INTRODUCTION:

COVID-19, a global pandemic declared by WHO, is a highly infectious and severe acute respiratory disorder caused by a pathogenic virus called SARS-CoV-2 which is transmitted to humans via contact and feeding on infected animals. The COVID-19 clinical manifestations are very similar to viral pneumonia such as fever, fatigue, cough, shortness of breath, and other complications. According to reports obtained on WHO and NCDC websites as of 12th July 2020, the coronavirus breakout in Wuhan, a city in Hubei Province of China in November 2019 as spread to more than 200 countries in the world. This global pandemic has forced many nations to lock down their social activities which in turn have adverse effects on the economy¹.

Coronaviruses belong to the subfamily Coronavirinae in the family Coronaviridae of the order Nidovirales and can cause respiratory, digestive, and nervous system diseases in humans and many other animals².

Which consists of four genera namely: Alpha, Beta, Gamma, and Delta coronavirus. It is currently thought that, SARS-CoV-2 has azoonotic origin and has secondarily acquired human-to-human spreading capacity. In particular, the acquisition of 1)Mutations in the receptor-binding area, 2) A polybasic furin cleavage site (RRRAR)at the junction of subdomain 1 and 2 of the spike protein and 3) A site of O-linked glycosylation in the same area, have enabled the virus to efficiently interact with high affinity( via its spike protein) with its bona fide cellular receptor (angiotensin-converting enzyme 2[ACE-2]), to become more virulent and pathogenic, while potentially evading immune responses through O-glycan epitope maskimg³.

Morphology and genomic structure of HCoV:

Coronaviruses are spherical or pleomorphic, with diameter of 80-120nm. The virion surface is decorated with club like projections constituted by the trimeric spike (S). The viral envelop is supported by the membrane (M) proteins the most abundant structural protein. And a small transmembrane protein known as the envelop (E) protein is also present in a low amount in the envelope. The genomic RNA and phosphorylated nucleocapsid (N) protein form a spiral nucleocapsid, which is located within the envelope. The coronavirus genome is comprised of a single-stranded positive-strand RNA ranging from 27 Kb to 32 Kb in length. The genomic RNA is 5’-capped and 3’-polyadenylated and contains multiple open reading frames (ORFs). The invariant gene order is 5’- replicase-S-E-M-N-3’, with numerous small ORFs (encoding accessory proteins) scattered among the structural genes⁴.

Entry mechanism of human coronaviruses:

The life cycle of SARS-CoV-2 in host cells- begins when S protein binds to the cellular receptor ACE2. After receptor binding, the conformation change in the S protein facilitates viral envelope fusion with the cell membrane through the endosomal pathway. Then SARS-CoV-2 releases RNA into the host cell. Genome RNA is translated into viral replicase polyproteins pp1a and 1ab, which are then cleaved into small products by viral proteinases. The polymerase produces a series of subgenomic mRNAs by discontinuous transcription and finally translated into relevant viral proteins. Viral proteins and genome RNA are subsequently assembled into virions in the ER and Golgi and then transported via vesicles and released out of the cell⁵.

Symptoms and effects of covid-19:

An infected COVID-19 patient can have two major states of infection, the asymptomatic state, and the symptomatic state. The symptomatic stage can develop into Acute Respiratory Disease Syndrome (ARDS) then rising infection can lead to multi- organ failure which can be fatal to the patient. An asymptomatic patient does not exhibit any symptoms of the disease due to high immunity but is still capable of infecting others, his state is extremely dangerous for the community and transmission of the virus. It is impossible to identify an asymptomatic patient without conducting an RT-PCR (Real-time polymerase chain reaction) test. Symptomatic patients exhibit varying level of severity of the disease, most patients display mild symptoms only like fever, cough, sore throat, headache, myalgia or severe symptoms like ARDS or organ failure. In the case of COVID-19, an extreme rise in inflammatory cytokines, monocytes, etc. leads to vasodilation. Which leads to the symptoms including shortness of breath, rapid breathing and bluish skin coloration⁶.

Prevention:

The prevention and management are very important issues to control COVID-19. Therefore, there is a great need for the collective efforts of the public and the government. The regular and the proper care of the homes and hospitals are very important to control this calamity. The hand cleaning with soap and sanitizer, mouth and nose coverage with mask during sneezing and coughing are essential. Touching specific parts of the face like eyes, nose, and mouth without washing the hands should be avoided as these are entry points for the virus. Avoiding person-to- person contact. Regular cleaning of the surface by the disinfectants may control the virus outbreak. It is always better to avoid the interactions with anyone; suspecting respiratory problems symptoms like sneezing, coughing, breathing problem, etc. Screening has a vital role as a preventative measure to detect a potential health problem in an individual who doesn’t have any signs and symptoms. Screening should be done in a multiphase level to aid further management of the disease⁷.

Immunity:

The immune system refers to a collection of cells and proteins that function to protect the skin, respiratory passages, intestinal tract and other areas from foreign antigens, such as microbes (organisms such as bacteria, fungi, and parasites), viruses, cancer cells, and toxins. The immune system can be simplistically viewed as having two “lines of defense”: innate immunity and adaptive immunity. Innate immunity represents the first line or defense to an intruding pathogen. It is an antigen-independent (non-specific) defense mechanism that is used by the host immediately or within hours of encountering an antigen. The innate immunity response has no immunologic memory and, therefore, it is unable to recognize or “memorize” the same pathogen should the body be exposed to it in the future. Adaptive immunity, on the other hand, is antigen- dependent and antigen-specific and, therefore, involves a lag time between exposure to the antigen and maximal response. The hallmark of adaptive immunity is the capacity for memory which enables the host to mount a more rapid and efficient immune response upon subsequent exposure to the antigen. Innate and adaptive immunity are not mutually exclusive mechanisms of host defense, but rather are complementary, with defects in either system resulting in host vulnerability⁸.

Immunomodulators:

An immunomodulator may be defined as a substance, biological or synthetic, which can stimulate, suppress or modulate any of the components of the immune system including both innate and adaptive arms of the immune response. modulation of the immune system denotes to There are generally of two types immunomodulators based on their effects: immune suppressants and immune stimulators. Specific immunomodulators administered together with antigens to boost the immune response to the vaccine constituents. For instance, a planet origin saponin used in veterinary medicine. Whereas, non-specific immunostimulators offer a generalized state of resistance to pathogens or tumors. The concept of immunomodulation relates to nonspecific activation of the function and efficiency of macrophages, granulocytes, complement, natural killer cells and lymphocytes and also to the production of various effectors molecules generated by activated cells. It is expected that theses nonspecific effects give protection against different pathogens including bacteria, viruses, fungi etc. and constitute an alternative to conventional chemotherapy⁹.

Our body temperature and wealth of nutrients provide an ideal home for these micro-organisms to thrive. The human immune system comprises innate and acquired immunity. Natural killer (NK) cells, complement system, macrophages, antigen presenting cells (APCs) and neutrophils make up the innate immune system and mounts an immediate non-specific response to foreign microbial agents. If microbes by-pass this primary defence, the acquired immune response, comprising humoral and cell mediated components, will then act to contain the invaders. The type of antigen (fungi, virus, bacteria, toxin) processed and presented by APCs to the CD4+ T cell determines the type of cytokines secreted, which in turn, determine the differentiation of helper T (TH) cells into TH1 or TH2 cells and B-cells to give immunoglobulin sub- types. TH1 response involves the activation of macrophages, which contain and destroy mycobacteria and fungal fungal pathogens. TH1 pathway also activates cell-mediated immunity. TH2 cells, on the other hand, effect immunoglobulin differentiation and antibody secretion, and therefore mediate humoral immunity. CD8 cytotoxic T cells induce apoptosis in antigen-laden cells⁹.

Ayurveda purview:

Ayurveda is a comprehensive scientific medicinal system indigenous to India. The term Ayurveda means ‘knowledge of life’. Which comprises two Sanskrit words, Ayu (life) and Veda (knowledge or science). Four Vedas, considered as a the oldest Indian literature (5000-1000 BC) contain information about natural remedies. Ayurveda was established as fully grown medicinal system. Charaka Samhita (focussing on internal medicine) and Susruta Samhita (focussing on surgery) were written systematically and considered as classical text of Ayurveda. Vital details of Charaka Samhita and Susruta samhita were compiled together and updated additionally in Astanga Sangraha and Astanga Hrdaya. Some other ancient classics which include minor work of Ayurveda includes Madhava Nidana (focusing on diagnosis of disease), Bhava Prakasa (focussing on additional information related to plant and diet), arngadhara Samhita (focusing on formulation and dosage form). Ayurveda was divided into eight major clinical subdivisions-Kayacikitsa (internal medicine), Salya Tantra (surgery), salakya (diseases of supra- clavicular origin), Kaumarabhrtya (paediatrics, obstetrics and gynaecology), Bhutavidya (psychiatry), Agada Tantra (toxicology), Rasayana Tantra (rejuvenation and geriatrics), Vajikarana (aphrodisiology and eugenics)¹⁰.

Concepts underpinning ayurvedic medicine:

The 3 basic principles, called doshas (vata, pitta, and kapha), are derived from 5 elements of Indian philosophy. Ayurveda’s doshas can be identified as regulatory control factors for fundamental physiologic processes in living systems that maintain their identity throughout biologic history: vata and its subdoshas regulating input/output processes and motion; pitta and its subdoshas regulating throughput, turnover, and hence energy; and kapha and its subdoshas regulating storage, structure, and lubrication. Factors such as food, activity, the climate and stress can, however, disrupt or destroy these functions. Ayurveda seeks to normalize body functions with varied techniques including advice onfood and activity, internal herbal preparations, purification treatments (panchakarma), and surgical methods (shalya chikitsa). Oral administration routes play a major role in influencing individuals’ doshas, via the ingestion of food, spices, and medicinal plants. These elements are influencing doshas in different ways: stabilizing, disturbing, and supporting the body’s healthy state¹¹.

Role of herbal drugs as immunity booster:

Plants are always the key source of drug or treatment strategy in different traditional medicinal systems. In recent years, many people are choosing to plant based medicines or products to improve their health conditions or as curative substance either alone or in combinations with others. According to the WHO, herbs or herbal products are used by the large number of populations for basic healthcare needs. Herbal medicine includes herbs, herbal materials (like plant parts) or preparations, processed and finished herbal products, active ingredients¹⁰.

1. Tulsi:

Many in-vitro, animal and human experimental scientific studies showed that; due to presence of eugenol, phenolic compounds, linoleic acid, etc. compounds Tulsi has antimicrobial (including antibacterial, antiviral, antimalarial), anti-diarrheal, anti-oxidant, anti-inflammatory, hepatoprotective, cardioprotective, reno-protective, analgesic, antipyretic, immunemodulatory properties and is thus recommended as a treatment for a range of diseases including features like cough, fever, asthma, anxiety, diarrhea, gastric, cardiac and genitourinary disorders. Due to its anti-inflammatory and antioxidant properties, it protects against toxic chemical-induced injury, enhance the antioxidant enzymes and protect cellular organelles and membranes by clearing damaged free radicals. The compounds such as ursolic acid, carnosol, rosmarinic acid, cirsilineol, apigenin, eugenol, and cirsimaritin present in O. sanctum increase haemoglobin concentration, enhance SRBC agglutinin titers, decrease cyclo-oxygenase (CoX)-2 and lipoxygenase (LOX)-5 enzymes activity, suppress NF-kB classical pathway, up regulation of IL-2, IFN-g and TNF-a, down regulation of IL-1b and produce of SRBC antigen-specific antibodies, which represent a major defense mechanism to assess T-cell-dependent antibody responses i.e. Tulsi by enhancing immune response boost the defense mechanism against the infection. Several studies have shown that Tulsi (aqueous and methanol extract of leaf and seed oil) besides improving vital capacity also is an immune-modulator and regulator as it enhances immune response by increasing T-helper and NK cells; phagocytic activity and index with the rise in lymphocyte count, neutrophil count and antibody titer ¹².

2. Ginger:

Ginger is the rhizome of Zingiber officinale Roscoe in the family Zingiberaceae and has been used as a food, spice, supplement and flavoring agent and in traditional medicines for more than 3000 years in countries. Ginger has been used in traditional medicines to treat diseases and symptoms, such as colds, headache, nausea, upset stomach, diarrhea, arthritis and rheumatism, or used as a carminative, antiflatulent and digestant. Furthermore, ginger is known to have pharmacological activity against natural, chemical and radiation-induced toxicities, such as radioprotective, hepatoprotective, nephroprotective, neuroprotective, gastroprotective and reproductive-system-protective effect. The bioactive compounds of ginger such as nevirapine, b-sitosterol, 6 gingediol, germacrene, methyl-6-shogaol, 6-gingerol, a-linalool, 6-shogaol, gingerdion, zingiberene, etc., are known to inhibit viral replication; among these the most potent inhibitors of reverse transcriptase (RT) enzyme is b-sitosterol, which is predicted to be used as non nucleoside reverse transcriptase (NNRTIs) HIV-1 inhibitors. It is reported that Ginger contains TNF-a which is also known as an anti-influenza cytokine.The rhizome of Ginger and its main components like gingerols, shogaols, etc inhibit prostaglandin and leukotriene biosynthesis, inhibit cyclooxygenase and lipoxygenase activities, inhibits the synthesis of pro-inflammatory cytokines such as IL-1, TNF-a, and IL-8 without any significant effect in IL-6 levels; inhibit the excessive production of NO, PGE (2), TNF-a, and IL-1beta, reduce the elevated expression of NFkB and TNF-a, downregulate inflammatory iNOS and COX-2 gene expression, inhibit thromboxane synthetase, raise levels of prostacyclin without a concomitant rise in PGE 2 or PGE 2 alpha, inhibit platelet aggregation, decrease age-related oxidative stress markers and enhance

Fibrinolysis. The concentration of IgM and eosinophil count in non-smokers was significantly increased in a comparative study of the effect of ginger extract among male smokers and non-smokers, whereas the concentration of hemoglobin and lymphocyte count in smokers was strongly increased. This indicates that in non-smokers, ginger results in a stronger antibody response or humoral immunity than in smokers¹².

3. Clove:

Cloves are an aromatic herb that has many useful purposes. Approximately, 72-90% of the essential oil extracted from cloves has Eugenol. Other are Acetyl eugenol, Beta-caryophyllene and vanillin, Crategolic acid, tannins, gallotannic acid, methyl salicylate (painkiller), Flavonoids eugenin, kaempferol, Triterpenoids like oleanolic acid. The dried buds of cloves contain antiseptic, and anti-fungal agent. It also holds aphrodisiac and circulation-stimulating capacities. The oil of cloves has been used in a variety of health conditions including indigestion, generalized stress, parasitic infestations, cough, toothaches, headache, and blood impurities. Clove is used extensively in dental care for relieving toothache, sore gums and oral ulcers. Gargling with clove oil can also aid in sore throat conditions and bad breathe. Clove oil clears the respiratory passages, acting as an expectorant for treating many upper-respiratory conditions including colds, bronchitis, sinus conditions, cough and asthma. Not only purifies the blood, but also aids in stabilizing blood sugar levels, and may have benefits for diabetic individuals. Clove's antiviral and cleansing properties purify the body, augmenting our resistance to disease^13-16.

4. Dalchini:

The Cinnamon popularly known as Dalchini ( Cinnamomum zeylanicum), belongs to the family Lauracae. Cinnamon has also been used for its medicinal properties for thousands of years. Made from the inner bark of the cinnamomum tree, its use has been dated as far back as ancient Egypt. Cinnamon is an immune simulator, protecting the body from bacterial or viral attacks. It helps your body fight infections and repair tissue damage. All the antioxidants are super powerful when it comes to bringing those anti-inflammatory properties. Cinnamon also gives us manganese, calcium, fiber and iron. Cinnamon also fights inflammation and helps ward off infections and herbal damaged tissue. Containing large amounts of polyphenol, cinnamon outranked “superfoods” like garlic and oregano in a study comparing the antioxidant, antitumor, antihypertensive, antilipemic, antidiabetic, gastroprotective, and immunomodulatory effects¹⁷. In addition to being lipid lowering and cardiovascular- disease- lowering compound, cinnamon has also reported to have activities against neurological disorders, such as Parkinson’s and Alzheimer’s diseases. Cinnamon is a coagulant and prevents bleeding. Cinnamon also increases the blood circulation in the uterus and advance tissue regeneration¹⁸.

In one study, cinnamon at high dose (100mg/kg) showed immune-stimulant activity as it significantly increased the phagocytic index, serum immunoglobulin levels and antibody titer and decreased the percentage reductions in neutrophil count. Cinnamon low dose (10mg/kg) increased serum immunoglobulin levels only. This showed that high dose increases both cell mediated and humoral immunity whereas low dose showed effect only on humoral immunity. The studies also suggest that cinnamaldehyde can act as a strong regulator of monocyte/macrophagemediated immune responses by inhibition of PI3K, PDK1 and NF-kB activation of signaling components. In addition to this, by the activation of CD29 and CD43, it blocked cell migration cellecell adhesion induced but not cell-fibronectin adhesion and it was able to suppress both the production of nitric oxide (NO) and up regulation of surface levels of co-stimulatory molecules (CD69 and CD80) and pattern recognition receptors (TLR2 and CR3).

5. Turmeric:

Turmeric (Curcuma longa), also known as “Indian saffron” due to its brilliant yellow colour, is a spice herb, member of the ginger family (Zingiberaceae) native to the Indian subcontinent and Southeast Asia, having more than a two centuries old scientific history. Turmeric obtained from ground‐dried root contains different percentages of volatile and non‐volatile oils, proteins, fats, minerals, carbohydrates, curcuminoids and moisture. Commercially available curcumin is a combination of three molecules, together called curcuminoids. Curcumin is the most represented (60–70%), followed by demethoxycurcumin (20–27%) and bisdemethoxycurcumin (10–15%). Besides curcuminoids, the other active components of turmeric include sesquiterpenes, diterpenes, triterpenoids¹⁹.

Turmeric has various useful properties with antioxidant activities. Turmeric has anti-inflammatory, anticancer, anti-diabetic, hypolipidemic, antimicrobial, anti- fertility, anti-venom, hepatoprotective, nephroprotective, anticoagulant property. The plant has also shown to possess anti HIV activity to combat AIDS¹⁷. The immunomodulatory abilities of curcumin arise from its interaction with various immunomodulators, including not only cellular components, such as dendritic cells, macrophages and both B and T lymphocytes, but also molecular components involved in the inflammatory processes, such as cytokines and various transcription factors with their downstream signalling pathways. Curcumin supplementation in rabbit diet (2,4and 6g/kg) significantly increased serum levels of IgG and IgM, thus suggesting that curcumin can also improve immune response²⁰.

6. Garlic:

Garlic (Allium sativum) is bulbous perennial plant with a powerful onion such as aroma and pungent taste that has been used as flavoring agent, condiment, and for medicinal purposes for over 5,000 years. Garlic contains a variety of bioactive constituents includindg sulfur compounds such as alliin, allicin, ajoene, allylpropyl disulfide, diallyl disulfide (DADS), diallyltrisulfide (DATS), S-allylcysteine (SAS); peroxidases and alliniase like enzyme, amino acids and important trace elements like Se, Ge and Te. Garlic is frequently used to treat aches and pains, leprosy, diarrhea, infections, dandruff, respiratory disorders. Garlic has been employed for management of blood pressure, atherosclerosis, high cholesterol, heart attack and coronary heart disease. Aged garlic has more potent immunomodulatory effects than raw garlic. Garlic is an effective therapeutic candidate to prevent the recurrent aphthous ulcer. Conditions like gout, rheumatoid arthritis, osteoarthritis, diabetes, allergic rhinitis, traveler’s diarrhea, bacterial and fungal infections, cold and flu are also known to cured by garlic. Other uses of garlic include treatment of fever, whooping cough, headache, stomach ache, sinus congestion, psoriasis, hair loss and hemorrhoids²¹.

7. Marich:

It has been also found to increase bioavailability, thus enhance the therapeutic efficacy of many drugs, vaccines and nutrients and have immune-modulatory, anti-oxidant, antiplatelets, antihypertensive, anti-asthmatic, antipyretic, analgesic, anti-carcinogenic, anti-inflammatory, anti-diarrheal, antispasmodic, anxiolytic, antidepressants, hepatoprotective, anti-ulcer, anti thyroids, antiapoptotic, anti-metastatic, antimutagenic, antibacterial, antifungal and anti-amoebic properties. The extract and its constituents like piperine, regulate the balance of the cytokines production of Th1, Th2, Th17, and Treg cells, reduce the accumulation of inflammatory cells, inhibit the expressions of GATA3, IL-4, IL-6, IL-1b, RORgt, IL-17A and TNF-a, increase INF-g and IL-10 secretions in BALF (Broncho-alveolar lavage fluid) and increase macrophage activation and T and B cell proliferation. Beside this, Marich possess cytotoxic activity, suppresses the levels of total IgE, anti-OVA IgE, anti-OVA IgG1 and histamine release in serum, ameliorates fibrosis and infiltration of inflammatory cells, inhibits the allergic responses, inhibitsTh2/Th17 responses and mast cells activation, inhibits NF-kB, c-Fos, cAMP response element-binding (CREB) and activated transcription factor (ATF-2); suppresses PMA-induced MMP-9 expression, inhibits PKCa/extracellular signal regulated kinase (ERK) 1/2 and reduces NF-kB/AP-1 activation. In addition, piperine also inhibits the Pglycoprotein (P-gp) and CYP3A4 functions. Piper nigrum is found to have dose dependent antifertility effects on mice²².

CONCLUSION:

COVID-19 viral spectre outbreak is spreading across different countries at an increasingly alarming rate. Currently, yet no any vaccine or medicine could be developed to cure COVID-19 and Scientist also utilizing hydroxychloroquine to treat COVID-19 but could not get positive response and has side effect. Immune systems in body play an important role to fight against unhealthy environment and microbes such as virus, bacteria, fungus etc. In the current pandemic infection of COVID-19 it is clear that those with weak immune system are highly susceptible to this infection and worst outcomes. In the case of infectious pandemics like this “prevention is always better than cure”. In this regard immune enhancing herbs may definitely be helpful for the body to fight COVID-19 infection. Tulsi, Ginger, Clove, Dalchini, Turmeric, Garlic, Marich these botanical plants having low cost, minimum toxicity and almost found everywhere in country, it has potential to enhance immunity to fight against COVID-19 and other infectious disease and play an important role to becomes fit and healthy India and world.

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Received on 15.05.2021 Modified on 26.05.2021

Asian J. Pharm. Res. 2021; 11(3):206-211.

DOI: 10.52711/2231-5691.2021.00037