Role Of Food Nutrients And Supplementation in Fighting Against Viral Infections And Boosting Immunity: A Review (Part 1)

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ABSTRACT

Background: Viral infections can be highly contagious and easily transmissible, which even can lead to a pandemic, like the recent COVID-19 outbreak, causing massive deaths worldwide. While, still the best practical way to prevent the transmission of viruses is to practice self-sanitation and follow social distancing principles, enhancing the individual's immunity through the consumption of proper foods containing balanced nutrients can have significant results against viral infections. Foods containing nutrients such as vitamins, minerals, fatty acids, a few polysaccharides, and some non-nutrient (i.e. polyphenols)have shown therapeutic potential against the function of viruses and can increase the immunity of people.

Scope and approach: The results of conducted works aiming to study the potential antiviral characteristics of diverse groups of foods and food's nutrients(in terms of polysaccharides, proteins. lipids, vitamins, and minerals)are critically discussed.

Key findings and conclusion: Nutrients, besides playing an important role in maintaining normal physiology of the human body and healthiness, are also required for enhancing the immunity of the body and can be effective against viral infections. They can present antiviral capacity either by entering into the defensive mechanism directly through interfering with the target viruses, or indirectly through activating the cells associated with the adaptive immune system. During the current situation of the COVID-19 pandemic(the lack of proper curative viral drug), enhancing the immunity of an individual's body through proposing the appropriate diet (rich in both macro and micro-nutrients)is one of the few practical preventive measures available in fighting against Coronaviruses, this significant health-threatening virus, as well as other viruses in general.

Keywords: Viral infection Virus Immunity Nutrients Foods

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1. Introduction

Many viral infections are highly contagious and easily transmissible which can lead to massive health problems or even deaths worldwide. Some of the emerging viral infections are caused by viruses such as Measles, HIV, Influenza, Herpes simplex virus, Dengue, Chikungunya, Zika, Hepatitis, etc. (Kapoor, Sharma,&Kanwar,2017). Few other viruses such as Severe Acute Respiratory Syndrome(SARS)and Middle East Respiratory Syndrome (MERS), causing respiratory illness, have also emerged recently. The outbreak of Spanish flu, caused by the H1N1 influenza virus at the beginning of the 20th century has been one of the deadliest viruses in human history (CDC and WHO). The recent outbreak of COVID-19, caused by the novel coronavirus SARS-CoV-2, related to the respiratory syndrome, was declared a pandemic by the WHO in March 2020. Paules, Marston, and Fauci(2020)reported that these viruses are mostly linked to the zoonotic types, originated from the animals, and transferred from animals to humans and humans to humans. Despite the wide range of antiviral drugs currently available to potentially be used in the process of finding an appropriate cure, the sudden emergence of novel viral strains makes it difficult to introduce effective drugs or cures on time. Therefore, the best way to prevent transmissible infections still is to practice self-sanitation, and social distance, and to enhance immunity against targeted viruses.

To boost the immunity of individuals, the consumption of proper foods containing a balanced nutritious diet is crucial. In this regard, foods containing more nutrients, such as vitamins, minerals, fatty acids, and a few polysaccharides and non-nutrient(i.e. polyphenols) which have therapeutic functions can be very beneficial. These compounds have the potential to either act against viruses directly or are effective against them by boosting the immunity of the body. For example, vitamins such as A, D, E, and Care are known for playing a crucial role in body development and repair mechanisms which can enhance immunity (Galanakis,2020; Zhang & Liu, 2020).

It has been shown that the consumption of foods like carrots, citrus fruits, fruit juices, germ oils, nuts, seeds, milk, and dairy products that are rich in those vitamins can be helpful in boosting immunity. An investigation carried out by Keil, Bowen, and Marschner(2016)on the effect of riboflavin against the MERS-CoV(EMC strain), showed a 4.07 log reduction in viral growth. Wang et al.(2020)reported that vitamin D played an important role as an immune modulator against the Hepatitis C virus. Most of the vitamins are potent antioxidants responsible for scavenging free radicals and reducing oxidative stress. The ability of vitamin C in reducing the severity of respiratory tract infection caused by SARS coronavirus was reported by Hemila and Chalker (2013). Lipids, particularly polyunsaturated fatty acids (PUFA) and a few medium-chain fatty acids, are potent antiviral agents (Das, 2020; Galanakis, 2020). Goldson et al.(2011)reported that PUFA's exhibited antiviral action against the chronic Hepatitis C virus (HCV) along with participating in normal physiological function. Regarding the minerals, zinc, selenium, iron, and chromium are crucial in increasing immunity because of possessing some antiviral properties. For instance, Shah, Verma, Oleske, Scolpino, and Bogden(2019)reported that zinc can be used as a supplement to reduce the intensity of COVID-19 infection and lessen respiratory tract infection.

Some of the non-nutrient components, particularly phytochemicals such as polyphenols, flavonoids, alkaloids, thiophenes, terpenoids, tannins, lignins, etc, have shown some important antiviral properties. Flavonoids are beneficial due to their antioxidant, antiviral, anticarcinogenic, and anti-inflammatory activities (Abdelkebir et al.,2019). The polyphenols such as epigallocatechin gallate, the phytochemical extracted from green tea showed an important antiviral activity against several viruses(Li et al., 2020). Furthermore, fruits and vegetables can also present valuable antiviral properties due to their high content in phytochemicals and some other minor health-related compounds (Martin-Acebes, Vazquez-Calvo, Caridi, Saiz,& Sobrino, 2012).

Regarding proteins, lectin has shown antiviral action against the coronaviruses (Mani et al.,2020). Furthermore, the essential oils extracted from plants, known for their antibacterial, antifungal, anti-viral, and antioxidant properties are also beneficial for the health of individuals. It was reported that traditional Chinese medicine can be effective against coronaviruses (Ling,2020; Luo et al.2020). For example, Shaikh et al.(2019)studied the antiviral potential of a traditional Chinese medicine compound known as ZINC32540717(1-{2-[3-hydroxy-4-(4-phenyl-1H-pyrazole-3)phenoxylethyl}

piperidine-4-carboxamide) against the Ebola virus. The authors observed an ICso（Inhibitory concentration） of 3.1± 0.02 μM at a concentration of 5 mg/ml for this antiviral compound.

Since the discovery of antiviral drugs for emerging viruses must go into a very time-consuming process(in-vitro and in-vivo analysis and clinical trials), using the available and practical options for fighting against viruses in outbreak situations sounds vital. In this aspect, the possibility of being able to enhance the body's immunity (innate and adaptive)to defend against the viruses, through the consumption of nutritious foods and bioactive compounds sounds like a very promising solution for researchers. In this review, the recent works conducted on evaluating the potential impact of a diverse group of nutrients and foods on immunity against viruses are comprehensively discussed.

2. Pathogenesis

Pathogenesis defines the way the virus enters the host and leads to the disease and it depends on the virulence and host defense mechanism. The process of pathogenesis includes the adsorption of viruses on the host surface, injection into the host, local replication inside the cells, cell to cell transfer, and finally transmission to the target organs. The respiratory tract is the most common route for viral entry.Mason(2020)described the pathogenesis of COVID-19 in 3 different stages. The first stage is the asymptomatic stage, in which the virus enters the nasal cavity, attaches to the epithelial cells, and starts replicating. During the second stage, the virus through the respiratory tract enters to lungs and the onset of early symptoms. The third stage is the complete development of the disease.

3. Nutrients possessing antiviral properties

Since the rapid changes in the lifestyle and socio-economic standards of people have posed an adverse effect on society, the balanced nutrition diet is still considered a crucial challenging factor in enhancing immunity to fight against several diseases. For example, the micronutrients such as vitamin A, C, D, and E and a few minerals such as iron, zinc, and selenium have shown an important role in modulating the immune functions as a preventive measure for COVID-19(Gasmi et al, 2020). Important cells belonging to adaptive immunity are T cells and B cells which can recognize the antigens through several surface receptors (Wessels & Rink,2020). The positive impact of the nutrient components can eliminate the threat of death because of the majority of infectious diseases(Macan et al,2019). This section critically discusses the relationship between the nutrients and their antiviral properties.

3.1. Polysaccharides

Polysaccharides are high molecular weight macromolecules essential for several physiological functions. They consist of chains of monosaccharides joined together via glycosidic links classified as homo-polysaccharides and hetero-polysaccharides. Cellulose, glycogen, and starch are important abundantly available polysaccharides that serve the main energy reservoirs in plants and animals. Polysaccharides possess some therapeutic properties such as antiviral, antioxidative, anticancer, and immunomodulating activities(Chang et al,2015). There are several reports showing that polysaccharides alone, or in combination with proteins and a few phenolic compounds exhibited interesting pharmacological activities. For instance, Chen and Huang (2018)reported that some polysaccharides (both natural and modified), showed antiviral properties against coxsackievirus, influenza virus, human immunodeficiency hepatitis virus, and herpes simplex virus. This section summarizes a few pieces of evidence of polysaccharides possessing antiviral and antioxidant properties and why they are essential for enhancing immunity.

3.1.1.-glucan

β-glucan is a soluble dietary polysaccharide comprising a β-glucose linkage, particularly found in cereal cell walls. It is known that β-glucan is associated with an anti-cholesterolemic activity, which is good for heart health. The β-glucan can directly inhibit and disrupt the virus particles or present its indirect effects by enhancing the immunity of the host (Urbancikova et al.,2020). In a study conducted by Legentil et al.(2015), they reported that there is evidence showing that β-glucan shares the best position among several immunomodulator materials. On the other hand, the antiviral property of β-glucan was investigated by Urbancikova et al.(2020); the immunomodulatory β-glucan effect was observed in the herpes simplex virus type 1. The authors described that β-glucan stimulated the production of cytokines and activation of natural killer cells, T lymphocytes, and dendritic cells, leading to enhanced host immunity. Similarly, Chaichian et al.(2020)also reported that β-glucan is effective against HIV infections. The mechanisms proposed by Vogt et al.(2013) state that β-glucan could modulate the immune system by binding to the pattern recognition receptors on the cells of dectin-1 and Toll-Like receptors. Likewise, Leg-entil et al. (2015)reported that the interaction of β-glucan with several receptors (particularly dectin-1)is responsible for its antiviral effects. Dectin-1 is a specific receptor for β-glucan, expressed on phagocytes and immunocompetent cells. The investigation of Park and Gallagher (2017), showed a decrease in the influenza virus replication due to an increase in the interferon-gamma and nitric oxide production. β-glucan is associated with immune-modulatory action like the production of nitric oxide (potent viral replication inhibitor), reactive oxygen species, and release of cytokines (Reboul,2017). Brown and Gordon (2005) reported that β-glucan activated in leukocytes was attributed to the production of cytokines and chemokines, like interleukins and tumor necrosis factors. Evidence showed that β-glucan can act as an immuno-stimulating agent by activating macrophages and natural killer cells.

3.1.2. Fructans

Fructans are among other groups of polysaccharides possessing antiviral properties, which are based on a chain of fructose molecules. Few fructans such as inulin are known to promote immunity leading to good health (Actor, Hwang,& Kruzel, 2009). Garlic, onion, chicory, garlic, asparagus, banana, and artichoke are some of the important sources of fructans (Sabater-Molina, Larqué, Torrella,& Zamora, 2009). Peshev and Van den Ende(2014) reported that fructans stimulated the function of immune cells mediated through the Toll-Like Receptors(TLR). The TLRs are known to be expressed in the innate immunity cells, particularly natural killer cells as the first line of defense against bacterial and viral infections(Luo et al.,2020). In another study, Dobrange, Peshev, Loedolff, and Van den Ende (2019)demonstrated the mechanism of an antiviral effect of fructans on the herpes simplex virus type 2, observing that these compounds can enhance the production of nitric oxide and immunostimulatory factors such as interleukins, interferon-gamma, and tumor necrosis factors. In the investigation of Kumar, Prashanth, and Venkatesh (2015), this author attributed the immune-modulatory action to the production of nitric oxide as they observed significant production of nitric oxide in the peritoneal exudate cells extracted from rats. On the other hand, He et al.(2020)reported that fructans extracted from onions showed similar antiviral effects on the A virus in mice. Through the other mechanism, the fructans can bind to the Toll-Like Receptors (particularly TLR2/TLR4), which can modulate the number of T cell regulators. These T cell regulators are considered the major regulators of the immune system which are crucial during infections(Jia et al,2017).

3.1.3. Sulfated polysaccharides

Polysaccharides with a substituted group of sulfate can possess some antiviral and therapeutic properties. However, the efficiency of sulfated polysaccharides highly depends on the degree of substitution and position, and the type of glycosidic linkages. Parts of some medicinal plants, edible and wild mushrooms, and marine algae are among the important sources of sulfated polysaccharides. Fucoid, galactan, carrageenan, shaman, and Ulvan,  are among sulfated polysaccharides that have shown antiviral properties against some viruses such as Hepatitis, influenza, herpes simplex virus, HIV, rotavirus, enterovirus, and coxsackievirus B3(CVB3)(Chen & Huang,2018; He et al.,2020). The sulfated polysaccharides are known to interact with positively charged domains of target viruses' envelope and prevent their adsorption and penetration processes(He et al,2020), thus regulating the function of macrophages, lymphocytes, and natural killer cells, generating anti-bodies, and promoting the secretion of NO (Huang, Shen, Morris,& Xie,2019). Moreover, they activate the T cells by enhancing T helper-1 response, acting as a high immunostimulatory substance (Kim, Cho, Karnjanapratum, Shin, & You, 2011). In this line, the immunostimulating effect of sulfated polysaccharide on herpes simplex virus type 2 was studied by Lee and Han (2018), observing an increase in cytokine mRNA expressions of Interleukine 1β, 6,10 and tumor necrosis factor-α. Tuvaanjav et al.(2016) also investigated the effect of sulfated polysaccharides on the HV virus using a surface plasmon resonance. The model interaction between the sulfated polysaccharide and poly-L-lysine revealed an inhibitory effect on the HIV virus. Moreover, Kwon et al.(2020)assessed the antiviral effect of sulfated polysaccharides at a concentration of 1 μM on the SARS-CoV-2 protein. They observed an inhibition effect against SARS-CoV-2 and reported that sulfated polysaccharides extracted from the seaweeds are considered generally regarded safe and can be administrated orally.

3.2.Proteins

Lectin and lactoferrin are among proteins possessing antiviral properties, which interfere with viral replication. The cell-to-cell involvement of lectin can be exploited to analyze its biological molecules' surface interactions and functions (Singh, Walia, & Kennedy, 2020). Lectins have shown viral inhibition. They can recognize the virus and irreversibly bind with the sugars through their binding sites. Lectins are effective against viruses such as HIV, influenza, Hepatitis C virus, and coronaviruses(Hwang et al.,2020; Mazalovska & Kouokam, 2018). In this sense, most of the mannose-binding lectins showed antiviral effects against the coronaviruses (SARS-CoV)(Keyaerts et al.,2007). Lectins mainly bind to the specific carbohydrate structures-like virus envelopes(glycoproteins) and mainly high mannose glycan (Mitchell, Ramessar,&O'Keefe, 2017). The authors also reported that lectin is a potent inhibitor of the HIV virus by interacting with the glycosylation moieties present on the cell surface and restricting the conformational change required for virus attachment(Fig.1a). Likewise, the lectin affected the coronavirus spike prohibiting its entry pathway by inhibiting the specific receptors ACE2 on the cell membrane(Fig. 1b)(Key-aerts et al.,2007). The mechanism of lectin as an anti-HIV virus was reviewed by Mazalovska and Kouokam(2018). The authors reported that lectins had a high affinity towards the glycoproteins gp120 and gp41, present in the envelope of the HIV virus, blocking its entry into the human cells. Similarly, lectins exhibited antiviral properties, by binding to the E1 and E2 glycosylation sites present in the envelope of the hepatitis C virus and inhibiting its entry into the cell (Tuvaanjav et al, 2016). The secondary category of the antiviral property of lectins is through regulating the innate immune system during the infection. For example, plant lectins showed an important immunomodulatory activity by enhancing the expression of I-1β, TNFα, and INFy genes and were beneficial for controlling infections (Sabater-Molina et al,2009). Evidence showed that lectins had high mitogenicity activity, thus increasing the cell division of natural killer lymphocytes and inhibiting the herpes virus inhibition (Wetprasit, Threesangsri, Klamklai,& Chu-lavatnatol, 2000). Similar evidence was reported by Peumans et al (2000)who showed that lectins are powerful T-cell mitogens. Moreover, some lectins possess an insecticidal property that prevents the transfer of viruses through insects (Snene et al.,2017).

Lactoferrin is an avid iron-binding protein commonly found in the milk of mammals called the red protein of milk(Siqueiros-Crendon et al.。,2014). The concentration of lactoferrin varies from milk to milk and mainly depends on the stage of lactation. Lactoferrin helps in innate immunity and is considered the first line of defense mechanism against several infections (Actor et al.,2009). Lactoferrin works as an antimicrobial, anti-inflammatory, and immunomodulating agent required for newborn protection(Giansanti, Panella, Leboffe,& Anto-nini, 2016). Lactoferrin modulates the overall immune responses by increasing cytokine production, maturing T-helper cells, and scavenging the intracellular reactive oxygen species (Siqueiros-Cendon et al,2014). Lactoferrin has been effective against several viruses such as Adenovirus, Rotavirus, Poliovirus, HSV, HIV, influenza virus, and hepatitis viruses(Wakabayashi, Oda, Yamauchi, & Abe, 2014). It inhibits the herpes simplex virus glycoproteins(GC or GB)attachment to the heparin sulfate on the host's cell surface (Fig. la)(Jensen, 2005). For example, Farnaud and Evans(2003)reported that after the initial contact, the virus enters the host cell through specific cell surface receptors. Lactoferrin could inhibit the virus particle adsorption and during virus replication, it enhanced the production and activity of natural killer cells, interferon α/β, and T helper cells(Wakabayashi et al,2014). Similarly, Mayeur, Spahis, Pouliot, and Levy (2016)showed that lactoferrin increased the activation of T helper cells and cytotoxic T cells through the modulation of dendritic cells. The inter-action of lactoferrin and antigen-presenting cells, reported by Siqueiros-Cendon et al.(2014), resulted in an increase of macrophages and activation of dendritic cells required for maintenance of innate immunity. The macrophages are involved in the phagocytosis of microbes, type II inflammation, and tissue repairing (Siqueiros-Cendon et al.,2014). The iron present in the lactoferrin acts as an antioxidant required for scavenging formed intracellular reactive oxygen species (Actor et al.,2009). Macan et al.(2019) reported that lactoferrin inhibited the spread and replication of the HIV virus at a concentration of 10 μM and 0.4 μM， respectively. Berlutti et al.（2011）stated that human lactoferrin not only inhibited the viral attachment and absorption into the host cells but also was able to neutralize the herpes simplex virus cell to cell transmission.

3.3. Lipids

During infections, viruses require fatty acids for their replication in the host cell. However, some fatty acids can inactive microbes(either directly or indirectly) and enhance the immunity of the body. For example, the important class of omega 3 fatty acids abundantly available in fish oil, can serve as endogenous compounds enhancing the immunity against the hepatitis C virus, SARS-CoV-2, SARS, and MERS infections (Das,2020).Das(2018)explained that the PUFA can directly attack the microbial cell wall which results in the leakage and lysis of the membrane, thus enhancing the formation of bioactive metabolites such as prostaglandins, which inhibit the viral replication. The omega-3 fatty acids metabolites have some immune regulatory functions known as pro-resolving mediators(Gutierrez, Svahn,& Johansson,2019). In a study carried out by Martin-Acebes et al.(2012), these authors reported that hepatitis C virus replication was inhibited by carbonyl groups produced from the conversion of PUFA via lipid peroxidation, induced by arachidonic acid. Lipoxin a bioactive autacoid metabolite of arachidonic acid can also increase the host's defense capacities and decrease the virulence of pathogens (Wu et al,2016). The medium-chain fatty acids are also potent antiviral agents against a few viruses such as HSP and HIV(Hilmarsson, Traustason, Kristmundsdottir,& Thormar,2007). For example, the palmitate could inhibit the virus-cell membrane fusion by fixing the peptides at the site of S protein cleavage interfering with refolding and virus replication (Park and Gallagher(2017)(Fig.2). Hilmarsson et al.(2007) demonstrated that both fatty acids of lauric acid and palmitoleic acid in the acidic medium at a concentration of 1.25 mM could completely inactivate the respiratory syncytial virus (RSV). For instance, the lauric acid antiviral activity on arenavirus was reported by Bartolotta, Garci, Candurra, and Damonte(2001); the fatty acid restricted the insertion of glycoprotein into the cell membrane.