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Cover page of the Journal of Health Sciences

 Table of Contents  
Year : 2022  |  Volume : 15  |  Issue : 3  |  Page : 204-210

Immunological characteristics of CoVID-19 and its implications

1 Department of Biochemistry, Medical College, Kolkata, West Bengal, India
2 Department of Community Medicine, MGM Medical College and LSK Hospital, Kishanganj, Bihar, India
3 Department of Pharmacy, Birla Institute of Technology and Science, Pilani – Hyderabad Campus, Hyderabad, Telangana, India
4 Department of Critical Care Medicine, Critical Care Unit, Centro Policlinico del Olaya, Bogota; Center of Biomedical Research, Universidad de Cartagena, Cartagena; Colombian Clinical Research Group in Neurocritical Care, Bogota, Colombia
5 Department of Anatomy, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, Karnataka, India
6 Department of Neurosurgery, General University Hospital, Valencia, Spain
7 Department of Neurosurgery, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India

Date of Submission08-Feb-2022
Date of Acceptance21-May-2022
Date of Web Publication17-Sep-2022

Correspondence Address:
Dr. Amrita Ghosh
Department of Biochemistry, Medical College, 88 College Street, Kolkata - 700 073, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/kleuhsj.kleuhsj_126_22

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CoVID-19 is the most formidable unequaled global challenge invading 220 countries and territories in this millennium to uncountable saga of mortality, disability as humanity is witnessing devastation of socio-economy with more than 4 million deaths till date. The natural history of CoVID-19 from transmission through varied clinical features to overt complications is still under global research and research groups are on the run to trace its ramifications. This ranges from primary involvement of the pulmonary system to multisystem involvement through web of immunological pathways associated with susceptibility, clinical presentations, and severity of COVID-19. It has been hypothesized that the safe and effective mass vaccination program across the globe can ensure flattening of the pandemic curve to prepandemic normal life. This research group explored the basic and applied researches on molecular and immune mechanisms of SARS COV-2 virus. A sincere attempt has been made in futuristic research vision to find potential strengths, shortfalls, and efficacy of the plant-based immunotherapy, antibodies, and vaccine. Different research groups have hypothesized for the best possible use of these indigenous, stable, secure, efficacious natural products by searching their potential to accomplish emergency demands in this trying time. There is an urgent need to understand the inherent immunological predictors of the natural history of the disease spread over the spectrum from mild to severe forms of the disease and harp on these issues. In the wake of multiple waves with worse situations of evolving clinical features with the “variants of concern” and “variants of interest” and innovative interventions, this research group believes in optimum mix of microbial-derived biologicals with immune modifying drugs will broaden the preventive and curative spectrum.

Keywords: CoVID-19, immunology, phytochemicals, plant-based immunotherapy

How to cite this article:
Ghosh A, Pal R, Dominic RE, Mittal M, Moscote-Salazar LR, Murlimanju BV, Cincu R, Agrawal A. Immunological characteristics of CoVID-19 and its implications. Indian J Health Sci Biomed Res 2022;15:204-10

How to cite this URL:
Ghosh A, Pal R, Dominic RE, Mittal M, Moscote-Salazar LR, Murlimanju BV, Cincu R, Agrawal A. Immunological characteristics of CoVID-19 and its implications. Indian J Health Sci Biomed Res [serial online] 2022 [cited 2023 Jan 28];15:204-10. Available from: https://www.ijournalhs.org/text.asp?2022/15/3/204/356263

  Introduction Top

Research groups are relentlessly working on effective vaccines, therapeutics, and antiviral drugs to halt this pandemic. Plant products have been innovatively hypothesized as potential resources for vaccines, monoclonal antibodies (mAbs), drugs, immune-modulators, and pharmacologically active molecules.[1] In the link between disease severity, viral multiplication, and cytokine release syndrome trail is still unclear, what triggers onset and its progression to fatal outcomes in patient subsets;[2],[3] how otherwise natural protective cytokine response against infection turn into a lethal pathogenesis by sharp reduction of NK cell and elevations of D-dimer, C-reactive protein, ferritin, procalcitonin levels;[4] neutrophils compared to lymphopenia, liver enzymes, interleukin (IL)-6, lactate dehydrogenase, prothrombin time, troponin, and creatine phosphokinase.[5],[6] Most accepted hypothesis zeroed on initial viral binding to the angiotensin-converting enzyme 2 (ACE2) receptors of pulmonary alveolar epithelial cells to instigate cascade effects by augmented immune response and toxicity with associated morbidity, disability, and mortality[7],[8] affecting kidneys, heart, and intestines leading to multiple organ dysfunction syndrome termed as “cytokine release syndrome”[9],[10],[11] with cognitive decline and higher risk of neurodegenerative sequel among survivors.[12],[13] Hospitalized serious CoVID-19 children and adolescent have reported comparable “Multisystem inflammatory syndrome in children.”[14] This research group aimed to illustrate the basics of immunology in SARS COV-2 and plant-based immunotherapy of CoVID-19 cases.

  Immunology of CoVID-19 Top
[Table 1]
Table 1: Immunology of severe acute respiratory syndrome coronavirus 2 infection

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In the prepathogenesis and pathogenesis phases after entry into the human cells, SARS COV-2 is hypothesized to evolve strategies to avert triggering of host immune responses by counteracting natural pathogen recognition and cascade of innate antiviral mechanism,[15] while virulence and pathology depend on immunological process in addition to structural proteins, genome, and mutation factors. SARS-specific IgG antibodies act predominantly against S-and N-proteins though anti-S-neutralizing antibodies at initial stages may have a higher mortality risk, due to excessive complement activation.[16] Research groups are correlating immune response for different phases of infection as SARS-CoV-2 cause CD147 (syn. basigin or extracellular matrix metalloproteinase inducer, to enter T-cell lines and epithelial cells.[17] Nature, duration, and effectiveness of acquired immunity (natural or from vaccines) are unknown; threshold of herd immunity depends on viral infectious force, i.e., reproductive number (R0); cost of achieving herd immunity is calculated on infection fatality rate. The positive serological positivity rates, may not indicate antibody effectiveness and safety of returning to high-risk workplaces (Immunity Passport); individuals might ignore rules-possibly increase the spread. Recurrence may be due to false-negative tests and prolonged viral excretion; reinfection may occur from differences in nucleotides in virus (number and bases); severe symptoms can be due to antibody-dependent enhancement of infection i.e., antibodies might bind to virus, instead of neutralizing facilitate entry into immune cells, displaying receptors for the antibody.[18]

  Overview Top

Innate immune sensing of SARS-COV-2 showed similar sequence homology to other CoVs; downstream cascade results in interferons (IFN) Type I/III, tumor necrosis factor-Alpha, IL-1, IL-6, IL-18 cytokine production to induce antiviral programs in target cells and potentiates adaptive immune response; dysregulation drives acute respiratory distress syndrome (ARDS), cytokine release syndrome and lymphopenia. IFN-signaling and monocyte recruitment reduce alveolar patency and promote ARDS.[19] Adaptive immunity to SARS-COV-2 develops within 7–10 days of infection. Memory B-cell and plasmablast expansion detected early in infection, immunoglobulin M (IgM) and immunoglobulin A (IgA) detected from day 5 to 7 (declines from day 28) and immunoglobulin G (IgG) from day 7 to 10 (peaks 49d) after onset of symptoms. T-cells are activated within a week and virus-specific memory CD4+ and CD8+ T-cells peak at 2 weeks and remain for 100 days (lower levels). The magnitude of IgG and IgA (to spike) correlates to CD4+ T-cell response and IgG1 and 3 (to RBD) correlates to viral neutralization. Antibody levels decline after acute phase as plasmablasts are short-lived and CD8+ T-cells decline; depend on what antibody titer stabilizes (after natural infection or vaccination).[20]

  Role of Host Cell Responses Top

Early rapid host cell responses are critical to prevent infection from invading the lower respiratory tract and the onset of hyperinflammation. Age, gender, viral, and host factors (IFN-1 evasion) play an important role in the early T-cell response; females have stronger early T-cell response; T and B coordination disrupted in elderly males; however, for kids, decreased IFN+ CD4+ and CD25+ CD4+ T cells noted in less severe cases. Regarding longevity and memory T cell formation, CD4+ response is stronger than CD8+ response; however, their tissue specificity and protective power without neutralizing antibodies unknown. Long-CoVID occurs due to persistent tissue damage, recurring immune activation and/or inflammation; females have higher incidence (c. f. auto-immune response of T-cell, cross-reactivity with self-antigens, e.g., human leukocyte antigen).[21] Viral variants, shape, genome, infectivity, comorbidities, high mutation rate and high-capacity pathogens, specific systems involvement affect natural history; ACE2 has role in all stages from acute ling injury to lung fibrosis. Immune response varies from direct effect on T-cells causing apoptosis with lymphopenia while overactivation of immune system leading to poor prognosis. NK cells and cytotoxic T-cells are reduced and are restored once the patient recovers; decreased number of highly activated T-cells and increased impairment of T-cell activation that delays the adaptive immune response and prolonged virus clearance; Cytokine IFN-gamma inhibits viral replication and enhances antigen presentation. Apo e4 genotype has an enhanced risk of dementia due to the expression of ACE2 and ApoE e4 on the type 2 alveolar epithelial cells.[22]

  Immunological Memory Top

Immunological memory to SARS-CoV-2 varies and ineffective innate immunopathology was related with higher risk of fatality. Passive transfer of neutralizing antibodies provided preinfection protection. The spike IgG titers last for 6–8 months and heterogeneity is a central feature to the immune memory postinfection. Antibody response showed initially by short lived plasma cells followed by long-lived plasma cells with affinity maturation playing role. Memory B-cells specific to the virus were detected at 5–8 months with no apparent half-life. T-cell memory might reach a stable plateau or slow decay phase after initial 8 months of infection; component of immune memory provide truly sterilizing immunity.[23] Upon entry into the host, SARS COV-2 presents structural and nonstructural proteins to antigen-presenting cells (APC) mediating antiviral mechanism; IgM antibody levels is undetectable after 12th week, IgG remains extended periods. B-cell responses first observed against the nucleocapsid (N) protein followed by responses to S protein within 4–8 days after onset of symptoms. A hyper-inflammatory condition associated with hyper-cytokinemia is followed by multiple organ failure.[24]

  Management of CoVID-19 and Immunotherapy Links Top

Interventions on COVID-19 were initially focused on the symptomatic approach and control of secondary infections by the administration of broad-spectrum antibiotics, oxygen, and fluid control.[24] Later on therapeutic approaches included anti-IL-6R antibodies, IL-1R antagonists, JAK-STAT inhibitors or inhibition of entrance by anti-CD147 antibodies 240 and convalescent plasma. Mucosal anti-viral immunity can be regulated by the microbiota through multiple mechanisms.[17] Convalescent plasma therapy with neutralizing antibodies, Human mAbs namely 80 R, m396, and S230.15 specific for the S1 domain of the SARS CoV have been tried with conflicting findings.[24] Natural human immune response may not provide sterilizing immunity; shorten viral shedding duration, reduce spread, and prevent disease. CD4+ memory T-cell response (Th1 phenotype) noted in asymptomatic to mild cases; not known whether this response can provide protection in the absence of circulating antibodies; preexisting CD4+ Memory T-cell responses (N, S, NSP proteins recognition) from endemic betacoronaviruses may help.[20]

  Vaccine and Therapeutic Advanced Research on SARS COV-2 Top

Distinctive challenges for SARS-CoV-2 vaccine development include ethical issues, defining a correlate of protection, proving efficacy and effectiveness as well as urgency for general use; scientific process that involves large sample sizes to conduct research; high costs and failure rates; strict sequence of multiple rounds of data analysis and good manufacturing practices; Global stakeholders are busy with vaccine research; yet most significant challenge after vaccine development is the fair distribution across rich and poor countries. Viral vector-based platforms, nucleic acid-based platforms, adjuvanted recombinant protein (RBDDimer) subunit vaccine, LNP-encapsulated mRNA and 3 LNPmRNAs and killed vaccine are under studies to provide wider options for vaccine researches. Time will prove whether these novel platforms are scalable and if it is possible to produce sufficient quantities using the existing capacity.[24]

  Neutralizing Antibodies Top

Neutralizing antibodies and Th1 cells to spike protein are the basis of researches and virus neutralization is the basis for mAbs though variants in the spike protein are true challenges. Effective vaccine that boosts neutralizing antibodies and Th1 levels is necessary instead of relying on herd immunity even after cure for infection. Boosting antiviral CD8+ and TH1 CD4+ T-cells recognizing spike and epitopes from other conserved regions of the proteome is crucial in limiting replication and disease severity synchronizing with the path of immunity to other endemic coronaviruses.[20] Vaccine-induced Th1 or Tfh responses need to be ascertained on host factors related to age and duration of protection; antibody levels wane after vaccine or ineffective against new strains by vaccine-induced CD8+ response.[21] Both S and N proteins are immunogenic; N protein vaccination elicited an eosinophilic response; while recognition by APC is important for humoral immunity; postinfection IgM declines earlier, and IgG persists.[22]

  Phytochemicals and Plant Biotechnology to Combat CoVID-19 Top

Nanotechnology in plant source has a positive role in scalability and manufacturing compared to conventional vaccine processes using bioreactors fermentation-based platform, molecular farming; upstream production processes, i.e., low manufacturing costs, inability of human pathogens to replicate in plant cells, and relatively non-sophisticated infrastructure that could be implemented in resource-poor settings and countries; evade challenges to practical vaccine delivery, distribution, and administration. Plant virus nanoparticles are stable under alimentary conditions and orally bioavailable, therefore opening the door for global distribution and oral vaccination namely single-dose slow-release implants, film-based vaccines, and microneedle-based patches reduce reliance on the cold chain and ensure better vaccine coverage.[25]

  Role of Nanoparticles Top

Nanoparticles are similar in size to virus and can move in the body without compromising host immune functions; can be targeted to lungs with precision in ARDS (polymeric, self-assembling proteins, peptide-based, iron oxide, magnetic field targeting). Metallic nanoparticles have superior capacities in early detection at very low viral loads and therapies at affordable cost; magnetic nanoparticles, nanopore target sequencing, quantum dots, fluorescent QDs, QD conjugated RNA aptamer, immunoassay strips for Ig antibody detection, nanoparticles in enzyme-linked immunosorbent assay and reverse-transcription-LAMP; advanced proteomics detect essential proteins, protein corona assay; magnetic levitation helps to prioritize cases and reduce socio-economic burden. Nanoparticle-based vaccines induce higher protective immunity with targeted delivery offering techniques for novel mass vaccine production. Lipid-based nanoparticles, polymer-based formulations, dendrimers, nanocapsules, nanospheres, peptides, carbon nanoformulations (CNTs, graphene oxide nanoparticles, fullerenes), quantum dots, metallic nanoparticles, super magnetic iron nanoparticles, titanium nanoparticles are being studied for CoVID-19 treatment protocols.[26]

  Phytochemicals Top

Phytochemicals are secondary metabolites of plants with a diverse range of chemical entities namely polyphenols, flavonoids, steroidal saponins, sulfur compounds, and vitamins with potentials of antioxidant, anti-inflammatory, anticancer, antibacterial, antifungal, and antiviral activities with high bioavailability and low cytotoxicity. Phytochemicals attach to those sites of ACE2, bind to spikes to serve dual inhibitory machinery by blocking host cell receptor and viral protein entry; inhibit viral 3CL protease, and block activity of viral RNA-dependent RNA polymerase.[27] Herbal-based drugs provide immunomodulation properties at multiple intervention stages starting from prevention namely infection, immunosuppression, and stages involving multiorgan failure and domiciliary management. The cultivation of transgenic plants is relatively easy and cost-effective; transient expression in plants is inherently safer as no human pathogens infect plant systems without any chance of contamination during gene transformation and production. The plant systems are better than prokaryotic ones for complex protein expression, for example, mAbs or membrane protein expression; perform post-translational modifications (e. g., glycosylation) similar to mammalian cells.[28] Plant virus nanoparticles have been recognized as excellent platform technology for potential applications in nanomedicine to confer efficient lymphatic trafficking and targeting of APC; their adjuvant properties lead to robust antibody levels against target S-protein. High thermal and pH stability of plant virus nanotechnology alleviates cold chain requirements; patches can be shipped globally and self-administered.[29]

  Plant Molecular Farming Top

Plant molecular farming provides different expression technologies, ranging from stable nuclear transformation (transgenic plants) or plastid transformation (transplastomic plants) to transient expression without stable transgene integration; create chemicals mimicking viral antigens for robust, rapid, and flexible system of diagnostic reagents and immunological assays.[30] Sulfated polysaccharides from sea-weed are complex poly-anionic macromolecules with promising properties; red and green inhibit attachment of virus onto host and prevent viral entry; red, brown useful as anti-oxidant, hydroxy, superoxide radical scavenging, ferrous chelating, anti-coagulant by inhibiting thrombin. Carrageenan inhibits viral synthesis of protein; 1/15th of heparin, immunomodulatory, cytokine mRNA stimulator, increases interferon and IL; carbohydrate-binding protein Griffithsin from red algae acts against the enveloped virus.[31] Molecular pharming by the recombinant expression of pharmaceutically useful plant proteins help rapid production at low cost with high levels.[32] Cloning the candidate into a plant expression system and having the plant express the gene and then makes the protein–antigen. Ongoing studies on plant-based SARS CoV-2 vaccine is using tomato and tobacco; Fungi and yeast for oral vaccine.[1] Vitex trifolia and Sphaeranthus indicus decrease inflammation of cytokines through modulating NF-kB pathway; Clitoriaternatea inhibits metalloproteinase (ADAM17) involved in ACE shredding; Coriandrum sativum, Cosciniumfenestratum, Cynara scolymus, Punica granatum, and Cassia occidentalis do ACE inhibition; Glycyrrhiza glabra and Allium sativum inhibit viral replication; Clerodendrum Inerme Gaertn inactivates SARS-CoV-2 ribosome and protein translation. Strobilanthes cusia inhibits RNA genome formation.[33] Plant-derived phytochemicals (particularly polyphenols) with putative active substances (e.g., flavonoids, gallate, and quercetin) are potent agents to prohibit proliferation SARS COV-2. The plant molecular farming produces virus-like particle that is composed of a plant lipid membrane and spike protein. Cowpea mosaic virus-like particles with B- and T-cell epitopes from the S protein of SARS-CoV-2 are displayed on their icosahedral surfaces-recombinant virus harboring these epitopes elicit immune response.[34]

  Salutogenesis Models: The Penultimate Solution to Flatten the Pandemic Curve Top

Across the paradigms, pathies, myths, beliefs, and practices forced the folks to move from pillar to post in search of safety terminals ranging from healthy diet (c. f. superfood), exercise (c. f. contracting skeletal muscle produces IL-7 to increase thymic mass and function); sunlight exposure (c. f. Vitamin D production); Broccoli intake (c. f. help T-cell to produce virus-killing granzyme B); Blueberry (c. f. increase natural killer cell and anti-inflammatory cytokines, and reduce oxidative stress); avoid ketogenic diets (c. f. suppress immune system); consuming large volumes of fish or fish oil (c. f. reduce inflammation because they reduce immune function).[35] To improve immunity hypothesis are abounded. Vitamin D supplement enhances resistance; Selenium helps redox homeostasis and antioxidant properties; Zinc protects respiratory epithelium by antiinflammatory and antioxidant activities, regulate tight junction proteins with claudin1 and Zonula occludens1, inhibit RNAdependent RNA polymerases; strict serum iron regulation has favorable outcomes. Antioxidant and mucolytic effects of N-acetyl cysteine improve airway function, alleviate oxidative stress and inflammation. Arginine inactivates viruses by acting synergistically with virucidal conditions, for example pyrexia and acidic pH levels; inactivate enveloped viruses; pore formation and destabilization of viral membrane, inhibition of function of nonstructural proteins, suppression of protein–protein interactions and aggregation. Glutamine reduces the destruction of lung tissue, lung edema, cytokine production, and neutrophil recruitment into airways. Probiotics and Omega3 PUFA are beneficial in CoVID-19 prevention; latter promote lung surfactants, hostmicrobial interactions, alter blood rheology and produce endogenous eicosanoids; suppress synthesis of IgE, reduce airway inflammation and bronchoconstriction. B-Glucans activate immune cells including neutrophils, natural killer cells, macrophages. Herbs have protective effects, namely Triterpene Glycosides inhibit viral replication, absorption, and penetration in early infection; Houttuynia and Glycyrrhiza have direct antiviral effect; Nigella sativa has antiinflammatory, bronchodilatory effects.[36]

  Future Perspective Top

In this study, the research group has initiated a holistic approach immunology as the backbone of management and incorporating phytochemicals as additional weapon in the armouray with potentials to help fight SARS COV-2 from prepathogenesis stages in apparently healthy persons at risk in the community to the last man on the queue to seek care in this pandemic. With limited resources, we did a situational analysis on prospects of phytochemicals in the backdrop of the immunologica aspects of SARS COV-2 infection. Unrelenting researches on vaccine and antibodies can ensure effectively combat pathophysiology and natural history of CoVID-19 by highly potent neutralizing mAbs to complement vaccines against emerging variants; help patients who are sick or at risk and preventive for health-care workers when vaccine coverage is less.

  Conclusions Top

Early diagnosis and optimum outcome is the pivotal step in the infrastructure compromised healthcare delivery systems, especially in low- and middle-income countries. To effectively set up intensive care capacity building might not match the increasing demand of rapidly upcoming waves after waves. We need to find user-friendly and cost-effective tools for demarcating immunological markers of SARS COV-2 and exploration of the plant-based immunotherapy. CoVID immunology is evolving over time with newer variants, vaccine and therapeutic approaches should be based on immunological aspects thus phytochemicals need to be explored to halt this pandemic. Unique observations from the present work would be attempted to be explained in the light of pharmacokinetics and pharmacodynamics; whenever possible implemented carefully on the establishment of specificity, reliability, and validity while utmost care will be taken to avoid biases. Further, attempts have been made to pave the way for the futuristic research vision and mission to develop effective therapy guidelines with or without antibodies and vaccine research to combat pathophysiology of natural history of CoVID-19. The translational research to detect neutralizing antibodies is the key to define protection. Finally, prospective, randomized, placebo-controlled trials ensure clinical potential of immune-modulatory or passive immunization therapies.

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Conflicts of interest

There are no conflicts of interest.

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   Role of Host Cel...
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   Management of Co...
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   Neutralizing Ant...
   Phytochemicals a...
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