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Author: Arnab Kumar Ghosh

Designing of vaccines and immunostimulating agents against COVID-19: A novel approach for human welfare

Student co-ordinator:  Subidita Pal, Saloni Ghosh, (Students of UG VI B.Tech in Biotechnology)

Introduction

Our universe is currently facing a huge crisis due to the outbreak and challenges of COVID-19 globally. This virus which was identified in Wuhan Market, China in December 2019 uses the bat as the natural host. More than 233,000  persons died worldwide as of May 1, 2020. The identification of coronaviridae was done in the middle of 1960, which infected humans and a variety of mammals.  Two coronaviruses (can cause infection of higher animals) were evolved since 2002 and showed outbreaks in humans: the first one was discovered at south China in 2003, i.e. SARS-CoV (Severe Acute Respiratory Syndrome Coronavirus), and the later one at Saudi Arabia in 2012, which is MERS-CoV (Middle East Respiratory Syndrome Coronavirus). The recently discovered coronavirus is identified is known as SARS-CoV-2 and the disease associated with it is called or coronavirus disease 19 (COVID-19), a type of respiratory illness. The World Health Organisation(WHO) declared the disease mediated by this virus as pandemic on 11th March 2020 due to its pattern of spreading throughout the universe.

SARS-CoV-2 carries a positive-sense single-stranded RNA as its genome. Infection by this virus is usually spread between individuals of the human population through close contact and via respiratory droplets produced from coughs or sneezes, which indicates its highly contagious nature. The symptoms of the disease can range from mild to severe.  Individuals who are infected with the virus take 1 to 14 days to develop the symptoms. It enters into the human cells by binding to (ACE2) within the cytoplasm of the target cell.

Initiatives taken to discover the vaccine

Scientific researches are also running to fight against this virus are two different approaches: Vaccination and improvision of antibody-dependent cell-mediated cytotoxicity(ADCC).

The vaccine will be the ultimate weapon through which the whole world needs to fight this outbreak. On the other hand, the defense system of the human body is capable of generating immune response through the activation of both cell-mediated and humoral immune system upon recognizing and engulfing the foreign antigenic particles. Researchers throughout the world are studying to initiate a natural physiological mechanism within our body, which will make our body to become capable to eliminate this deadly virus. It nearly takes 12-18 months to invent a vaccine but our researchers are trying to achieve success within a small period although they need to be very efficient to avoid the spoil of work in haste.

Oxford University, Europe had its first human trial of Coronavirus vaccine. BothSARS-COV-1andSARS-COV-2arecloselyrelatedviruses.ButthevaccineforSARS-COV-1wasnotdevelopedproperly.ThecurrentcrisisdemandsoneforSARS-CoV-2.They are highly confident and optimistic about its chances. By the end of 2020, it is believed that the markets would launch vaccines in a small amount across the globe, where the success rate is still questionable for the kids and aged people. Most recently Italy developed a vaccine and passed. They injected the vaccine in mouse and it generates antibody which blocks the viral protein.

Discussion

“Better late than never” i.e. all outstanding and beneficial discoveries in the scientific field take time. Till then we need to boost up our immunity by exercising and treating the human body with natural household remedies to ensure prevention. This is the time where we have to come together as a community, take the initiative to prevent the transmission of disease from the infected person to noninfected person, to help the doctors(are involved in the treatment of COVID-19) and scientists(are involved to design vaccine and immunotherapeutics). In this way, the life-threatening condition that is mediated by the SARS-CoV2 can easily be overcome by us, which will be accompanied by a glorious sunrise of the corona free world.

COVID-19 induced alveolar damage: Protection by melatonin through multiple molecular dimensions

Student Contributors: Manisha De, Shashanka Debnath, Deblina Chakraborty, Indranil Chowdhury (UG VI of B.Sc in Biochemistry)

Introduction

In recent times, the well-known pandemic COVID-19 has been the most devastating event, taking away the lives worldwide of not less than lakhs in number. But among the population where there are individuals of diverse ages, it is observed that the virus induces relatively minor damage in the young persons compared to the healthy populations, imposing the later to a life-threatening consequence. Elderly aged population, possessing a comparatively lower level of Melatonin are found to be at a high risk of infection.

Melatonin i.e. N-acetyl serotonin, secreted from the pineal gland located on the third ventricle of the brain, possesses several important physiological functions in mammals including widespread anti-inflammatory, anti-oxidant, and reactive oxygen (ROS) and nitrogen species (RNS) scavenging actions(Figure 1). Also, melatonin can increase the activity of the electron transport system in mitochondria, thereby restricts unwanted electron leakage and ROS generation. Thereby, we can try to think about a distinct relationship between the loss of lives due to the pandemic and the pineal secretory product- melatonin.

Figure 1

Molecular mechanisms through which melatonin can protect against COVID-19

  • Melatonin as an anti-oxidant:

The fatal consequences due to infection of alveolar tissue with SARS-CoV 2 are associated with oxidative stress characterized by elevated levels of ROS or RNS and melatonin is the promising endogenous antioxidant. But melatonin is observed to be lost with age. One molecule of melatonin can bind with 10 free radicals maximally. Melatonin scavenges the hydroxyl radical(•OH) i.e. a potent mediator of peroxidation of membrane lipids, carbonylation of proteins, and DNA damage, which results in the damage of alveolar tissue. It is also known to detoxify cell-damaging radicals like superoxide anion radical(O2•–) nitric oxide (NO•). Moreover, SARS-CoV induces oxidative stress; which in turn, induces  PLA2G2D phospholipase synthesis; at an abnormally high concentration which can reduce the immunity against a viral antigen, thereby making the biochemical situation more lethal to the human. Also, melatonin inhibits inducible nitric oxide synthase(iNOS) and stimulates several antioxidant enzymes like superoxide dismutase, glutathione, catalase, glutathione peroxidase, and glutathione reductase supporting its indirect antioxidant action. On the other hand, Melatonin is also a good preventor of fibrosis which is the most fatal consequence in COVID-19 patients.

Melatonin is further observed to reduce oxidative stress by recycling the glutathione(GSH) level in the body which gets reduced during the excess oxidative stress condition. During this, oxidation of GSH to its dimerized form occurs, GSSG. Melatonin stimulates the Glutathione reductase(GR) enzyme which quickly converts GSSG to form GSH(through the reduction/hydrogenation of disulphide linkages) again by the action of the rate-limiting enzyme, gamma-glutamylcysteine synthetase. Furthermore, Melatonin can donate one or more electrons to free radicals detoxifies them. In this situation, melatonin becomes a free radical itself, which doesn’t possess any toxicity to cells.  Metabolites that are formed during this process are Cyclic3-hydroxymelatonin (c3OHM), N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK). This oxidation process results in the formation of several hydroxylated products which proves the binding of melatonin with diamagnetic hydroxyl radicals, that is indicating towards the construction of never-ending antioxidant cascade in the cells of the mammalian system.

  • The inhibitory action of melatonin against ROS generation:

 ROS generation is a major factor for lung injury during COVID-19 infection as a result of mitochondria, where the molecular oxygen(O2) is reduced to water via electron transport chain(ETC), which is the main source of ROS generation due to its primary target of ATP production. In mitochondria, there is several sites where superoxide radical(O2•–) are produced including complex I, complex III, glycerol 3-phosphate dehydrogenase, , pyruvate dehydrogenase, and 2-oxoglutarate dehydrogenase. Mn-SOD(Mn-Superoxide Dismutase) (mitochondrial)and Cu-Zn-SOD(Cytosolic) converts the superoxide radical into hydrogen peroxide(H2O2). The H2O2 in the mitochondrial membrane is also converted into hydroxyl radical(OH•) via a Fenton reaction catalyzed by mitochondrial aconitase. The cytosolic catalytic cycle is another site for the production of ROS.

During COVID-19 infection, increased oxidative stress inhibits mitochondrial Kreb’s cycle enzymes, and ETC associated enzymes of the lung that results in free electron leakage and increases the ROS level. As a result, the intensity of alveolar tissue damage will increase due to the persistence of inflammatory signaling.

Several studies had shown that Melatonin and its metabolites not only stimulate the activity of SOD for scavenging the ROS generation but also stimulates the proper activities of ETC associated enzymes and Kreb’s cycle enzymes(at nM to µM concentration in vitro system) and blocks the free-electron leakage and the formation of excess ROS.

  • Melatonin also induces the antioxidant enzyme encoding genes through G-protein coupled receptor(GPCR):

Melatonin binds to its transmembrane bound GPCR(comprised of α, β and γ subunits )(MT1 and MT2). Upon binding, the Gα sub-unit dissociates from GPCR transmembrane receptors and activate phospholipase C-β, to phosphorylate and activate the JAK-Erk complex, which in turn increase the Nrf2 expression level through SIRT-1 activation, upon entering into the nucleus which increases the expression of the genes encoding the antioxidant enzymes.

  • Melatonin and its anti-inflammatory action:

Inflammation of alveoli of the lung is one of the major hallmarks of COVID-19 patients. In the case of coronavirus, its ssRNA is first detected by TLR7(Toll-like receptor 7) and is then directed for lysosomal degradation. It then activates the Type 1-Interferon reaction and releases many other pro-inflammatory cytokines [IL-1β, IL-2, IL-6, IL-8, both IFN-α/β, Tumor necrosis factor(TNF), C-C motif chemokine 3(CCL3), CCL5, CCL2, etc]. But in some cases, excessive generation of pro-inflammatory cytokines might lead to ‘cytokine storm’ causing host cell damage and thus, inducing acute lung injury(ALI)/acute respiratory distress syndrome(ARDS) or even death. Therefore, to decrease mortality, the inflammation needs to be suppressed. The anti-inflammatory properties of melatonin suppress this following consequences of inflammation:

  1. TLR recognizes PAMP(pathogen-associated molecular pattern), thereby initiates the signaling cascade to create inflammatory responses by the induction of the gene encoding TLR2, TLR4, TLR9. Melatonin downregulates the expression of the mentioned TLR encoding genes to suppress inflammatory responses.
  2. At the lower concentration, melatonin reduces the expression of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-8(which are induced during COVID-19 infection) and increases the rate of expression of anti-inflammatory cytokine IL-10.
  3. Melatonin also suppresses activation of NF-κβ, which would otherwise mediate inflammation, by downregulating its activation in T-cells and lung cells.
  4. Elevated activity of NOD-like receptor 3(NLRP3) inflammasome leads to amplification of inflammatory responses. Melatonin can repress NLRP3 inflammasome activation.

 

Discussion:

             The endogenous melatonin may possess the ability to protect ourselves, but its concentration is not sufficient to combat against inflammation-mediated ROS generation, so if the people take the melatonin tablet(an available form is “Meloset-3 mg”), then it can protect human being by the mechanisms as mentioned above. On the other hand, some recent research works showed that melatonin inhibits the electron leakage from the ETC is generally accompanied by an increase in the activity of cardiac mitochondrial ATP synthase activity resulting in the higher synthesis of ATP, i.e. enabling higher energy to sustain life without any side effects. So, by enhancing the energy metabolism in heart, melatonin provides not only the support life of COVID-19 patients but also provides the time to the medical practitioners for providing proper treatment and healthy life to the SARS-COV2 infected patients. Therefore, it further suggests that melatonin due to its high redox potential produces a beneficiary effect not only on the mitochondrial complexes but on the overall physiological system and thereby able to protect the human being from the present global life-threatening situation.

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