Oxidative Cascade Prognosis, Antioxidants & Selected Trace Elements in COVID-19

COVID-19 pandemic has now become a challenging global public health concern, having higher risk of developing fatal respiratory disease due to severe inflammatory responses associated with the virus-mediated oxidative stress. The respiratory system is most preferred target organ for this novel virus as the lung is well oxygenated and having large surface area available to the virus for exposure and successively augmenting the health complications. Oxidative stress (OS) is an important factor causing metabolic and physiological alteration and various disease augmentations within the body. Respiratory viral infection has general consociation with cytokine production, inflammation, cell death and other pathophysiological processes which may be the result of perturbed redox balance. Apart from this, the presence of conditions likes aging, diabetes and hypertension and chronic obstructive pulmonary diseases (COPD) are the risk factor for making severity of such infection outcome. It has been well established that an overproduction of reactive oxygen species (ROS) and antioxidant mechanisms deprivation are vital step for viral replica production and consequent release of pro-inflammatory cytokines is also an important factor of the innate immune responses to the pathogens that may result into acute lung damage. Additionally, ROS can damage various vital biological molecules and inactivation of essential enzymes. Oxidative stress is an important factor causing metabolic and other pathophysiological alterations, such as protein oxidations and various associated diseases. Therefore, in this paper, the significant adverse impact of virus on host cell and underlying possible biochemical mechanism has been discussed.


Introduction
Serious health issues and deaths associated from novel COVID-19 pandemic are now global public health concern originated from China in 2019. Corona virus is single stranded RNA virus that affects the respiratory system in human. Such notorious viruses exploit the host defense mechanism in various ways for their replication and infections [1] [2]. There is a key role of an imbalance of the redox cascade conditions during viral infections [3]. Lung inflammation is the main target organ as respiratory disorder at severe stage of such respiratory viral infections is, in general, associated with the impaired redox homeostasis or oxidative stress (OS). Inflammation is an important protective phenomenon responsible to cellular or tissue damage. The main function of this process is to destroy and remove the harmful agent and damaged tissues, therefore enhancing tissue repair. Whenever this vital and normally beneficial response takes place in an uncontrolled way, the result is extreme cellular or tissue damage that comes out in the form of chronic inflammation and destruction of normal tissue. Many pro-oxidants such as the superoxide anion one of the important reactive oxygen species (ROS), generated by phagocytes deployed to sites of inflammation, are proposed to be a major cause of the cell and tissue damage, comprising apoptosis, associated with many chronic inflammatory diseases [4] [5]. Alveolar epithelial type II cells present in lung cells, in particular, are highly susceptible to the injurious effects of oxidants. The primary site of influenza virus infection in mammals includes pseudostratified, ciliated, columnar epithelium of the upper respiratory tract [6]. Influenza virus infection of the pulmonary mucosa could have important influence on airway functions, and, this mechanism is still merely understood. The cytopathology of replicating influenza virus in the airway epithelium can disrupt normal cellular architecture and morphology. After entering the host cell through any mucosa, the virus will undergo significant changes such as fusion, endocytosis and cytolysis, which will cause new virions to enter the host cell, resulting in the release of a large amount of pro-inflammatory cytokines and the change of cellular redox status.

Viral Infection and Perturbed Redox State
Oxidative deterioration of biomolecules like lipids, proteins, and DNA [7] has been reported since long time. The reactive intermediates include the superoxide anion ( 2 O − ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radicals (OH . ) all are referred as reactive oxygen species (ROS) and very reactive in nature. Each ROS has been shown to have different inherent chemical properties, which guiding its reactivity and most favored biological targets. It has been observed for H 2 O 2 that can regulate the signaling pathway by oxidizing thiols moiety within proteins [8]. There are many enzymes that can bring back this oxidation to return the protein to their natural reduced state. This is very similar to the process of phosphorylation and dephosphorylation-dependent signaling pathway very common in redox biology. The levels of H 2 O 2 involved with signaling cascade Open Journal of Applied Sciences may range from picomolar to nanomolar concentration and the higher concentration may cause proteins to be inactive by hyperoxidizing thiols moiety the concerned protein [9]. Redox signaling brings up the thiol oxidation-dependent signaling changes, whereas oxidative stress refers to damage of lipids, proteins, and DNA or disruption of thiol-dependent signaling and inactivation of essential enzymes.
There is undoubted report available showing that oxidative stress is almost inevitably associated with various toxicities, the first phenomenon in many diseases that may results into multi organ failure and death. The imbalance between reactive oxygen species (ROS) production and their effective removal by antioxidants and ROS scavengers has been in consideration since long to contribute many pathological conditions for critical illnesses such as acute respiratory distress syndrome (ARDS), pulmonary fibrosis, sepsis and many others. Thus, oxidative stress has drawn much arousing interest as therapeutic target in critical illness, and antioxidants have been tested in critically ill patients for decades. It is also important to mention that ROS serve as crucial signaling molecules for cell homeostasis and adaptation to the various cellular stress such hypoxia and many others, processes that may be related to perturbed mechanism of antioxidants system [10].
Furthermore, Oxidative stress has been found to be implicative in several diseases such as diabetes and cardiovascular disease. Recent evidence has shown that ROS can play an important role as secondary messengers in signal transduction pathways [11] [12]. Cell has been equipped with a number of many enzymes like catalase, glutathione peroxidases, thioredoxin reductase, and superoxide dismutase available to overcome the oxidative stress conditions. These include. The cell also possesses a variety of lower molecular weight molecules such as tripeptide glutathione (GSH) that can counteract the harmful effects of ROS. Glutathione is present at very low concentration (millimolar) in the cell [13], is an important in detoxification pathways via glutathione transferases enzyme systems [14], and is vital for sustaining the redox potential of the cell. It is now well understood that the redox potential of the cell can regulate the activation of many genes through triggering the transcription factors including nuclear factor (NF-κB) and activator protein (AP-1) that are important for immune function [15] [16], antioxidant defense [17], and induction of apoptosis [18] [19].

Interferons and Chemokines Generation in Response to Oxidative Stress
More recently, it has been well established that the level of oxidative stress is also very vital factor for the immune responses to viruses. Both types of immunity (innate and acquired) are required to fight any viral infection, responsible for morbidity and mortality in critically ill patients suffering from diseases. It has been reported in one of the finding during in vitro and in vivo study that Den-  [20] and alteration in redox state increases the disease severity [21].
In response to oxidative stress, lung cells have been found to liberate many in-

Glutathione (GSH) against Inflammatory Responses
In one of the study it has been observed that when whole blood culture of HIV positive individual infected with Mycobacterium tuberculosis, there was an increased release of inflammatory mediator cytokines such as IL-1, TNF-α, IL-6.
However, there was interesting finding was reported in reduction of these proinflammatory cytokines (IL-1, TNF-α, and IL-6) when whole blood culture was supplemented with GSH precursor N-acetyl cysteine (NAC) [24]. High levels of such pro-inflammatory cytokines may have detrimental effect to the host because it may result to augmentation of fever, cachexia, hemorrhagic necrosis, and lethal shock [25] [26] [27]. Furthermore, the macrophage activity may be affected with the increased level of proinflammatory cytokine like IL-6 and may be deleterious to the host cell.
The mechanisms by which pro-inflammatory cytokines decrease intracellular GSH may be in response to increased levels of free radicals. It has been observed that increases in pro-inflammatory cytokines and an increase of free radicals are proportionally correlated which is targeted by free GSH responsible for counteracting the adverse effects in host cells. In individuals positive for HIV, there is large number production of pro-inflammatory cytokines, which results into decrease in GSH because the antioxidant is being depleted as it is involved in scavenging free radicals. Furthermore, increased number of IL-1 may also participate in reducing the intracellular GSH as it is accepted that IL-1 fasten the process of depletion of intracellular cysteine thus decreasing GSH generation and decreasing levels of GSH [28].
Human subjects infected with the HIV have shown to have lower levels of GSH in their macrophages, NK and T cells compared to individuals [29] [30] [31]. It has been reported the contribution of GSH to be involved through different mechanism to enhance the functions of NK and T cells, acts as an anti-

Role of GSH in Immune Responses
In the redox state counter balance, GSH is found to be key intracellular antioxidant that exerts an efficient protection against ROS, through the thiol group of its cysteine where oxidation (GSSG) and reduction (GSH) takes place by the enzyme glutathione reductase. Moreover, it has also important role in cellular signaling processes and the mechanism comprising innate immune responses to viruses [36] [37] [38]. GSH is essential to combat pathogens growth and their attack to human body including T-lymphocyte proliferation [39] [40], phagocytic activity of polymorphonuclear neutrophils (PMN) and dendritic cells [41].

Most of the basic interactions between acquired and innate immune cells are in
the form of peptide antigen presentation representing major histocompatability complex formation. Important role of GSH has been for the first step in antigen degradation and processing is the reduction of disulfide bond which requires [42] [43]. GSH has been shown to alter cytokine expression specifically by enhancement through NAC [28] [44] [45] and γ-glutamyl cysteine synthase [46].

The specific role of GSH functions in adaptive immune cells is an important
phenomenon to understand the correlation between the absence of intracellular glutathione and its reduced ability to remove the microbial infection by host cell.

GSH and Its Effectiveness for Other Viral Infections
Viral pathophysiology mechanism is reported to be associated with disruption of the redox status of the cell in favor of oxidative stress which results into disturbed function of GSH [47]. Reduced form of the GSH is a major intracellular redox biological molecule that plays a vital role in protecting cells against damage from oxidants [48]. Viral infection studies had shown that oxidative stress and a decreased level of intracellular GSH occurs together in the host cells after infection such as HIV, hepatitis C [49], herpes simplex type 1 [50], Sendai (parainfluenza) virus [51], rhinovirus [52] and influenza virus [53].
A murine model of influenza-A virus infection has shown the loss of reduced GSH in vivo [54]. It has been observed that the virus alone has not been able to show cytopathic effect on the epithelial cells lining of the respiratory tract and complicated pneumonia resulted from infection has not been explained properly [55]. Therefore findings support the hypothesis that the tissue damage may be due to the host itself inflammatory response to the virus and not directly from the virus. It is further suggested that the effector mechanisms involved in the  [56]. ROS themselves also impart their role to the damaging effect in the lungs cells after viral infection by oxidation of lipids and damaging cell membranes, proteins and nucleic acid [57] or inactivating vital antioxidant enzymes [58]. Further it was also observed a decrease in total GSH, increased GSSG during this disturbed mechanism and apart from this an increased level of malondialdehyde, which is a biomarker of lipid peroxidation [59] in bronchoaleveolar lavage (BAL) fluid from mice infected with influenza virus.

Viral Infection and Cellular Deprivation of GSH
Intracellular GSH depletion has already been reported in various viral infections through multiple mechanisms. Cellular GSH loss has been reported with Sendai Secondly deprivation of GSH after viral infection associated with viral replication and infected cells have been found to show a decrease in GSH content and an increase in mixed disulfide complex formation [51]. It supposed that the second expiration of GSH during viral replication is because of the rapid incorporation of cysteine amino acid into the viral gene RNA proteins [50] [62] [63].
There is clear evidence that an increased oxidative state favors the cellular environment for viral replication and it is also observed that the administration of the antioxidant dithiothreitol (DTT) to maintain high GSH levels in the cells resulted in a decrease in virus production. It was speculated that the higher GSH levels can inhibit the formation of mixed disulfides compound and results in the production of inactive virus by inhibiting the folding process of viral proteins [64]. There are well studied reports having evidence that decreasing GSH with a mixed disulfide-forming agent resulted in an increase in viral replication [51].

Viral Infection and Role of Trace Elements
Malnutrition has shown its impacts on increased susceptibility to various infectious diseases. The malnourished host believed to be susceptible for contagious disease that may results into impaired immune responses, which could influence the immune responses by inducing potential ability to counter the challenges of contagious disease [65].  [67], support healthy immune system. Sufficient zinc level is necessary for the division of T-cell their maturation and differentiation. The immune system is supposed to be badly affected if zinc deficiency occurs [68]. Zinc may induce the synthesis of metallothionein, sulfhydril rich protein that protect against free radicals [69].

Conclusion
There is a demand of understanding the redox-regulated intracellular pathways rendered active and manipulated by the virus. Therefore, a new approach is required to inhibit the cell pathways that are responsible for viral replication and to combat the serious health issues. Furthermore, antioxidants possibly interrupt the normal signaling processes that control the usual response to intense infection. The virus-induced oxidative stress through various mechanisms is attributed to the production of proinflammatory cytokines IL-1b and IL-18, which are crucial for host defense to pathogens. Widely used precursor of glutathione such as NAC has been found to reduce the over activation of signaling process