain the right ratio of oxidized
glutathione to glutathione, which is important for the defence system and helps the immune
system fight invasive infections. During SARS-CoV-2 infection, the depletion of GSH caused by
the inhibition of the pentose phosphate pathway leads to oxidative damage. Furthermore, a lack
of glucose-6-phosphate dehydrogenase, a crucial enzyme in the pentose phosphate pathway,
could lead to cell death and the release of inflammatory cytokines, as shown in COVID-19
infection (Mahrooz et al., 2021; Smith et al., 2021).
 Fig. 1 SARS-CoV-2-induced alterations in glucose metabolism.

Glucose metabolism was found to be a driving force behind the start of the often-lethal
inflammatory response known as a cytokine storm in a mouse study of influenza A virus
infection. Glucosamine-treated animals produced considerably more inflammatory cytokines and
Chemokines than glucosamine-untreated mice. Researchers discovered that the hexamine
Biosynthetic pathway, which metabolizes a small percentage of glucose, plays an important role
in the cytokine storms induced by the influenza virus when they compared blood glucose levels
in patients with influenza A and healthy controls. These findings may help to explain why
diabetics are more likely to develop major complications and die from illnesses like influenza.
The study suggests that the same case appeared in covid-19 infection as well (Pirelli & Lapolla,
2020). There appears to be a direct link between coronavirus infection and T2DM (Type-2
Diabetes Mellitus), in addition to a link between coronavirus infection and hypertension. The
SARS coronavirus binds to its receptor, ACE2, in the pancreas, which destroys islets and lowers
insulin secretion (Bornstein et al., 2020; Codo et al., 2020).

Covid-19 effect on amino acid metabolism:

A metabolomics analysis revealed dysregulation of pathways connected to energy
generation and amino acid catabolism (threonine, glutamine, and Glutamate) in COVID-19
patients. Infected patients had a significant increase in three different α hydroxyl acids linked to
valine and threonine catabolism, leading to the hypothesis that the α-KA derived from these
amino acids become the final electron acceptors through the activity of their corresponding α-
keto-acid oxidases in hypoxic patients. As a result, enhanced transaminase activity, could be
linked to an increase in serum glutamate in COVID-19 patients. COVID-19 patients had lower
levels of several amino acids as well as glyceric and citric acid, according to a study. Infected
patients, on the other hand, had higher levels of three different α-hydroxyisovaleric acid, α-
hydroxybutyric and 2,3 dihydroxybutanoic acid, and malic acid, as well as two amino acids.
Patients with mild and COVID-19, as well as controls, had different expression levels of
pathways related to BCAA, glutamate, and phenylalanine metabolism. The researchers also
discovered that BCAA metabolism differed amongst the groups investigated, and that glutamine
and glutamate metabolism had a significant impact on the metabolic profile of COVID-19
patients. In serum, samples from mild and severe COVID-19 patients, abnormal amounts of
amino acids, Krebs cycle mediators, and α-HA were discovered (Páez-Franco et al., 2021).

Several studies have suggested that adding enteral L-glutamine to regular nutrition reduces
hospitalization time and improve outcomes in mild to severe COVID19 cases. Two additional
amino acids, Citrulline and ornithine, implicated in arginine degradation via the Urea cycle,
differs significantly between the acute and recovery stages. Changes in L-arginine levels, on the
contrary, were not seen. Low blood plasma Citrulline levels have already been recorded in
COVID-19 patients, whilst decreased Citrulline levels have been linked to acute respiratory
distress syndrome in patients with severe sepsis. Because arginine can be converted to creatine
and then to creatinine, both of which vary greatly in our study group based on routine blood tests
performed during hospitalization, arginine catabolism could be a factor in COVID-19 patients’
impaired kidney function. 3 out of 22 metabolites showing significantly changed levels between
acute infection and recovery phase are involved in the tryptophan-kynurenine pathway:

L-tryptophan, kynurenine, and 3-hydroxy-DL-kynurenine. 3-hydroxyDL-kynurenine

was the marker with the most pronounced fold change between the acute and recovery phases.
The acute phase results in a decrease in tryptophan levels and an increase in kynurenine and
3hydroxy-DL-kynurenine, confirming prior findings and confirming this pathway’s importance
in severe COVID-19 cases. Dysregulated tryptophan metabolism, an important regulator of
inflammation and immunity, may be a possible explanation for severity in older COVID-19
patients, according to a study (Ansone et al., 2021). COVID19, IL-6 levels, amino acid
metabolism, purines, acylcarnitines, and fatty acids are all linked by hierarchical clustering
analysis. Using metabolite set enrichment analysis of integrated targeted and untargeted
metabolomics data, COVID19 was revealed to have a significant impact on five amino acid
metabolism pathways. Creatinine, Creatinine, and the polyamines spermidine and acetyl-
spermidine are all elevated in COVID-19 patients with moderate-to-high levels of IL-6 (Asim et
al., 2020).

Covid-19 effect on lipid metabolism:

Enteric symptomology seen in early-stage severe acute respiratory syndrome and
COVID-19 is evidence of virus replication occurring in the intestine, liver and pancreas.
Aberrant lipid metabolism in morbidly obese individuals adversely affects the COVID-19
immune response and increases disease severity. Such observations are in line with the
importance of lipid metabolism in COVID-19, and point to the gut as a site for intervention as
well as a therapeutic target in treating the disease. Formation of complex lipid membranes of
coronavirus proteins are essential during viral replication and assembly. Inhibition of fatty acid
synthase (FASN) and restoration of lipid catabolism by activation of AMP-activated protein
kinase impede replication of coronaviruses closely related to SARS-coronavirus-2. In vitro
findings and clinical data reveal that the FASN inhibitor, orlistat, and the AMPK activator,
metformin, may inhibit coronavirus replication and reduce systemic inflammation to restore
immune homeostasis. Such observations, along with the known mechanisms of action for these
types of drugs, suggest that targeting fatty acid lipid metabolism could directly inhibit virus
replication while positively impacting the patient’s response to COVID-19.
 Fig. 2. Entry of SARS-CoV-2 into the host cell

During bacterial, viral, and parasitic infections, significant changes in metabolic regulation, have
been reported. HDL and apoA-I, have pleiotropic properties, including cholesterol transport,
neutralisation of lipopolysaccharide (LPS) and lipoteichoic acid (LTA), anti-inflammatory, anti-
thrombotic, anti-oxidative, anti-apoptotic, and endotheliocyte protection. Reduced HDL and
apoA-I concentrations have been linked to a poor prognosis in patients suffering from sepsis,
pneumonia, and other infections. LDL-C, TC, and HDL-C concentrations in COVID-19 patients
have recently dropped dramatically but alterations and impacts of lipoprotein and apolipoprotein
concentrations, as well as dynamic changes in lipid profiles in severe COVID-19 patients, have
been seldom described. Lipid metabolism is heavily reliant on the liver, and liver impairment
caused by SARS-CoV2 infection or prospective medications has an impact on lipid production.
Hepatic dysfunction was seen in 14 percent to 53 percent of COVID-19 patients, mainly in
severe and serious cases. A severe inflammatory response may also result in capillary leakage,
resulting in the leakage of lipoproteins and apolipoproteins particles from intravascular to
extravascular compartments. In our research, we discovered that HDL-C and apoA-I were
closely linked to the inflammatory marker CRP, which could help to explain the link between
hyperlipidaemia and inflammatory response in COVID-19 patients with severe COVID-19.
Finally, a recent study found that an uncommon missense mutation in the cholesteryl ester
transfer protein gene is linked to a significant drop in HDL-C levels and a poor prognosis during
sepsis. When compared to non-carriers, COVID-19 patients who carry the A allele may have a
lower HDL concentration and a worse prognosis (Kočar et al., 2021; Li et al., 2021). Low HDL
cholesterol (HDL-C) and sometimes low LDL cholesterol (LDL-C) levels are commonly
associated with infectious disorders, although triglyceride levels are usually maintained or even
raised. Low levels of HDL-C have been suggested as a risk biomarker for a variety of illnesses.
In the case of SARSCoV-2 infection, low LDL-C, HDL-C, and triglyceride (TG) levels have
been linked to increased infection severity (Masana et al., 2021).

Summary:

When it comes to infectious-disease pandemics, it's more important to consider when the
next one will strike, rather than if one will strike at all. It's unlikely that viable vaccines or
antimicrobial-based techniques will be available to combat the next outbreak; the 'enemy' will
remain unknown until it strikes. Supportive treatment has been the first line of defence in each
pandemic, promoting patient illness tolerance and allowing patients to recover from infection.
The pathology of infectious-disease outbreaks has remained consistent over the last century,
despite the fact that the pathogens have changed. The COVID-19 pandemic has acted as a stark
reminder that our understanding of infectious diseases must widen. To understand how
pathology originates, how physiological function changes as a result of the damage, what ways
we may use to guard against pathology, physiological dysfunction, and the immune response,
and how to eradicate the pathogen, we need to take a more holistic approach to infectious
diseases. We must start building disease-tolerance-based measures now, so that when the next
pandemic strikes, we will be prepared.

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