Plant resources for immunonutrients and immunomodulators to combat infectious respiratory viral diseases: a review

Abstract

Boosting the immune system has become a crucial aspect in the global battle against the COVID-19 pandemic and other similar infections to protect oneself against symptoms, especially in the prevention of viral infections of the lower respiratory tract. The importance of conducting more studies to create successful herbal formulations as infection prevention measures is emphasized in this review, which looks at the function of immune-boosting nutrients, medicinal plants, and herbal treatments. We reviewed and analyzed 207 studies published from 1946 to the present using reputable databases like Google Scholar, PubMed, and NCBI. The review examined 115 plant species in total and identified 12 key nutrients, including vitamins A, D, C, omega-3 fatty acids, iron, and zinc, while noting that four plant families, Rosaceae, Asteraceae, Amaryllidaceae, and Acanthaceae, show potential against respiratory infections like influenza, RSV, and SARS-CoV. To lower the risk of infection, it is recommended to consume nutritious meals that have immune-modulating qualities. Information on the bioactive components of medicinal herbs, spices, and plants that have been effective in treating respiratory viral infections and related conditions is compiled in this review, which highlights phytoactive substances with antibacterial and antiviral activity as effective modulators to lower the risk of infections. Furthermore, it is highlighted that ancient knowledge systems, like Ayurveda and Naturopathy, should be integrated to help develop new herbal formulations. To improve immunity and lessen vulnerability to serious respiratory infections, the results highlight the need for including immune-modulating foods and plant-based medicines into everyday routines.

Introduction

Based on a review of the human population and the environment over the last 50,000–100,000 years, we find a steady increase in population (until the recent decades) around the world, as well as the development of new powerful infectious agents, including viruses (McMichael 2004). When humans lived in isolated, small communities, most pandemic, and epidemic illnesses did not exist (Barrett et al. 1998). With the advance of time and globalization, several epidemics and pandemics have been recorded in human history and some of the major ones are presented in Table 1. During the global struggle to combat the COVID-19 pandemic, meditating on traditional knowledge offered essential guidance and inspiration for mankind to traverse the 2-year battle with fair success, despite the unfortunate loss of many lives worldwide. This resulted in the emergence of innovative concepts and tactics from earlier periods that may be reintroduced for the advancement of contemporary natural and synthetic treatments.

Table 1.

Chronological order of pandemics from the nineteenth century till date

S. no.	Type of pandemic	Year range	Location	Estimated/recorded death toll	References
1.	First cholera	1817–1824	Asia, Europe	> 100,000	Hays (2005)
2.	Second cholera	1827–1835	Asia, Europe, North America	> 100,000	Hays (2005)
3.	Third cholera	1839–1856	Russia	1,000,000	Hays (2005)
4.	Third plague	1855–1860	Worldwide	> 12 million in India and China alone	Pryor (1975) and Stenseth (2008)
5.	Flu	1889–1890	Worldwide	1,000,000	Local Government Board (1893)
6.	Encephalitis lethargica	1915–1926	Worldwide	1.5 million	Foster and Hoffer (2007)
7.	Spanish flu	1918	Worldwide	50–100 million	Jilani et al. (2024), Patterson and Pyle (1991) and Spreeuwenberg et al. (2018)
8.	Seventh cholera	1961–present	Worldwide	NA*	Hays (2005)
9.	HIV/AIDS	1981–2018	Worldwide	32 million	Sharp and Hahn (2011) and UNAIDS (2019)
10.	SARS*	2002–2004	Worldwide	774	WHO (2003)
11.	Swine flu	2009–10	Worldwide	151,700–575,400	CDC (2012)
12.	MERS*	2012–present	Worldwide	871 (8 April 2020)	WHO (2019, 2020)
13.	Corona virus (COVID-19)	2019–present	Worldwide	3 519 175 (29 May 2021)	WHO (2021)

NA, not available; HIV/AIDS, human immuno virus/acquired immuno deficiency syndrome; SARS, severe acute respiratory syndrome; MERS, middle east respiratory syndrome

From the listed pandemics in Table 1, it is evident that a new viral or bacterial infection usually lasted for a minimum of 2–3 years, causing devastating effects on the entire human population. In this struggle against the disease-causing agent, some succumbed, while others traversed successfully, indicating compliance with the concept of “survival of the fittest” of Darwin’s theory of natural selection. What could be the reasons for periodic threats to the human race in the form of biological agents? Are epidemics and pandemics the result of natural processes of genome evolution resulting in potentially harmful agents, or from human activities against Mother Nature? Is nature reminding humanity of maintaining equilibrium in complex ecosystems, or could there be another explanation yet to be explored?

Infection outbreak

Respiratory syncytial virus (RSV) was initially discovered in 1955 from a chimpanzee, and its infectivity in humans was established the following year. RSV is an enveloped and cytoplasmic virus with a single-stranded negative-sense RNA genome that produces the multinucleated masses known as “syncytia.” RSV contains both viral RNA and proteins with nucleocapsid cores packaged within lipid envelopes. It belongs to the family Paramyxoviridae and falls within its respective genera Pneumovirus and Pneumovires. RSV is one of the main causes of bronchiolitis and pneumonia among very young children, often seen during regular annual epidemics that clinicians recognize every year (Ruuskanen and Ogra 1993).

Influenza is historically an ancient disease that continues to be in epidemics and pandemics alike, killing 36,000 individuals annually in the US alone. Antigenic variation among the viral glycoproteins hemagglutinin (HA) and neuraminidase (NA), including seasonal influenza viruses, may reduce their impact with antigenically targeted vaccines and anti-influenza drugs (Salomon and Webster 2009). Notable pandemics include the H1N1 Spanish influenza of 1918, which resulted in over 50 million global deaths; the H2N2 Asian flu of 1957, which claimed 1 million deaths; and the H3N2 Hong Kong flu of 1968, which claimed approximately half a million global fatalities. Aquatic birds serve as natural reservoirs of influenza A viruses; infection of humans occurs either directly through transmission (Spanish influenza) or indirectly via reassortment between segmented RNA genomes of both bird- and human influenza viruses (the Asian and Hong Kong pandemics) (Salomon and Webster 2009).

Influenza A, B, and C viruses—three genera within the family Orthomyxoviridae—share segmented negative-strand RNA genomes that exhibit segmentation. Influenza viruses further distinguish themselves by subtypic surface glycoproteins: hemagglutinin (HA) and neuraminidase (NA). The influenza B-virus-structure also mirrors influenza A-viruses with four envelope-proteins such as HA and NA (common for Influenza A and B-viruses), and M2 (unique for Influenza A), represented as NB2 and BM2 (transmembrane glycoproteins equivalent to M2 protein of Influenza A-virus) in Influenza B-virus. Influenza C viruses exhibit only one major surface glycoprotein: hemagglutinin esterase-fusion (HEF) (Bouvier and Palese 2008).

Corona viruses (CoVs), members of the family Coronaviridae, can affect respiratory and digestive systems in animals as well as humans; they were only considered seriously infectious until COVID-19 struck in 2019—7 years after MERS-CoV first emerged, inflicting coronavirus disease known as COVID-19 according to the International Committee for Taxonomy of Viruses classification standards (Fan et al. 2020). COVID-19 disease, caused by SARS-CoV-2 coronaviruses and associated with severe respiratory symptoms, posed an immediate and global public health threat. (Gorbalenya et al. 2020; Kupferschmidt and Cohen 2020). The COVID-19 pandemic has resulted in a significant increase in infections, with the JN.1 variety emerging as the prevailing strain in the United States, responsible for more than 60% of cases. This particular strain, which is derived from BA.2.86, possessed genetic changes that improved its capacity to resist the immune system and spread more effectively, resulting in a significant increase in the number of infections (Yishan et al. 2024). Notwithstanding the swift dissemination, existing vaccinations and antiviral therapies continue to be efficacious. There has been a recent emergence of a new strain of influenza, which emphasizes the potential danger of different flu varieties and the necessity for regularly updated immunizations. This COVID-19-like respiratory viral infections leads to severe pneumonia with a reported lethal result of 15–20% (CDC 2003).

The ripple effect of this flare-up has led to the significant use of antiviral agents and antibiotics in affected individuals. Since the beginning of the COVID pandemic in 2019, the WHO has played a crucial role in developing and updating treatment protocols periodically and the apex medical boards of countries across the world have also played a significant role in controlling the pandemic. All countries follow preventive measures such as maintaining physical distance, self-isolation, quarantine, using masks and sanitizers, and confinement to a particular geographical location. However, total isolation for long durations is impossible for livelihood and other basic survival needs. Further, these prophylactic measures will help humankind only to a certain extent; however, serious efforts must be made to acquire knowledge of the viral replication components to focus on antiviral treatments and immunization.

Treatment guidelines: a gist

Immune mechanisms appear to play an integral role in the development of severe RSV infections that often recur annually. The commercial tests can quickly detect RSV from nasal/pharyngeal mucus samples within 1 h, with specific antiviral therapy with ribavirin being available as treatment. The research conducted in the 1990s suggested that P-adrenergic medications may offer advantages for certain individuals with bronchiolitis (Ruuskanen and Ogra 1993). Currently, many methods are being pursued to develop a vaccination that is both safe and efficient against this condition. Germany permitted three antiviral products for treating influenza virus infections: amantadine, oseltamivir, and zanamivir which are approved and licensed for prophylactic use (Wutzler et al. 2004). However, the first consensus Conference on Antiviral Treatment and Prophylaxis of Influenza in 2002 recommended using oseltamivir and zanamivir for treatment, but not amantadine, which is not effective against influenza B viruses and can cause adverse events. Amantadine is rarely prescribed due to side effects, and rimantadine falls into this active ingredient group; both options provide effective solutions against influenza infections (Arbeitskreis 2009). Anti-influenza drugs approved for clinical use include the following neuraminidase inhibitors: orally administered Oseltamivir under its trade name Tamiflu, and inhaled Zanamivir under Relenza, along with inhibitors of viral M2 matrix protein ion channels such as adamantanes, amantadine, and rimantadine. Peramivir; pyrrolidine derivative A315675 as well as long-acting R-118958 compounds) may also provide effective protection from influenza infection (Wutzler et al. 2004; Salomon and Webster 2009).

Outpatients with mild to moderate COVID-19 who are at a higher risk of subsequent severity were treated with either of the anti-SARS-CoV-2 monoclonal antibody combinations, namely, bamlanivimab 700 mg and etesevimab 1400 mg or casirivimab 1200 mg and imdevimab 1200 mg (AIIA), in addition to supportive care as per the Emergency Use Authorization criteria (https://www.covid19). It needs to be noted that the panel recommended (May 14, 2021) against the use of chloroquine, hydroxychloroquine, lopinavir, and ritonavir, with or without azithromycin (AI), dexamethasone or other systemic glucocorticoids (AIII), and antibacterial therapy. Remdesivir, an FDA-approved nucleoside-analog prodrug administered intravenously, targets viral RNA-dependent RNA polymerase and delays viral replication through early termination of transcription. It was intended to be administered to hospitalized patients requiring supplemented oxygen via a nasal cannula or mask. However, the WHO issued a conditional recommendation against its use in November 2020 because of the lack of evidence supporting its role in improving survival and other outcomes in hospitalized patients.

Dexamethasone [or its equivalents like prednisone, methylprednisolone, or hydrocortisone (BIII)], a corticosteroid, has been found to improve survival in hospitalized patients in need of supplemental O₂ therapy or mechanical ventilation. In addition to dexamethasone therapy, tocilizumab, an anti-IL6 receptor monoclonal antibody, was found to benefit patients manifesting rapid respiratory decompensation due to COVID-19 (Baxter et al. 1998; Gordon et al. 2021; Horby et al. 2021). Remdesivir and dexamethasone therapy can be continued in hospitalized patients who require invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) (AI) because of COVID-19. However, the panel recommended the use of Remdesivir monotherapy (AIIa). Tocilizumab is recommended with dexamethasone or a corticosteroid of equivalent dose. Prophylactic treatment with ivermectin is recommended in patients from areas of endemic strongyloidiasis, a nematode infection (Horby et al. 2021).

Safe and effective vaccines change the scenario; hence, worldwide research and development of vaccines resulted in the development of 15 vaccines for use. In total, 184 vaccines are in preclinical trials (experiments in laboratories and on animals are in progress). Of these, 35 were in phase I trials (effectiveness testing on healthy individuals), 36 were in phase II (tested on broader groups of people), 25 were in phase III (large international trials to study the impact on COVID-19), and 5 were in phase IV (being monitored in a wider population after approval) (https://www.gavi.org/vaccineswork/topics/science). While various therapeutic agents exist for COVID-19 treatment, herbal drugs and dietary supplements have also shown tremendous effectiveness for treatment purposes; various plant species containing phytochemicals provide additional therapies in addition to conventional pharmaceutical approaches against this viral infection. This review aims to communicate the importance of consuming proven essential nutrients for improved immunity and various antiviral immunomodulators to effectively treat COVID-19 symptoms. In addition, an attempt is made to tap our ancient knowledge to unfold remedies for managing symptomatic COVID-19 and asymptomatic human subjects with morbidities that make them vulnerable to viral attacks.

Nutritional immunity

Immunity is the body’s natural system of defense against all diseases and disorders (Patil et al. 2012). Immune functions are crucial for safeguarding the body against foreign invaders and play a significant role in the healthy maintenance of the body (Fig. 1) (Kaminogawa and Nanno 2004).

Fig. 1.

Drugs and Vaccines used to treat viral infections with a mention of the type of immune system that gets activated and brings about the activation of the concerned molecular pathways

There are two types of immune mechanisms: the primary line of defense is the highly adaptive immune system, which is tangled by memory, complexity, and diversity (Nicholson 2016). Adaptive immune reactions can be divided into two broad categories: humoral reactions mediated through B lymphocytes that produce antibodies and cell-mediated cytotoxic responses mediated by T cells that release interferon g (IFN g) (Benjamini et al. 2000). It is necessary to understand that the structural components of immune cells are derived through hematopoiesis from the bone marrow (Nicholson 2016).

Nutrient accessibility can influence all parameters of immunity. In general, the inadequacy of various nutrients will lead to hindered immune responses, and replacement of those particular components will usually re-establish the affected responses (Stephensen and Zunino 2011). Therefore, consuming foods with immune-modulating activities (Fig. 1) boosts the immune system and consequently aids in maintaining immune functions, thereby reducing the risk of infection (Kaminogawa and Nanno 2004).

Methodology

This article is based on a search strategy to address the question, “How to boost one’s immune system, and more particularly, how to protect an individual from the symptoms of serious lower respiratory tract infections?”. Google Scholar (https://scholar.google.com/), PubMed (https://pubmed.ncbi.nlm.nih.gov/), NCBI (https://www.ncbi.nlm.nih.gov/pmc/), and Research Gate (https://www.researchgate.net/search) and general Google searches with keywords such as “immunomodulators,” “nutrition,” “antiviral herbal drugs,” and “bioactive compounds for immunity” were used to extract a broad array of research articles from reputed journals, conference proceedings, and published books from 1946 to date. From a thousand plus hits obtained, 200 research publications and 13 Google searches were considered for reviewing the literature on the immunomodulatory molecules of plant origin.

The data were extracted, screened, and thoroughly assessed on the basis of the selection criteria, which included the correlation between nutrition and drug-mediated immune modulation, herbs that demonstrate antiviral action in addition to their bioactive compounds, and a detailed description of the properties of common traditional herbs and health drinks.

Finally, 195 references from Google Scholar, PubMed, and NCBI and 12 from Google searches were selected for the present review to investigate nutrition/drug/phyto-mediated immunity, modulation, and ancient knowledge to combat viral infections, including corona viruses and other similar infections. The essence of 213 references was synthesized in the results section in a gist format.

Results

Nutrition-mediated immunomodulation

The nutritional supplements such as vitamins are necessary for immune cell proliferation, differentiation, and proper expression of cytokines (Noor et al. 2021), thus contributing to the establishment and maintenance of an effective immune system in both children and adults. Regular intake of a suitable combination of vitamins, peptides, carbohydrates, fatty acids, and minerals is essential for human subjects to fight infection-mediated damage to cellular machinery. A detailed description of the management of respiratory tract infections and flu symptoms through a consortium of immune nutrients, with evidence of some research in this direction, is provided in Table 2. From the research studies cited in Table 2, it is evident that nutrient conditioning with vitamins (A, D, and C), omega-3-fatty acids, iron, zinc, Cr-III, amino acids, peptides, and carbohydrates plays an essential role in alleviating respiratory tract infections. Vitamin D and marine-derived omega 3 fatty acids are also being explored as potential autoimmune disease treatments. Magnesium deficiency may contribute to respiratory-disease symptoms, while vitamin A and zinc may protect against respiratory infections. Zinc supplementation may increase treatment efficacy and decrease symptoms, as it has dual immunomodulatory and anti-viral properties (Shakoor et al. 2020).

Table 2.

Immuno-nutrients with their reported mechanism of action

S. no.	Type of nutrient	Action mechanism	References
1.	Vitamin A (periodic high doses)	Reduction in acute lower respiratory tract infections in infants	Fawzi et al. (1999)
2.	Vitamin D	Plays a pivotal role in pulmonary resistance and its deficiency leads to various respiratory infections	de Tena et al. (2014)
3.	Fish oil	Decreases inflammatory response by hampering TNF and IL-1 synthesis in asthmatic conditions	Endres et al. (1989)
4.	Amino acids and peptides	Innate lung defense	Mager and Sloan (2003)
5.	Omega 3-fatty acids supplemented parenteral nutrition	Decreases pro-inflammatory cytokines with improved respiratory function in patients and also decreases the production of the metabolites of arachidonic acid which can lead to lung inflammation	Wang et al. (2008) and O’Leary and Coakley (1996)
6.	Carbohydrates	By giving low carbohydrate diet, patients with sepsis and ARDS (acute respiratory distress syndrome) manifest improved oxygenation/lung micro-vascular permeability, and decreased lung inflammation	Gadek et al. (1999)
7.	Pressured whey hydrolysate	Binds to TLR4 (transmembrane protein) by suppressing IL-8 production through lipo-polysaccharides in respiratory epithelial cell lines	Iskandar et al. (2015)
8.	Vitamin D active form [1,25(OH)2D3]	By increasing inflammatory cytokine modulation and CAMP expression, respiratory tract infections in asthmatic patients was reduced	Ramos-Martínez et al. (2018)
9.	Zinc	Shields against respiratory infections in children	Sazawal et al. (1998) and Bhutta et al. (1999)
10.	Vitamin C	Protects host cells from free radicals which were generated during respiratory burst in phagocytes	Hartel et al. (2007)
11.	Iron	Plays an important role during respiratory burst in mitochondria	David et al. (2004) and Gyana and Sunita Sahoo (2015)
12.	Probiotics (Bifidobacteriumbreve YIT4064)	Boosts immune system against oral influenza virus by producing high amount of anti-influenza virus-specific IgG	Islam et al. (2022)

Immunomodulators

These are primarily synthetic molecules that can provoke, hinder, or morph any immune system related feature, including innate and adaptive defense responses (Fig. 2). Immunomodulators can be categorized into three categories based on clinical perspectives: (a) Immunoadjuvants are specific immune stimulants designed to increase vaccine efficacy by acting as immune response modulators. They were exploited as choosers between helper T1 and T2 cells, immune-destructive and immune-protective properties, and reactive IgE and IgG. Hence, they present a stiff challenge in designing a vaccine. (b) Immunostimulants are intrinsically non-specific as they improve the body’s resistance to infection. They can manage immune responses mediated by both innate and adaptive mechanisms. These immune stimulants serve as promoters and prophylactic agents in healthy individuals. Moreover, they can act as healing agents in immune-impaired individuals. (c) “Immunosuppressants” is a term that refers to a group of drugs or compounds commonly used for treating autoimmune diseases, including graft versus host reactions (El-Sheikh 2008).

Fig. 2.

Chemical structure of some representative natural bioactive molecules from the four identified families of vascular plants with a mention of their role in strengthening the immune system

Drug-mediated immuno-modulation

To manage the COVID-19 pandemic, every nation continued to depend on the strategy of “drug repurposing,” with simultaneous efforts to find effective and target-specific drugs. A list of FDA-approved antiviral and antiparasitic drugs, with their general and specific mechanisms of action, extracted from the drug bank (https://www.drugbank.com), is detailed in Table 3.

Table 3.

Immunomodulatory drugs for repurposing against respiratory viral infections along with their known mechanisms of action

S. no.	Drug	General mechanism of action	Specific action mechanism	References
1.	19 approved anti-viral drugs, 10 natural inhibitory ligands from PubChem, 10 natural sources optimized for E. coli BL21 (DE3)	Inhibition of viral proteases by binding to their active sites	Binding to the SARS-CoV-2 main protease (PDB# 6YB7) and its inhibition by 39 ligands of which Ritonavir was identified as potent inhibitor for SARS-CoV-2pneumonia	El-Hoshoudy (2020)
2.	61 molecules in clinics or clinical scrutiny as anti-viral agents: 37 molecules were found to be effective	Inhibition of viral enzymes; Protein synthesis (Methisazone), CGP42112A—an angiotensin AT2 receptor agonist and ABT450, an inhibitor of the non-structural protein 3-4A	Binding to and inhibition of covid 19 enzyme by HIV-1 protease inhibitors and RNA-dependent RNA polymerase inhibitors	Shah et al. (2020)
3.	7 lead compounds—4 FDA approved drugs viz. Glecaprevir, Daclatasvir, Paritaprevir, Atazanavir and 3 phytochemicals-Vincapusine, Alloyohimbine, Gummadiol	3C-like protease (3 CLpro) inhibition of SARS-CoV-2, SARS-CoV and MERS-CoV	3C-like protease (3 CLpro) inhibition of Sars-Cov-2, SARS-CoV and Mers-Cov	Gurung et al. (2020)
4.	Acyclovir and its derivatives including Ganciclovir, Penciclovir, Valaciclovir, and deoxy guanosine	Inhibition of SARS-CoV-2 protease—6LU7	Inhibition of SARS-CoV-2 protease—6LU7	Arun Kumar et al. (2020)
5.	Baricitinib	Treatment for severe rheumatoid arthritis in adult patients	A JAK inhibitor that may interpose with the inflammatory processes	Richardson et al. (2020)
6.	Chloroquine	An antiparasitic drug to treat rheumatic diseases, malaria, prophylaxis of Zika virus, and extraintestinal amoebiasis	Inhibitor of heme polymerase in malarial parasite that blocks conversion of heme to hemazoin leading to death of parasite	Guo (2020) and Coronado et al. (2014)
7.	Darunavir	A HIV-1 protease inhibitor used for the treatment of HIV-1 infected patients with prior history antiretroviral therapies	Inhibits viral proteases such as 3CLpro or PLpro	China Intellectual Property News (2020)
8.	Favipiravir	Used to treat viral infections viz. Ebola and Lassa viruses, and nowCOVID19 virus	Inhibits RNA-dependent RNA polymerases to choke viral replication	Lagocka et al. (2021) and Mifsud et al. (2019)
9.	Galidesivir and BCX-4430 (salt form of galidesivir)	Used to treat hepatitis C, Ebola virus, Marburg virus	A nucleotide analog which may block viral nucleotide synthesis to hamper viral replication	Warren et al. (2014)
10.	Ivermectin	An antiparasitic medication to treat intestinal strongyloidiasis, tapeworms, and onchocerciasis	Hampers viral replication with ivermectin’s nuclear transport inhibitory activity	Caly et al. (2020)
11.	Lopinavir	An HIV-1 protease inhibitor utilized in amalgamation with ritonavir to treat HIV infection	Protease inhibitor (Nope)	Li et al. (2020)
12.	Nelfinavir	A viral protease inhibitor used in the treatment of HIV-1 infection	Protease inhibitor (Nope)	Hsieh et al. (2010)
13.	Nitazoxanide	An anti-infective and thiazolide used to treat infections by viruses, anaerobic bacteria, protozoa, helminths, and microaerophilic bacteria	Inhibits viral protein expression	Jean-François Rossignol (2014)
14.	Out of 145 phyto-compounds selected from Kabasura Kudineer (KK)—a polyherbal formulation recommended by AYUSH for COVID-19, 15 compounds were identified to be effective from molecular docking studies	Inhibition of viral protease—SARS-CoV-2 3CLpro—A and B chains	Inhibition of SARS-CoV-2main protease, 3CLpro (6LU7)	Vincent et al. (2020)
15.	Phytochemicals viz. Naringin, Quercetin, Capsaicin, Psychotrine and Gallic acid	Inhibition of proteases	Inhibition of COVID-19 protease (6LU7)	Alrasheid et al. (2021)
16.	Remdesivir	A nucleotide analog used to treat RNA virus infections	Inhibits RNA-dependent RNA polymerases to choke viral replication	Agostini et al. (2018) and Brown et al. (2019)
17.	Ribavirin	A guanosine nucleoside used for treating few forms of Hepatitis C	A nucleotide analog which may block viral nucleotide synthesis to hamper viral replication	Morse et al. (2020), Arabi et al. (2017) and Guo (2020)
18.	Sofosbuvir	Treatment for hepatitis C virus (HCV) infections	Inhibits RNA-dependent RNA polymerases to choke viral replication upon molecular docking studies	Elfiky (2020)
19.	Tenofovir	Effective against hepatitis B virus, HIV-1, and HSV-2	Inhibits RNA-dependent RNA polymerases to choke viral replication (upon molecular docking studies)	Elfiky (2020)

Phyto-mediated immunomodulation

The plant kingdom produces several mini-organic molecules called secondary metabolites. However, because of their limited distribution, these molecules can only be found in certain plant species (Lattanzio 2003; Lattanzio et al. 2006; Dey 2016). According to Hartman et al. (2007), these secondary plant metabolites play a significant role in evolutionary development in adapting to environmental conditions. However, these secondary metabolites are used in textiles, pharmaceuticals (medicines and supplements), cosmetics, and recreational drugs (Hartmann 2007). Different herbal medicines have been demonstrated to balance different segments of the innate and acquired systems. Appropriate comprehension of the different immunomodulatory activities of herbs and the secondary metabolites derived and used as natural products could lay the path for their development as active pharmaceutical ingredients (API). Herbal medicine serves as an integrative means of immunomodulation, helping to prevent infections from spreading further and thus decreasing the risk of disease (Sharma et al. 2017). Approximately 25% of drugs derived from a consortium of flora from distinct forest habitats have established novel foundations for secondary metabolites as antiviral agents (Lancet 1994; Kala et al. 2006) in modern treatment methods and serve as the prototype analog compounds for building the synthetic therapeutics.

Tables 4 and 5 display notable research findings that showcase secondary metabolites with a crucial function in regulating respiratory tract infections. The data will assist us in effectively managing the introduction of novel disease strains through a rigorous scientific approach, hence mitigating the occurrence of catastrophic pandemics in the future. The synthesized gist of Tables 4 and 5 shows that four plant families of 21 plants with their corresponding metabolites, such as tannins, catechins, triterpenoids, polyphenols, lectins, anthocyanins, phenolic caffeic acid, alkylamides, coumarins, isovaleric acid, sterols, quercetin, ellagic acid, myricetin, ajoene, allicin, fructan, andrographolide, iridoid, and lignan from “Rosaceae” (Agrimonia pilosa, Chaenomeles sinensis, Prunus mume, Rosa nutkana/Amelanchier alnifolia, Aronia melanocarpa, Potentilla arguta), “Asteraceae” (Echinacea purpurea, Aster spathulifolius, Achillea millefolium, Calendula officinalis, Blumea laciniata/Elephantopus scaber/Laggera pterodonta), “Amaryllidaceae” (Allium sativum, Allium fistulosum, Narcissus tazetta), and “Acanthaceae” (Clinacanthus siamensis, Rhinacanthus nasutus, Barleria prionitis, Andrographis paniculata) could be powerful sources for drug discovery and herbal medicine formulations. The above four plant families could be considered powerful sources for fighting against the consortium of respiratory tract infections in the present and future (Fig. 2).

Table 4.

List of some important herbs and their active ingredients that demonstrated anti-viral action

S. no.	Botanical name (family name)	Active extract/bioactive metabolites	Active against virus (name)	Mode of action with cell type	References
1.	Achillea millefolium (Asteraceae)	Leaf and flower/coumarins, isovaleric acid, bitters salicylic acid, sterols asparagin, flavonoids, and tannins	Influenza	Used as anti-inflammatory agent in chest rubs	ESCOP (1996) and Blumenthal et al. (1998)
2.	Agrimonia pilosa (Rosaceae)	Whole plant ethanolic extract/tannins, flavonoids (catechins), triterpenoids	Influenza A/B	Hampered RNA synthesis in embryonated chicken eggs and MDCK cells. Prevents viral adsorption of host cells	Shin et al. (2010)
3.	Allium fistulosum (Amaryllidaceae)	Ethanolic extract of green leafy parts/polysaccharide (fructan)	Influenza	Inhibition of viral replication in mice model. Generates neutralizing antibodies against the infection	Lee et al. (2012)
4.	Allium oreoprasum (Alliaceae)	Methanolic-aqueous extracts	Influenza	Strong anti-viral activity on MDCK cells	Rajbhandari et al. (2001)
5.	Allium sativum (Amaryllidaceae)	Ajoene and allicin from fresh garlic extracts and oil-macerates	Para-influenza virus 3	Inhibited virus adsorption and penetration in HeLa/Vero cells	Weber et al. (1992) and Umakanth et al. (2020)
6.	Aloe arbadensis (Asphodelaceae)	Hot glycerine extracts/Aloe-emodin, anthraquinone	Influenza	Devastation of viral envelope partially in Vero cells	Sydiskis et al. (1991)
7.	Androsace strigilosa/Bergenia ligulata (Saxifragaceae)	Methanolic-aqueous extracts	Influenza	Strong anti-viral activity on MDCK cells	Rajbhandari et al. (2001)
8.	Asparagus filicinus (Asparagaceae)	Methanolic-aqueous extracts	Influenza	Strong anti-viral activity on MDCK cells	Rajbhandari et al. (2001)
9.	Aster spathulifolius (Asteraceae)	Whole plant methanolic extract	Influenza	Reduction of visible cytopathogenic effects in MDCK cell lines	Won et al. (2013)
10.	Bergenia ciliate (Saxifragaceae)	Methanolic extract	Influenza	MDCK cells	Rajbhandari et al. (2007)
11.	Blumea laciniata/Elephantopus scaber/Laggera pterodonta (Asteraceae)	Aqueous extracts/polyphenolic compounds	RSV	Exhibits anti-viral activity on cytopathogenic effect (CPE) reduction assay	Li et al. (2004)
12.	Calendula officinalis (Asteraceae)	Flower extract/rutin, hyperoside, quercetin, calendulosides, 3-O-glycosides of isorhamnetin, astragalin, and isoquercitrin	Influenza A2 and APR-8	Inhibits viral replication	WHO (2002)
13.	Camellia sinensis (Theaceae)	Tea/catechin derivatives	Influenza	Hampered viral replication and hemagglutination	Song et al. (2005)
14.	Chaenomeles sinensis (Rosaceae)	Fruit ethanolic extract/active polyphenols	Influenza A/B	Hampers NS2 protein synthesis and hemagglutination activity on MDCK cells	Sawai et al. (2008)
15.	Chamaecyparis obtuse var. formosana/Cryptomeria japonica (Cupressaceae)	Heartwood ethyl acetate extracts/lignoids, abietane and labdane-type diterpenes, and sesquiterpenes	SARS-CoV	Inhibition of viral replication and cytopathic effect on Vero E6 cells	Wen et al. (2007)
16.	Cicer arietinum (Fabaceae)	Phenolic compounds from aerial parts, skin, seed, fruit, and skin	Para-influenza virus 3	Antiviral activity in Vero and MDBK cell lines	Kan et al. (2009)
17.	Cistus incanus (Cistaceae)	Polyphenol (CYSTUS052)	Influenza	Blocked the viral entry by morphing the viral surface structures of MDCK cells	Ehrhardt et al. (2007) and Kalus et al. (2009)
18.	Clinacanthus siamensis (Acanthaceae)	Ethanolic extracts of leaf	Influenza	Generated antibodies against virus in MDCK cells and mouse studies	Wirotesangthong et al. (2009)
19.	Commelina communis (Commelinaceae)	Alkaloids	Influenza	Hampered the viral growth and decreased viral load in lungs in mice and MDCK cells	Bing et al. (2009)
20.	Echinacea purpurea (Asteraceae)	Commercial extract: Echina fractions/phenolic caffeic acid derivatives, alkylamides, and polysaccharides	Influenza	Blocked viral entry by hampering replication and receptor binding in H-1 subclones of HeLa cells	Vimalanathan et al. (2005) and Pleschka et al. (2009)
21.	Echinacea species (Asteraceae)	Aqueous and Ethanolic extracts of aerial parts and roots/polyphenols	Influenza and corona virus sub types/RSV	Inhibits hemagglutinin and neuraminidase, targets membrane components	Hudson and Vimalanathan (2011)
22.	Elsholtzia rugulosa (Lamiaceae)	Apigenin and luteolin	H3N2	In vitro antiviral activity assay using cytopathogenic effect	Liu et al. (2008 a)
23.	Eugenia singampattiana (Myrtaceae)	Methanol extract/kaempferol, ferulic acid, 4-hydroxybenzoic acid, quercetin, caffeic acid, coumaric acid, rutin, epigallocatechin gallate, and myricetin	PRRSV*	In vitro antiviral activity	John et al. (2014)
24.	Geranium sanguineum (Geraniaceae)	Methanolic extract/polyphenols	Influenza	Modified the viral protein expression on the cell surface of murine model	Serkedjieva (1996) and Sokmen et al. (2005)
25.	Ginkgo biloba (Ginkgoaceae)	Ginkgetin	Influenza	Targets Sialidase	Kitazato et al. (2007)
26.	Glycyrrhiza glabra (Fabaceae)	Glycyrrhizinic acid	SARS-CoV	Inhibits viral replication in Vero cells	Fiore et al. (2008)
27.	Houttuynia cordata (Saururaceae)	Aqueous extract	SARS‑CoV	Inhibits 3CL protease	Lau et al. (2008) and Lin et al. (2005)
28.	Isatis indigotica (Apiaceae)	Phenolic compounds	SARS‑CoV	Inhibits 3CL protease	Lin et al. (1999)
29.	Juniperus formosana (Cupressaceae)	Triterpenoids (betulinic acid)	SARS-CoV	Inhibits 3CLpro	Ryu et al. (2010a, b)
30.	Lonicera japonica (Caprifoliaceae)	Flower extract/iridoid glycosides, mono and sesquiterpenes, caffeic and quinic acids	Influenza, Swine flu, Pneumonia	Treatment for upper respiratory tract infections	Packman and London (1980)
31.	Lycoris radiata (Amaryllis)	Ethanolic extract of stem cortex	SARS‑CoV	Antiviral activity in Vero cells	Li et al. (2005a, b)
32.	Meliaceae species	Triterpenoids and limonoids	RSV	Inhibits RSV replication	Bueno et al. (2009)
33.	Mussaenda pubescens (Rubiaceae)	Aqueous extracts/polyphenolic compounds	RSV	Exhibits anti-viral activity on cytopathogenic effect (CPE) reduction assay	Li et al. (2004)
34.	Myrica rubra (Myricaceae)	Leaf ethanolic extract	Influenza	Anti-influenza activity on MDCK cells, irrespective of its sub types	Mochida (2008)
35.	Nerium indicum (Apocynaceae)	Methanolic-aqueous extracts	Influenza	Strong anti-viral activity on MDCK cells	Rajbhandari et al. (2001)
36.	Opuntia streptacantha (Cactaceae)	Crude extract	Influenza virus	Inhibits viral replication	Ahmad et al. (1996)
37.	Peganum harmala (Nitrariaceae)	Seed extract/alkaloids (beta-carbolines)	Influenza	Herbal medicine	Moradi et al. (2017)
38.	Pinus thunbergil (Pinaceae)	Methanolic extract of stem, leaves	Influenza	Reduction of visible cytopathogenic effects	Won et al. (2013)
39.	Prunus mume (Rosaceae)	Fruit juice/lectin molecules	H3N2 and H1N1	In vitro anti-influenza activity by preventing viral adsorption and inhibits viral hemagglutinin in MDCK cells	Yingsakmongkon et al. (2008)
40.	Psidium guajava (Myrtaceae)	Leaves (tea)	Clinical isolates of H1N1 virus	Inhibits viral hemagglutination, neuraminidase, and sialidase activity on 19-h influenza growth inhibition assay	Sriwilaijaroen et al. (2012)
41.	Punica granatum (Puncaceae)	Polyphenols (luteolin, caffeic and ellagic acid, and punicalagin)	Influenza	Inhibits viral replication	Haidar et al. (2009)
42.	Rheum officinale and Polygonum multiflorum (Polygonaceae)	Root tubers aqueous extracts/emodin	SARS-CoV	Blocks ‘S’ protein and inhibits the interaction of ACE2	Ho et al. (2007)
43.	Rheum palmatum (Polygonaceae)	Natural anthraquinone, Aloe-emodin (1,8-dihydroxy-3-hydroxymethyl-anthraquinone)	Influenza	Traditionally used in Chinese medicine	Sydiskis et al. (1991)
44.	Rosa nutkana/Amelanchier alnifolia (Rosaceae)	Methanolic extract of branches	Enteric corona virus	Inhibition of cytopathogenic effects during in vitro antiviral testing	McCutcheon et al. (1995)
45.	Sanicula europaea (Apiaceae)	Acidic fraction of the crude extract	Parainfluenza virus type 2	Inhibits viral replication	Karagoz et al. (1999)
46.	Schefflera heptaphylla (Araliaceae)	Dicaffeoylquinic acids from leaf stalks	RSV*	Hampers RSV replication	Li et al. (2005a, b)
47.	Schefflera octophylla (Araliaceae)	Aqueous extracts/polyphenolic compounds	RSV	Exhibits anti-viral activity on cytopathogenic effect (CPE) reduction assay	Li et al. (2004)
48.	Scutellaria baicalensis (Lamiaceae)	Isoscutellarein-8-methylether from roots	Influenza	Hampered viral replication	Nagai et al. (1995)
49.	Scutellaria indica (Labiatae)	Aqueous extracts/polyphenolic compounds	RSV	Exhibits anti-viral activity on cytopathogenic effect (CPE) reduction assay	Li et al. (2004)
50.	Thuja orientalis (Cupressaceae)	Methanolic extract of leaves	Influenza	Reduction of visible cytopathic effects	Won et al. (2013)
51.	Torreya nucifera (Taxaceae)	Ethanolic extract of leaves/ferruginol	SARS-CoV	Potent inhibitor of 3CLpro	Ryu et al. (2010a, b)
52.	Tripteryguim regelii (Celastraceae)	Methanolic extract of bark/celastrol, pristimererin, tingenone, and iguesterin	SARS-CoV	Potent inhibitor of 3CLpro	Ryu et al. (2010a, b)
53.	Trollius chinensis (Ranunculaceae)	Ethanolic extract/flavonoids such as proglobeflowery acid, vitexin, and orientin	Parainfluenza type 3	Treatment of bronchitis and upper respiratory tract infections	Li et al. (2002)
54.	Uncaria hynchophylla (Rubiaceae)	Indole alkaloid	Influenza	Inhibits virus replication	Kitazato et al. (2007)
55.	Verbascum thapsus (Scrophulariaceae)	Methanolic-aqueous extracts	Influenza	Strong anti-viral activity on MDCK cells	Rajbhandari et al. (2001)

RSV, respiratory syncytial virus; PRRSV, porcine reproductive and respiratory syndrome

Table 5.

List of plants showing antiviral activity against respiratory syncytial virus (RSV), influenza virus and its subtypes

S. no.	Botanical name (family name)	Active extract/bioactive metabolites	Active against virus name	References
1.	Adenium obesum (Apocynaceae)	Cardiotonic glycoside	Influenza	Kiyohara et al. (2012a, b)
2.	Aesculus hippocastanum (Sapindaceae)	Triterpenoid	Influenza	Hiller (1987)
3.	Andrographis paniculata (Acanthaceae)	Whole plant/Andrographolide	H1N1, H9N2, H5N1, SARS-CoV2. Inhibits viral production and suppresses the main protease	Parimala and Manoharan (2009) and Adiguna et al. (2021)
4.	Aronia melanocarpa (Rosaceae)	Fruit juice/anthocyanins/polyphenols-ellagic acid and myricetin	Influenza A	Valcheva-Kuzmanova and Belcheva (2006) and Platonova et al. (2021)
5.	Barleria prionitis (Acanthaceae)	Iridoid: 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester and its cis isomer	RSV	Chen et al. (1998)
6.	Bupleurum falcatum L. (Umbilliferae)	Saikosaponin-A	Influenza	Hiller (1987)
7.	Carnavalia ensiformis L. (Leguminosae)	Canavanine	Influenza	Pilcher et al. (1955)
8.	Chelidonium majus L. (Papaveraceae)	Chelidonine	Influenza	Manske and Brossi (1987)
9.	Coffea arabica (Rubiaceae)	Caffeic acid	Influenza	Molgaard and Ravn (1988)
10.	Curcuma longa (Zingiberaceae)	Rhizomes	H1N1, H6N1	Parimala and Manoharan (2009)
11.	Digitalis lanata Ehrh. (Scrophulariaceae)	Lanatoside D	Influenza	Koch and Sandor (1969)
12.	Eleutherococcus senticosus (Araliaceae)	Root extract	RSV/influenza A virus	Glatthaar-Saalmuller (2001)
13.	Emblica officinalis (Euphorbiaceae)	Fruit and seed extract	Influenza	Parimala and Manoharan (2009)
14.	Glycyrrhiza inflate (Fabaceae)	Ketone (chalcones) from roots	Influenza A (H1N1)	Dao et al. (2011)
15.	Glycyrrhiza uralensis (Fabaceae)	Polyphenols from the roots	Influenza	Grienke et al. (2012)
16.	Gossypium herbaceum (Malvaceae)	Gossypol	Influenza	Harborne and Baxter (1993)
17.	Gymnema sylvestre (Asclepiadaceae)	Gymnemic acid	COVID-19	Subramani et al. (2020)
18.	Holoptelia integrifolia (Ulmaceae)	Crude extract	Influenza virus	Rajbhandari et al. (2007)
19.	Ipomopsis aggregate (Polemoniaceae)	Whole plant extract	Type 3 parainfluenza virus	McCutcheon et al. (1995)
20.	Markhamia lutea (Bignoniaceae)	Verbascosidea, isoverbascoside, and luteosided from roots	RSV	Kernan et al. (1998)
21.	Narcissus tazetta (Amaryllidaceae)	Lectin from bulbs	Influenza/RSV	Ooi et al. (2010)
22.	Pandanus amaryllifolius (Pandanaceae)	Saline extract of the leaves/lectin (pandanin)	Influenza	Ooi et al. (2004)
23.	Pogostemon cablin (Lamiaceae)	Patchouli alcohol from leaves	Influenza	Kiyohara et al. (2012a, b)
24.	Potentilla argute (Rosaceae)	Root extract/polyphenols	Bovine RSV	McCutcheon et al. (1995)
25.	Rhinacanthus nasutus (Acanthaceae)	Aerila parts/lignan (rhinacanthin E and F)	Influenza	Kernan et al. (1997)
26.	Rhus succedanea L. (Anacardiaceae)/Garcinia multiflora (Clusiaceae)	Agathisflavone, rhusflavanone, amentoflavone, robustaflavone, and succedanea flavanone	Influenza A and B, parainfluenza type 3, RSV	Lin et al. (1999)
27.	Sambucus nigra (Adoxaceae)	α- and β-amyrin, ursolic acid, campesterol, oleanolic acid, stigmasterol, b-sitosterol and glycosides (chlorogenic, caffeic and p-coumaric acids, and ferulic)	H3N2, H1N1	Parimala and Manoharan (2009)
28.	Sambucus racemose (Adoxaceae)	Branch tip extract	RSV	McCutcheon et al. (1995)
29.	Saponaria officinalis (Caryophyllaceae)	Lyophilized infusion	Influenza	Serkedjieva et al. (1990)
30.	Selaginella sinesis (Selaginellaceae)	Ethanolic extract/amentoflavone	RSV	Ma et al. (2001)
31.	Strophanthus kombe (Apocynaceae)	Strophanthin G	Influenza	Kaij-a-Kamb et al. (1992)
32.	Theobroma cacao L. (Sterculiaceae)	Caffeine	Influenza	Yamazaki and Tagaya (1980)
33.	Urginea scilla Steinh (Liliaceae)	Proscillaridin A and scillarenin	Influenza	Koch and Sandor (1969)

Based on this analysis, it is evident that among the four families consisting of 21 plants, metabolites such as polysaccharides, polyphenols and triterpenoids are prominently present and have a crucial function in fighting respiratory illnesses like influenza, RSV, and SARS-CoV. This information is shown in Tables 4 and 5.

Absorption and bioavailability limitations of phytochemicals

Phytochemicals are receiving greater attention for the development of new pharmaceuticals because of their high potency, low toxicity, and specificity in targeting desired molecules expressed on the cell surface. Food supplements with bioactives that do not add calories can be included as part of diets for their prophylactic and therapeutic advantages, but their major disadvantages include poor hydrophilicity, rapid metabolism, short half-life, and gastritis-causing potential (Siddiqui et al. 2023). Unfortunately, their application benefits are severely restricted by non-reproducible absorption rates, variable bioavailability, therapeutic dosage regimens, and subject-to-subject variations that impede application benefits (Porter and Charman 2001). The lipid-based formulations appear to be one promising solution to address the issues of poor absorption, permeability, bioavailability, and sustained release of phytochemicals in the animal and human models studied (Mouhid et al. 2017). A predictive model study was conducted to determine the time required to achieve maximum plasma concentration (C_max) of the drug, an important pharmacokinetic parameter, in humans with different phytochemicals in fruits and vegetables. This investigation included 67 dietary phytochemicals from 31 clinical studies as a training set. A model was developed and validated using three independent datasets comprising 108 dietary phytochemicals and 98 pharmaceutical compounds (Selby-Pham et al. 2017). From the study, it was inferred that predicting T_max of dietary phytochemicals can help design clinical studies and optimize protective efficacy. Matching T_max to OSI (oxidative stress and inflammation) i.e., biological cycles maximizes suppression and minimizes tissue damage. Combining phytochemical-rich foods based on computable physicochemical properties helps understand absorption characteristics, maximizing phytochemicals’ potential for health benefits. Further, the prediction model utilized T_max instead of maximal plasma concentration (C_max) since it is less influenced by dosage. Larger levels of phytochemicals can potentially act as pro-oxidants and facilitate oxidative stress, rendering C_max less valuable than T_max. Hence, a good understanding of the C_max and T_max is essential to maximize the phytochemical efficacy.

The antivirals used for treating viral infections affecting 3–5 million patients annually can have serious adverse side effects. The phytopharmacotherapy offers an alternative treatment approach with few side effects (Ben-Shabat et al. 2020). Although herbal extracts have been used since ancient times, there have been limited reports on the pharmacokinetics of herbal pharmaceuticals. However, in recent years, these studies have been initiated to understand and improve the pharmacokinetics of herbal drugs. This is due to the advent of novel pharmaceutical formulation and delivery strategies that include self-nano emulsifying and self-micro emulsifying drug delivery systems (SNEDDS and SMEDDS) (Buya et al. 2020), in addition to widely used approaches such as nanoparticles, pyrosomes, hydrogels, microspheres, transferases, and ethosomes (Chauhan et al. 2022). These improved phytodrug formulations have excellent solubility, oral absorption, systemic bioavailability, safety, and delayed metabolism, thereby enhancing their efficiency. Some well-known phytochemicals such as myricetin, apigenin, baicalin, quercetin, andrographolide, curcumin, naringenin, honokiol, and oleanolic acids have been studied and demonstrated to have enhanced antiviral efficacy (Ben-Shabat et al. 2020). These novel formulations were subjected to in vitro and in vivo tests. In the case of myricetin, self-emulsifying drug delivery systems (SNEDDSs), which are isotropic mixtures capable of producing fine oil-in-water emulsions, demonstrated over 90% drug release after 1 min after single pass intestinal perfusion and had significantly higher permeability coefficients (1.2–2.2 fold increase) (Qian et al. 2017).

In animals, a small particle size is essential for high bioavailability through absorption into the lymphatic system. For apigenin, a poorly soluble flavonoid, water-in-oil (W/o) emulsions gave higher oral bioavailability with a ninefold higher maximal plasma concentration as opposed to its suspension dosage form (Kim et al. 2016). Similarly, the oral absorption of baicalin was improved by forming micelles with pluronic P123 copolymer and sodium taurocholate (Zhang et al. 2016).

The sustained release effect of curcumin was achieved using modified-nanolipid carrier systems containing higher N-acetyl L-cysteine PEG levels (Tian et al. 2017). In essence, different phytochemicals with different physicochemical properties require different formulation strategies for effective absorption and consequent enhancement of bioavailability. The critical characteristics are logP and melting point, in addition to molecular weight and chemical structure. Through appropriate formulation strategies, an agreement between the solubility and permeability of any phytochemical drug in the presence of its excipients should be established.

Ancient knowledge

When there is a dangerous situation, we usually discover its underlying cause and remove it. Therefore, it is worth looking back into the past and reflecting on the strategies of our ancestors, who battled these pandemics using traditional medicines and herbal extracts.

From the beginning of time, plants have had an important place in the medication used by humankind. Antiquated civilizations consumed herbs in their crude form. Humankind took steps to comprehend that consuming herbs at the right time could improve their sustainability, immunity, and life for longer periods (Sumner and Plotkin 2000). The Egyptians portrayed numerous forms of herbal formulations around 1500 BC. A few balm and tea extracts have been proposed to treat various diseases (Sumner and Plotkin 2000).

Ayurveda is an alternative, traditional medicine system with historical roots that is extensively practiced in India and other countries. The primary classical references that explain nearly 700 herbs are Charak Samhita/Sushrut Samhita (1000–500 BC) and Atharvaveda (around 1200 BC). In Ayurveda, the word "Rasayana" (rasa = nutrition, ayana = transit all over the body) is known to improve quality of life and immunity (Chulet and Pradhan 2009).

South India is one of the significant assets for plenty of assorted therapeutic plant biodiversity (particularly the Western Ghats) and is accounted for in terms of customary use against different maladies. Indeed, the birthplace of the more recent variety of Siddha medicine followed and practiced by Siddhas was seen as proof of South India’s diverse variety of restorative plants. Even today, numerous individuals are using plant hotshots for their essential clinical needs, not just in South India but everywhere worldwide (Goleniowski et al. 2006; Gurib-Fakim 2006).

Hokari et al. (2012) reported that Japanese herbal medicines (Shahakusan and hochuekkito) showed in vivo antiviral activity against influenza virus (Hokari et al. 2012). Zhong et al. (2013) stated that archaic Chinese medicine (Jinchai) hampered influenza viral adsorption by obstructing replication and transcription (Zhong et al. 2013). Duan et al. (2011) outlined the use of a Chinese natural medicine (LianhuaQingwen cap), which had therapeutic effects similar to those of oseltamivir, in terms of reducing the duration of influenza infection. Intriguingly, it has been reported that the most common spices in Indian cuisines (Table 6) boost the immune system and help prevent viral infections (Umakanth et al. 2020).

Table 6.

List of a few common traditional herbs and spices with their properties

S. no.	Plant common name/botanical name	Bioactive compounds	Property	References
1.	Ajwain (Trachyspermum ammi)	Essential oil thymol contains, limonene, dillapiole, and carvone	Treatment for pleurisy and cough	Choudhury et al. (1998) and Avicenna (1998)
2.	Boneset (Eupatorium perfoliatum)	Sterols, eupatorin, flavonoids, gallic acid and tannins	Treatment of flu and common cold	Skwarek (1979)
3.	Cardamom [Elettaria cardamomum (L.) Maton]	Carotenoids (lutein and β-carotene) and flavonoids (quercetin, catechin, kaempferol, and myricetin)	Treatment for asthma and bronchitis	Ashok Kumar et al. (2020), Al-Zuhair et al. (1996), Bisht et al. (2011) and Umakanth et al. (2020)
4.	Cinnamon (Cinnamomum zeylanicum)	Eugenol	Treatment for colds and respiratory disorders	Paranagama et al. (2001), Sadlon and Lamson (2010) and Umakanth et al. (2020)
5.	Clove (Syzygium aromaticum)	Essential oil (eugenol)	Treatment of cough, bronchial congestions, and respiratory tract infections	WHO (2002) and Umakanth et al. (2020)
6.	Cumin (Cuminum cyminum)	Cuminaldehyde, cymene, cuminic alcohol, and terpenoids	Asthma, diabetes, inflammation, and hypertension	Umakanth et al. (2020)
7.	Curry leaves (Murraya koenigii)	Carbazole alkaloids	Treatment of influenza	Chakraborty et al. (1965) and Tachibana et al. (2001)
8.	Eucalyptus (Eucalyptus globules)	1,8-Cineole	Nasal decongestant activity and treating influenza	WHO (2002)
9.	Fennel seeds (Foeniculum vulgare)	Phenylpropanoid (trans-anethole) as major component	Treatment for cough and cold	Diao et al. (2014), Savo et al. (2011) and Lisa Aston Philander (2011)
10.	Garlic (Allium sativum)	Allicin	Stimulates T lymphocytes and NK cells. Enhances WBC and CD4 counts	Bongiorno et al. (2008)
11.	Ginger (Zingiber officinale)	Gingerols and shogaols	Treatment of cold symptoms	ESCOP (1996) and Blumenthal et al. (1998)
12.	Kalonji seeds (Nigella sativa L.)	Thymoquinone	Treatment for asthma, cough, and bronchitis	Yimer et al. (2019)
13.	Korean ginseng (Araliaceae)	Ginsenosides, polysaccharides, polystyrenes, phytosterols, and essential oils	The antiviral action of Korean red ginseng extract (RGE) against influenza A virus boosts immune cell survival and reduces cytokine production, boosting the immune system’s resistance to COVID-19	Abedini et al. (2022)
14.	Mustard seeds (Brassica juncea)	Polyhydroxy steroids	Antiviral activity against influenza virus (H1N1)	Kumar and Andy (2012) and Lee et al. (2014)
15.	Peppermint leaf and oil (Menthae piperitae)	Menthol and menthone	Suppresses cold and cough reflexes	WHO (2002) and Gobel et al. (1994)
16.	Pumpkin (Cucurbitaceae)	Carotenoids (β-carotene), fatty-acids, polyphenols	Immunomodulation activity by managing systemic inflammation and endothelial damage, which are major pathological drivers of COVID-19 prevalence	Hussain et al. (2023)
17.	Star anise (Illicium verum)	Phenolic and flavonoid compounds; two coumarin derivatives viz.7-hydroxyl coumarin and 7-methoxycoumarin	carminative, antispasmodic, antiseptic, antimicrobial, anti-diarrheal activities and is used to treat colics and as a tranquilizer	Umakanth et al. (2020)
18.	Tamarind (Tamarindus indica)	Triterpenes and phenolic compounds	Effective in cough and allergic asthma	Kuru (2014)
19.	Tulsi (Ocimum sanctum)	1,8-Cineole, eugenol/methyleugenol, and a- and b-caryophyllene, ethylchavicol, and linalool	Treatment of common cold, asthma, influenza, and bronchitis	Singh and Agrawal (1991), Singh et al. (1996) and Maheshwari et al. (1987)
20.	Turmeric (Curcuma longa)	Curcumin	Treatment of cold, cough, and sinusitis	Wachtel-Garol (2011), Prasad and Aggarwal (2011) and Gupta et al. (2013)

In the wake of the COVID-19 flare-up, humanity across the globe is making brave efforts to contain it and tackle post-COVID morbidities. Although there is no specific or targeted medication for COVID-19, taking precautionary measures to improve immunity will be acceptable. The Ministry of AYUSH (Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homeopathy) of the Government of India, put forth a few guidelines for immunity boosting with particular reference to respiratory health, assisted by scientific publications and Ayurvedic literature (Nesari et al. 2022), as listed here:

1. Meditation, yoga, asana, and pranayama as advised by the Ministry of AYUSH

2. Use of turmeric, cumin, coriander, and garlic in cooking

3. In the morning, intake of 10 g or 1 teaspoon of chyavanprash, and for diabetics, sugar-free chyavanprash is recommended.

4. Herbal tea preparation is made up of adding tulsi leaves (4 parts), cinnamon powder (2 parts), ginger powder (2 parts), and black pepper (1 part) to 150 mL of water and boil for 15–20 min. The filtrate can be served with honey, jaggery, or lemon juice (optional).

5. To make golden milk, mix 1/2 teaspoon turmeric powder into 150 mL of hot milk and drink it once or twice a day.

6. In the morning, apply ghee, coconut oil, or sesame oil to both nostrils; gargle for 2–3 min with 1 tsp coconut oil; and spit.

7. Steam inhalation with caraway seeds or mint.

8. A combination of honey and clove powder for throat irritation or cough.

The Central Council for Research in Homoeopathy (an autonomous body of the Ministry of AYUSH, Government of India) promotes the use of the prophylactic homeopathic medicine “Arsenicum album-30” against coronavirus infection, which has been generally prescribed for safeguarding against influenza-like illness (CCRH 2020).

The American Association of Naturopathic Physicians states that herbal plants such as licorice root, North American ginseng, elderberry, Echinacea, and garlic can prevent flu. Including nutrients in the diet, such as seaweed extract, zinc, probiotics, vitamin C, and selenium, aids in ensuring a sound immune system (AANP 2020).

In its guidelines, the World Naturopathic Federation (WNF) recommends the use of warming spices with antimicrobial and antiviral properties such as sage, garlic, thyme, ginger, and oregano, during the COVID-19 pandemic. WNF also supports the use of lean protein, vegetables, and whole grains for balanced nutrition (WNF 2020).

The above precautionary steps can be followed to the degree conceivable according to a person’s comfort. As there is no direct scientific evidence for these herbal remedies to cure COVID-19 infection, these measures are still considered useful across nations as they may boost our immunity against infections.

Mohammadi and Shaghaghi (2020) reported that molecular docking analysis of eight secondary metabolites from traditional medicinal plants, including diallyl disulfide from garlic, curcumin from turmeric, capsaicin from pepper, limonene from cardamom, thymol from pennyroyal, coumarin from licorice, and verbascoside from hedge nettle, revealed inhibitory activity against the COVID-19 protease enzyme. Of these tested compounds, curcumin showed the strongest interaction and high binding affinity with the COVID-19 protease enzyme.

Khaerunnisa et al. (2020) investigated luteolin-7-glucoside, kaempferol, quercetin, apigenin-7-glucoside, naringenin, oleuropein, demethoxycurcumin, curcumin, catechin, and epigallocatechin as potent inhibitor candidates for COVID-19 Mopar (PDB ID 6LU7) using molecular docking analysis, with nelfinavir and lopinavir used as standards (NCT04252885 2020). The binding affinity toward COVID-19 Mopar in terms of (ΔG) was in the decreasing order of nelfinavir to allicin through lopinavir, kaempferol, quercetin, luteolin-7-glucoside, demethoxycurcumin, naringenin, apigenine-7-glucoside, oleuropein, curcumin, catechin, epigallocatechin, zingerol, and gingerol. In silico analysis revealed that the secondary metabolites chosen for the study had a similar pharmacophore structure.

Chandel et al. (2020) discovered that withanolide D, nelfinavir, and withaferin A are effective COVID-19 major protease (6LU7) inhibitors. The order of affinity toward COVID-19 protease (6LU7) in terms of ΔG decreased from nelfinavir to aloe-emodin down through rhein, withanolide-D, withaferin-A, and enoxacin.

From Table 6, AYUSH preventive measures, and docking studies (Alrasheid et al. 2021), it is evident that most of the secondary metabolites are available in common household spices. A review of the literature on immunity boosting and warding off infectious agents by the regular use of common Asian spices indicates their possible role in reducing the harmful effects of SARS-CoV-2 infection (Umakanth et al. 2020). Because these spices have a mimetic nature similar to antiviral drugs, their regular intake acts as prophylaxis and preventive medicine for respiratory-related symptoms caused by viruses. However, more research is required to fully understand the medicinal plants’ action potentials with these secondary metabolites.

Conclusion

Contemporary concerns in the domain of viruses that pose threats to humans include both newly emerging and evolving illnesses. The emergence of the JN.1 COVID-19 variant is remarkable; this particular strain has recently become predominant in the United States, accounting for almost 60% of all cases. The modifications in this variant, derived from BA.2.86, enhance its ability to evade immunity and facilitate more efficient transmission of infections, leading to a significant surge in the number of cases. The Centre for Disease Control and Prevention (CDC) has reported that a new strain of influenza has become the primary cause of illness in the United States. The importance of maintaining current vaccinations is underscored by the ongoing threat of flu variations, which have the potential to induce widespread illness. Furthermore, the state-of-the-art genetic analysis has revealed new viruses that have the potential to produce global pandemics in the future, particularly through the process of host-switching in animals. This analysis underscores the crucial significance of specific nutrients and medicinal herbs for enhancing immune response and combating respiratory tract infections. To enhance the functioning of the immune system, it is essential to consume nutritional supplements containing vitamins A, D, and C, omega-3 fatty acids, iron, zinc, and other vital micronutrients. It is particularly crucial when managing viral illnesses including influenza, RSV, and SARS-CoV. The findings suggest that incorporating these nutrients into daily diets can reduce the severity and frequency of respiratory tract infections, offering a preventive strategy for susceptible populations. In addition, the analysis identifies 115 medicinal plants from four plant families: Rosaceae, Asteraceae, Amaryllidaceae, and Acanthaceae. These families include a total of 21 species that exhibit potent antiviral and antibacterial properties. These plant species show promise in treating respiratory diseases and can be valuable resources for developing herbal formulations. Incorporating bioactive components derived from these plants into our daily diet could serve as a pragmatic approach to bolstering the immune system, particularly those included in commonly used spices.

The escalating issue of viral resistance underscores the need for alternative therapies, notwithstanding the shown efficacy of customized antiviral medications such as Paxlovid. Herbal therapy is an attractive option due to its high absorption, ability to imitate synthetic antiviral compounds, and minimal toxicity. However, further research is necessary to validate the efficacy of these medicines derived from plants and their bioactive components. Moreover, by combining old medical systems such as Ayurveda with modern science, there is the possibility of developing standardized herbal formulations that can offer dependable and effective treatment for viral infections. It is important to promptly explore plant-based alternatives to synthetic antiviral medications that could potentially have lower toxicity and higher bioavailability. There is a pressing need for in-depth studies to analyze how nutrition and bioactive chemicals might directly affect the immune system at the molecular level and inhibit viral infections. Metabolomics and proteomics, advanced research techniques, can be employed to identify the specific biological pathways involved. Moreover, it is imperative to prioritize randomized controlled trials (RCTs) to systematically assess the efficacy of plant-based formulations and dietary supplements in preventing and treating respiratory infections. Exploring the synergistic effects of many medicinal plants, such as those seen in traditional formulations like rasayanas, holds great promise for the future advancements in herbal therapy. It is also essential to utilize computational biology and high-throughput screening techniques to identify bioactive chemicals in these medicinal plants that have the potential to be developed into innovative antiviral medications. Advanced computational methods are assisting in the detection and monitoring of newly arising dangers. Supplementing one's diet with vitamins, omega-3 fatty acids, iron, zinc, Cr-III, amino acids, peptides, carbs, and probiotics is essential for reducing the severity of respiratory tract infections. Metabolomic studies and medication repurposing, including herbal medicines, offers significant potential for the creation and advancement of novel therapeutic discovery and development programs targeting various viral diseases.

Declarations

Conflict of interest

The authors declare that there are no conflict of interest.