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Functional food: complementary to fight against COVID-19

Background The novel coronavirus has embarked on a global pandemic and severe mortality with limited access for its treatments and medications. For the lack of time, research, and enough efficacy, most vaccines are underdeveloped or unreachable to society. However, many recent studies suggest various alternative, complementary remedies for COVID-19, which are functional foods. This review provides an overview of how functional foods can play a great role through modulating the host immune system, generating antiviral activities, and synthesizing biologically active agents effective against the coronavirus. Main body This review article summarizes the natural defense mechanisms in tackling SARS-CoV-2 alongside conventional therapeutic options and their corresponding harmful side effects. By analyzing bioactive components of functional foods, we have outlined its different contributions to human health and its potential immunomodulatory and antiviral properties that can enhance resistivity to viral infection. Moreover, we have provided a myriad of accessible and cost-effective functional foods that could be further investigated to target specific key symptoms of COVID-19 infections. Finally, we have found various functional foods with potent bioactive compounds that can inhibit or prevent COVID-19 infections and disease progression. Short conclusion Numerous functional foods can help the body fight COVID-19 through several mechanisms such as the reduced release of pro-inflammatory cytokines, reduced expression of ACE2 receptors in cells, and inhibiting essential enzymes in SARS-CoV-2.


Background
The pandemic "Coronavirus Disease 2019" (COVID- 19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and was officially identified in late December 2019 at Wuhan, China. COVID-19 is highly contagious and mainly characterized by mild to severe respiratory infections in humans [1]. SARS-CoV-2 is mainly spread by respiratory droplets of an infected individual while coughing, sneezing, and talking. As of 10th February 2022, more than 404 million cases with over 5.5 million deaths have been reported worldwide [2]. Moreover, many countries of the world have faced several waves of reoccurring pandemic with different mutated strain of this virus [3].
The vaccine is the ultimate target to prevent and control COVID-19. Currently, there are 13 authorized vaccines available against SARS-CoV-2 with an accuracy of 75-95% [4,5]. However, as of February 2022, a total of 10.1 billon vaccine doses have been administered [6]. Every country of the world is looking for these vaccines, but due to urgent demand compared to production capacity, high price, less efficacy, and possible side effects, it may take years to ensure vaccination [7,8]. As a result, most affected countries implemented complimentary restrictive measures, including wearing masks, social distancing, and lockdowns to slow down the spread of this virus.
Moreover, synthetic antiviral drugs are also underdeveloped, expensive, might have adverse impacts, and are only used in selected situations to reduce the duration of illness [9][10][11]. Thus, it necessitates alternative, complementary remedies for COVID-19. The rapid changes in the strains of SARS-CoV-2 have led to diversified forms of medications and dietary profiles for controlling and preventing the infection risk [12]. Functional foods can play a great role through modulating the host immune system, generating antiviral activities within the host, and synthesizing biologically active agents effective against the current COVID-19 pandemic [13]. This review featured the possible pathomechanism of SARS-COV-2 and the mechanisms of functional food to fight against it.

Pathomechanism of COVID-19
The pathogenesis of COVID-19 is still not fully understood. SARS-CoV-2 is primarily transmitted by microdroplets exhaled by infected individuals or fomites and bind with the ACE2 receptor to get entry to lung cells, and then the virus targets type-II ACE2 + alveolar cells present in the lungs [14]. The infected lung cells secrete cytokine IL-8, which attracts T lymphocytes and neutrophils [15]. The innate immune system initially attempts to defend the body in various ways: mucosa-associated lymphoid tissues (MALT) protect mucosal surfaces, and Pattern Recognition Receptors (PRR) such as TLR7 recognize pathogen-associated molecular patterns (PAMPS). Additionally, activation of transcription factors such as nuclear factor κB (NF-κB) and activator protein 1 (AP-1) results in the release of pro-inflammatory cytokines such as IL-6, TNF-α, and interferon 1 [16][17][18]. Due to the secretion of various chemokines, innate immune cells accumulate in the area of infection, which releases even more chemokines and recruit lymphocytes leading to antigen presentation via dendritic cells [19][20][21].
Meanwhile, neutrophils at the infection site attempt to eliminate the virus by using neutrophil extracellular traps (NETs), phagocytosis, and oxidative burst [22]. Antigen presentation starts the phase of adaptive immune response where it depends on T lymphocytes. Helper T cells stimulate B cells to produce SARS-Cov-2-specific antibodies, while Cytotoxic T cells remove infected cells. Research has shown that 80% of cell infiltration is done by Cytotoxic T cells in COVID-19 patients [23]. If Cytotoxic T cells fail to eliminate infected cells and the disease progress for a longer time, the release of pro-inflammatory cytokines becomes uncontrollable, leading to a cytokine storm. Ultimately, multiple complications such as acute respiratory distress syndrome (ARDS) and organ failure [24] occur in infected patients, which can eventually progress to death (Fig. 1). The overall process is summarized in Fig. 1.

Functional food and its essential components and properties
Functional foods, also known as nutraceuticals, are defined as foods containing bioactive compounds that have beneficial effects on consumer health. Bioactive compounds are phytochemicals extracted and consumed as supplements or may have medicinal value when engulfed as whole food. Functional food has gained popularity to prevent numerous diseases, boost growth, and enhance host metabolic activity [25,26]. In addition, such functional foods may be useful for preventing noncommunicable diseases like COVID-19.

Multivitamins
Functional food has several essential components, including vitamins. Vitamins are organic compounds required in the diet for the growth and development of the body. Serving countless functions in the body, deficiency of vitamins can hinder the proper functioning of the body and contribute to improper immune responses to infections. A summary of essential vitamins and their rules in the body found in different functional foods is summarized in Table 1.

Minerals
Minerals are inorganic, required in small amounts in the body for various functions, including adequate functioning of the immune system [47]. Some minerals are required in larger amounts, e.g., calcium, phosphorus, magnesium, sodium, potassium, and chloride. Others are required in minute amounts, also known as trace minerals, including zinc (Zn), copper (Cu), selenium (Se), and iron (Fe), serve critical roles in many biochemical processes (Table 2). Similar to vitamins, a deficiency in such elements hampers health [47]. Minerals, both abundant and trace, and their contributions to the immune system are outlined in Table 2.

Nutraceuticals supplements
Nutraceuticals, derived from "nutrition" and "pharmaceutics, " are substances used to improve health, slow down aging, enhance life expectancy, protect from chronic illnesses or help the body functions [51]. Nutraceutical products originate from herbs, diet supplements, particular diets, and processed foods.
Research has indicated the successful application of nutraceutical products for treating various disorders such as diabetes, atherosclerosis, CVDs, cancer, and neurological disorders (Table 3) [51]. While a myriad of nutraceutical supplements is available on the market, specific nutraceutical supplements are provided in Table 3 to summarize the overall benefits of nutraceuticals.

Probiotic supplements
Probiotics are live microorganisms that provide benefits to the host when ingested in adequate amounts [55]. Strains belonging to Lactobacillus and Bifidobacterium sp. are commonly used as probiotic preparations in fermented milk and yogurt. Probiotics maintain a healthy balance between pathogenic and non-pathogenic bacteria alongside pro-inflammatory and anti-inflammatory cytokines [51]. Furthermore, probiotics improving gut microbiome affect viral vaccine responses [56]. Therefore, probiotics might play a significant role in fighting COVID-19 by mediating the immune response of the infected patients.

Immunomodulatory Properties
Functional foods play immunomodulatory roles by improving both adaptive and innate immune responses, which are imperative to the viability of living organisms [26]. Additionally, functional foods facilitate the release of immunostimulatory chemicals like cytokines and stimulate TNF-α and macrophage release that strengthen the body's defense [57,58]. Various explanations have been proposed for these effects, including the interaction of immunomodulatory peptides and opioid receptors on the immune cell surface, presence of arginine at C-terminal of peptides similar to ACE-inhibitory peptides, and activation of reactive oxygen species [58]. Consequently, deficiencies in diet had negative consequences on immune system functions suggesting immunomodulatory functions of these nutrients. For example, protein-energy malnutrition (PEM) had reduced lymphocyte proliferation and opsonic plasma activity [59]. In other instances, reduced zinc levels resulted in lower cytokine concentration in plasma alongside less proliferation of T cells, while a vitamin B6 deficiency led to a decrease in antibody-forming cells [60,61].

Antiviral activities
The antiviral properties of functional foods have also been documented to be effective against different viruses. Glycyrrhizin is effective against Japanese encephalitis virus, Human immunodeficiency virus type 1 (HIV-1), and chronic hepatitis C virus (HCV) [62]. Glycyrrhizin in licorice roots has been shown to inhibit SARS-CoV replication as it affects cellular signaling pathways and induces nitrous oxide synthesis in macrophages, preventing the virus from replicating [12]. Epigallocatechin gallate (EGCG), found in green tea and its ester derivatives, has proven to inhibit the NS3/4A protease enzyme responsible for activating functional proteins in HCV [63].
Moreover, EGCG derivatives inhibit an α-glucosidase enzyme that prevents glycoprotein synthesis for the viral envelope [63]. Sulfated polysaccharides in seaweed compete with viruses for the binding site on cells and prevent their entry by synergistic interaction with the cell [64]. Therefore, consumption of seaweed is shown to be effective against Herpes simplex virus Types 1 and 2 (HSV-1 and HSV-2), human cytomegalovirus (HCMV), HIV-1, respiratory syncytial virus (RSV), influenza virus, and bovine viral diarrhea virus [64].

Currently available non-specific treatment options for COVID-19 and their side effects
Several domestic and foreign companies are using various technologies to develop antiviral drugs, immunotherapies, and vaccines with a diverse ranging limit of accuracy. Patients with early infection are mostly given antiviral agents to reduce viral load. However, patients with severe and late infections are given anti-inflammatory drugs [76]. These antibacterial and anti-inflammatory drugs are administered to prevent and treat probable secondary bacterial infections only. Hence, these cannot assure any direct or promised recovery from the virus itself. Besides, these drugs, potential vaccines, and therapies are still underdeveloped, raising the concern of creating various minor to severe side effects (Table 4). Moreover, the availability of these treatments is not yet reachable to many people depending on their geographical and economical differences. A selection of drugs and treatments being tested for COVID-19 is presented in Table 4.

Role of functional foods on respiratory and viral diseases
Respiratory viruses are the most frequent causes of human illness, which can cause respiratory tract infections that can range from mild to lethal [102]. To prevent respiratory tract infections, medicinal plants had been used for centuries in almost all cultures worldwide as traditional medicines. Leaves, roots, stems, fruits, flowers, and several other natural substances extracted from plants with therapeutic potential had been used to make herbal medicines. In addition, probiotics can have served as functional food supplements, which had the potential to cure several such health problems [103,104]. Like other members of the coronavirus family, SARS-CoV-2 causes severe respiratory tract infections and chronic obstructive pulmonary diseases (COPDs). Previous studies have shown that dietary supplement solutions containing whey protein, carbohydrates, and antioxidants helped increase the human body's muscle strength by improving airflow limitation and reduced blood levels of inflammatory cytokines [105,106]. In addition, it also showed that intake of vitamin E and D decreased the level of COPD risk, mortality rate, and increased inspiratory muscle strength [107,108].
Several vitamins, including Vitamin C and E, have been reported to play a significant role in alleviating the immune response against respiratory viral agents [109,110]. Respiratory infections deliberately lower the vitamin count from cells, negatively affecting the immune system causing severe diseases. Functional foods containing these vitamins have shown potential antioxidant effects against pulmonary diseases and prevented the severity of the infections [111,112]. Moreover, fruits and vegetables containing β-Carotene and Lycopene have also shown free radical-scavenging activity and antioxidant effect against COPDs [113,114]. Dietary supplements, vegetables, and fruits can also work over secondary bacterial infections due to coronavirus diseases, as they are important sources of nutrients, dietary fiber, and phytochemicals. A respiratory allergy experimental model has shown that probiotics induce a clear Th1 (elaborate) balance within the infected host favoring the production of IgG instead of IgE immunoglobulin and increasing the levels of IL-10 and IFN-γ cytokines, which reduces infection severity [115].
Another study revealed that Q. Infectoria, B. integerrima, C. microphylla, and O. acanthium extracts could exhibit ACE inhibition and antioxidant activities, which can be consumed as supplements [121]. These species could be promising sources of antiviral molecules that can decrease the reactive oxygen species (ROS) production in infected cells and target different oxidative stressrelated signaling pathways resulting in a reduction in viral spread [122].
Therefore, functional food, dietary and herbal-based supplements have shown a huge impact in combating the symptoms of coronaviruses and increasing the potential activity of human immunity [123]. Furthermore, besides promising inhibitory effects, these food supplements are safe and efficient according to their consumption limit.

Potential roles of functional foods for alleviating COVID-19
A combination of few common foods is sufficient to prevent many diseases and even alleviate symptoms of patients. For example, herbs such as garlic could be easily added to daily meals, improving the utility of such dishes alongside palatability. For example, bioactive compounds in garlic can inhibit the main protease in SARS-CoV-2, reducing the spread of the virus inside the patient's body (Table 5). Also, the simple and easy addition of beverages such as green tea can be immensely helpful in the prevention of critical life-threatening diseases. Therefore, supplementing expensive drugs and therapy with costeffective, simple food ingredients may be the best option for many patients, particularly those who cannot afford conventional medical treatments (Fig. 2).

Nutraceutical supplement Source (s) rich in the nutraceutical compound Functions References
Quercetin Onion, red grapes, broccoli, citrus fruits Protects blood vessels from oxidative stress and lowdensity lipoprotein [51,52] Omega-3 fatty acids Fish Treats eye disorders such as age-related macular degeneration (AMD); prevents heart damage in diabetic patients [51] Cod liver oil Cod liver Reduces symptoms of cardiovascular-related conditions [  Furthermore, intake of these simple foods is a good endeavor for avoiding many illnesses in the first place. While specific phytochemicals in these foods have the potential to mitigate COVID-19 (Fig. 3), large-scale clinical trials are required to propagate and justify the utilization of such foodstuffs for COVID-19 patients. A list of various functional foods is given in Table 5.
The severity of COVID-19 infections in patients consists of several key elements targeted with functional food as a therapeutic option instead of relying on costly medicines. One of the main symptoms of COVID-19 is a dry cough that is a nuisance to the patient and can propagate the virus particles into the air and other spaces, increasing the chance of infection. In some patients, coughing turns more severe and causes shortness of breath. Anti-inflammatory foods such as ginger can help reduce coughing. In addition, different compounds such as 6-gingerol and 8-gingerol relax the smooth muscles in the upper airways, reducing the incidence of coughing [146].
Additionally, Treg cells responsible for preventing cytokine storm alongside its associated complications are reported to be reduced in COVID-19 patients [147,148]. COVID-19 patients have reported thrombotic complications associated with vitamin D deficiency. Therefore, consuming vitamin D-rich foods such as mushrooms, milk, and egg yolk can help prevent such complications. Minerals such as zinc also decrease COVID-19 infections that reduce autophagy and allow in vitro RdRp activity in SARS-CoV-2 [149]. Zinc-rich foods such as eggs modulate the function and abundance of immune cells alongside cytokine production, stimulate autophagy, improve antiviral drugs' efficacy, and inhibit the processing of viral polyproteins.
Secondary bacterial infections contracted from longterm clinical settings have been an important recurrence in hospitalized COVID-19 patients. Healthcare-associated infections coupled with less strict antibiotic stewardship approaches led to antibiotic-resistant pathogens in the ICU and other areas of the hospitals. Overall, Gram-negative bacteria were more prevalent in patients with the infectious agent varying according to the length of the hospital stay [150,151]. In one hospital, Klebsiella pneumoniae was the predominant pathogen [151]. Garlic oil has demonstrated antimicrobial effects against Klebsiella pneumoniae and other pathogens [152]. Probiotics such as Pediococcus pentosaceus Li05 can be an effective prophylaxis to treat gastrointestinal infections [153].
Furthermore, SARS-CoV-2 alters redox homeostasis, accumulates excess reactive oxygen species (ROS), and produces oxidative stress in the body leading to lung and endothelial damage, cytokine storm, and insulin resistance [154]. Broccoli seeds were tested on COVID-19 patients, which quickly reduced cough, gastrointestinal symptoms, and other conditions associated with cytokine storm [155]. Nutrients interacting with nuclear factor (erythroid-derived 2)-like 2 (Nrf2), the most potent antioxidant, are present in various foods such as cabbage and fermented vegetables, which can downregulate the oxidative stress associated with COVID-19.
Importantly, post-COVID-19 complications can manifest in recovering individuals such as skeletomuscular symptoms (fatigue, muscle pain), gastrointestinal symptoms (diarrhea, nausea, vomiting), and neuronal symptoms (stroke, loss of taste/smell) [156]. Various functional foods can help alleviate these symptoms-Astragalus radix for fatigue; Sumac extract for muscle pain; zinc supplements for diarrhea, ginger for nausea and vomiting; omega-3 fatty acids for stroke, liposomal lactoferrin supplement for loss of taste/smell [157][158][159][160][161]. Finally, replication of SARS-CoV-2 can be prevented by inhibiting the essential protease enzymes, as demonstrated by molecular docking studies of compounds in garlic, ginger, Neem, tulsi, black pepper, and tea. In addition, foods such as licorice can downregulate ACE2 receptors, blocking viruses from entering cells (Table 5).
While many functional foods have been studied, countless foods targeting COVID-19 infections can be  Anti-inflammatory Glycyrrhizin inhibits the 11bHSD2 enzyme, which degrades cortisol to increase aldosterone levels, leading to downregulation of ACE2 receptors and potential virus entry points in certain organs. [125,126,133,134] Anti-oxidative Anticancer Hepatoprotective Immunostimulatory Anti-pyretic Anti-ulcer   developed to form viable therapeutic options. For example, active ingredients in Rhizoma polygonati, an herb in traditional Chinese medicine, were screened from various databases to find 23 targets were found in SARS-CoV-2 by active ingredients [162]. Additionally, ten active compounds in Rhizoma Polygonati had good molecular docking scores with different drug targets of SARS-CoV-2 such as ACE2, 3CL hydrolase, Spike protein S1, and RNA-dependent RNA polymerase RdRp. Also, active compounds of Stingless bee honey demonstrate antibacterial activity (preventing secondary bacterial infection), antioxidant properties (reducing oxidative stress) and downregulation of IL-6 (shortening viral endurance in the body) [163]. Foods like this can be developed into novel functional foods through rigorous testing of efficacy, safety, and toxicity to produce viable, effective therapeutic options for COVID-19 infections.

Conclusions
More than two years have progressed since the first case of the pandemic was contracted in Wuhan. Many countries are already experiencing multiple waves of COVID-19 with increasing strains on the health care system. As of June 2021, vaccines for COVID-19 have already been approved and distributed to millions of people worldwide, which has gradually reduced the infection rates in specific countries. However, the deployment of COVID-19 vaccines has raised concerns over equal, just access of different individuals to such an essential health care service. In December 2020, 51% of all vaccine doses were purchased by high-income countries that represent only 14% of the world population [164]. By April 2021, about 1 in 4 people were vaccinated in high-income countries compared to 1 in more than 500 in low-income countries [165].

Fig. 2
Comparison of conventional COVID-19 therapies with functional food therapy. Vaccines and drugs, both part of conventional therapy, pose many challenges such as side effects, inaccessibility, non-specificity, and inaccuracy. In addition, the long-term accuracy and side effects of all COVID-19 vaccines have not been studied, making vaccine treatment very uncertain. In contrast, functional foods are simple, cost-effective food ingredients that are available to everyone. Furthermore, since daily intakes for these foods have been studied rigorously and established, they are safe to consume while providing additional benefits and improving general health Additionally, vaccines have been reported to have a low incidence of severe side effects in the population, such as Guillain-Barre syndrome (GBS), blood clots, and heart muscle inflammation [166]. Although such instances are rare, they have made the headlines that have instilled fear in many individuals who have become hesitant to receive the vaccine. Furthermore, antiviral drugs such as Remdesivir, which are used to treat COVID-19 infections, have harmful side effects that prolong the suffering of patients (Table 4). Therefore, until sufficient vaccines are supplied, alternative therapeutic options through functional foods must be employed. However, prescription of the diet with functional foods needs to consider toxicology studies as well. Toxicological evaluations reveal the necessity of further safety tests of different functional foods and standardizing their levels in a regular diet with the latest research data is essential. Furthermore, as the dosage of functional food has different effects on pre-existing conditions, specific safety levels for such individuals must be evaluated. Alongside functional foods, healthy lifestyle choices and regular exercises (that strengthen the immune system) can significantly reduce the financial strain of COVID-19, suffering of patients and death rates across the globe during this pandemic.