key: cord-0991482-es2pmvb5
authors: Arunachalam, Karuppusamy; Sasidharan, Sreeja Puthanpura; Yang, Xuefei
title: A concise review of mushrooms antiviral and immunomodulatory properties that may combat against COVID-19
date: 2022-03-02
journal: Food Chemistry Advances
DOI: 10.1016/j.focha.2022.100023
sha: b7ce0ed1e4b00e9568248ca80c3421e5d89ad73c
doc_id: 991482
cord_uid: es2pmvb5

The World Health Organization (WHO) declared COVID-19 as a pandemic on March 11, 2020, because of its widespread transmission and infection rates. The unique severe disease was found in Wuhan, China, since December 2019, and swiftly spread throughout the world. The effectiveness of ordinary goods as antiviral medicines has been shown in a number of investigations. In this research, successful dietary treatments for different COVID illnesses were compared to potential of mushroom products in its therapy. In Google Scholar, Science Direct, PubMed, and Scopus, search phrases like COVID, COVID-19, SARS, MERS, mushrooms, and their compounds were utilized. To enhance the resistance response, mushrooms including Agaricus subrufescens Peck, Agaricus blazei Murill, Cordyceps sinensis (Berk.) Sacc., Ganoderma lucidum (Curtis.) P. Karst., Grifola frondosa (Dicks.) Gray, Hericium erinaceus (Bull.) Pers., Inonotus obliquus (Arch. Ex Pers.) Pilát., Lentinula edodes (Berk.) Pegler, Pleurotus ostreatus (Jacq.) P. Kumm., Poria cocos F.A. Wolf, and Trametes versicolor (L.) Lloyd., were utilized. Changed forms of β-Glucan seem to have a good impact on viral replication suppression and might be used in future studies. Furthermore, COVID-19 antagonists were found in concentrated form in terpenoids, lectins, glycoproteins, lentinan, galactomannan, and polysaccharides. Based on prior research, mushrooms may be proposed as a preventative and therapeutic agent in the battle against COVID–19.

(Middle East respiratory syndrome) in 2012 persuaded severe human diseases (WHO, 2020) . SARS and MERS are both zoonotic diseases that originated in bats. The capacity of these viruses to evolve quickly and adapt to a new host is one of their most distinguishing characteristics. These viruses' zoonotic origins allow them to move from host to host (Cui et al., 2019) . After seven years, SARS-CoV-2 (Severe Acute Respiratory Syndrome -Coronavirus-2) was detected in December 31, 2019 in Wuhan, the capital of Central China's Hubei Province (WHO, 2020) causing the pneumonia disease named as coronavirus disease 2019 (COVID-19) (formerly 2019-nCoV) by WHO. In comparison to SARS and MERS, COVID-19 causes an extreme acute respiratory syndrome in humans and animals, resulting in massive alveolar damage and progressive respiratory action stoppage, posing significant challenges to the medical and health communities (Velavan and Meyer, 2020).

The SARS-CoV-2 has emerged as the source of a global pandemic and after that WHO proclaimed the worldwide pandemic on March 11, 2020 due to the novel type of coronavirus (nCoV). Many of the early instances were linked to the Huanan market in Wuhan, but a comparable number were linked to other markets, and some were not linked to any markets at all. Transmission among the wider community in December might explain for cases not linked to the Huanan market, which, together with the occurrence of early cases not linked to the market, could indicate that the Huanan market was not the outbreak's genesis (WHO, 2021) . Eventhough, since then, it has rapidly spread across China and in other countries, raising major global concerns.

The nCoV is a polyadenylated, enveloped, positive, single-stranded big RNA virus with a size of 27-32 kb that belongs to the genus beta coronavirus and is 96% genetically identical to the bat SARS-alike coronavirus. Coronaviruses are spherical virions with a core shell and outward projections that resemble a solar corona, therefore the name (corona means "crown" in Latin). There are various subtypes of coronaviruses that can infect humans, such (VOC) respectively (Divya et al., 2020; Velavan & Meyer, 2020; Centers for Disease Control and Prevention, 2021; Wolter et al., 2021) .

It affects patients of all ages, albeit fewer occurrences have been documented in children, with an estimated time between infection, illness progression, and hospitalization in patients ranging from 9.1 to 12.5 days (Divya et al., 2020; Fauci et al., 2020) and that affected more than 224 countries and territories with over 422 million infected cases and deaths of 5.89 lakhs as of today (https://www.worldometers.info/coronavirus/and accessed on 19

February 2022). It mainly infects the lungs by exploiting the ACE2 (Angiotensin-converting enzyme II) receptor for receptor-mediated endocytosis into host lung alveolar epithelial cells (Velavan & Meyer, 2020) activating both innate and adaptive immune responses in the host, leading to uncontrolled inflammatory innate and impaired adaptive immunological responses.

In COVID-19 patients, the number of CD 4+ T, CD 8+ T, B, and natural killer (NK) cells, as well as the proportion of monocytes, eosinophils, and basophils, is significantly decreased.

The number of neutrophils, the neutrophil-to-lymphocyte ratio, and tiredness markers (NKG2A) on cytotoxic lymphocytes (NK and CD 8+ T cells) are all increased in infected individuals (Cao, 2020) .

The infection by nCoV increased the levels of pro-inflammatory cytokines such as IL-2, IL-6, IL-8, IL-1, IL-17, G-CSF, GM-CSF, IP10, MCP1, MIP1 (CCL3), and TNF, as well as the levels of C-reactive protein and D-dimer, which leads to cytokine storm (Cao, 2020) .

The TLR (Toll-like receptors) identifies viral particles and activates the NF-κB pathway, which leads to the transcription of cytokines like IFN-γ and IL-6. However, in the case of COVID-19, the virus inhibits the NF-κB-TLR4 pathway, delaying IFN-γ production and allowing the virus to replicate uncontrolled. While when COVID-19 virus particles connect to TLRs on macrophages, neutrophils, and dendritic cells, pro-IL-1 is produced, which is subsequently cleaved by caspase-1, culminating in the production of IL-1, a mediator of lung inflammation, fever, and fibrosis (Conti et al., 2020) .

As a result, there are three stages to the COVID-19 infection: early (phase one), pulmonary (phase two), and hyper-inflammation (phase three). The first phase is characterized by fever and cough caused by viral replication in the respiratory epithelium, whereas the second phase is marked by hypoxia. Phase three is characterized by the emergence of acute respiratory distress syndrome, septic shock, cytokine release syndrome, cardiac problems, and secondary hemophagocytic syndrome, which may appear between 9 and 12 days after the onset of the illness (Khadke et al., 2020) . Inflammatory variables were found in COVID-19 patients, including an increase in (IL)-6, IL-8, tumor necrosis factor (TNF)-α and IL-1β in non-survival groups compared to survival groups, according to the study. It is critical to understand how to block the Cytokine Storm and when to begin antiinflammation medication to lower the chance of mortality from COVID-19 (Del Valle et al., 2020) . Suppression of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 have been proven to improve a variety of inflammatory disorders, including viral infections which could be considered in the management and treatment of COVID-19 (Zhang et al., 2020) .

Among the antiviral drugs that are prescribed to treat viral infections, some antivirals were designed to fight specific viruses, while others are made to fight a broad spectrum of viruses. Some of these are Remdesivir (Veklury), AT-527, EIDD-2801, Favipiravir (Avidan), Fluvoxamine, Kaletra, Merimepodib (VX-497), Niclosamide, Umifenovir (Arbidol), and monoclonal antibodies from AstraZeneca and Celltrion. Immune modulators like dexamethasone, medicines like lopinavir and ritonavir and and tocilizumab, an IL-6 receptortargeted monoclonal antibody, have been linked to reduction in fever and improved respiratory function in the treatment of COVID-19 (Qomara et al., 2021) . Conversely, WHO recommended suspending hydroxychloroquine and lopinavir/ritonavir treatment for COVID-19 patients (Harris et al., 2020) . Therefore, the key goals in COVID-19 treatment are the creation of vaccinations and preventive agents. Several vaccinations to fight viral spread were produced within a year of the pandemic. Some of these vaccinations are being rolled out over the world to help reduce infection, illness severity, and death. The vaccinations produced against nCoV are split into four types: whole virus, protein subunit, viral vector, and nucleic acid (RNA and DNA) vaccines. Some try to inject the antigen into the circulation, while others, like the messenger RNA (mRNA) vaccination, employ the body's cells to produce the viral antigen (WHO, 2020 

Despite the fact that the number of COVID-19 positive cases and deaths is steadily growing, COVID-19 infection spreads swiftly and varies from previous SARS-CoV infections due to structural differences in 'S' proteins. Each variant brings new benefits to its family over the previous's and the new variant Omicron has a strong growth advantage over Delta, resulting in fast community dispersion and greater occurrence rates than that in prior pandemics (Callaway, 2021). Hence we have yet to find safe, highly effective, and widely available therapies for coronavirus disease 2019 , and even as the vaccine begins to roll out in many countries, there are still more questions than answers about the best method to treat COVID-19 and post COVID-19 symptoms.

As well as, since these treatments do not provide a full cure or are unsuccessful for any one infected individual, and because of the rising number of human setbacks, research has focused on better understanding the disease's concept in order to design convincing cures.

COVID-19 has yet to be identified with a particular therapy. Immunization is at a critical juncture, with many individuals currently undergoing clinical trials (Fauci, 2020) . Whereas, different pharmaceuticals have now been found and created as instruments for treating and smothering incendiary crises, using steroids, nonsteroidal relaxation medications, and immunosuppressants (Fauci, 2020) . As a consequence, a powerful antiviral with increased effectiveness for the prevention and treatment of COVID-19 illness is urgently needed.

In practice, the goal is to build a medicine from a basic feasible component that is more adequate. Increased use of these treatments, however, is associated with negative side effects such as ulceration, gastric aggravation, angioedema, hepatic disappointment, migraine, hemolytic fragility, hyperglycemia, immunodeficiency-related difficulties, and others (Fauci et al., 2020) . As a consequence, conventional medicinal treatments that are widely deemed to be safe as a type of optional therapy are being explored, as well as possible antiviral and immune booster herbal medications, extracts, or formulations.

Traditional or alternative remedies are frequently the only therapeutic options accessible in impoverished nations. Traditional, complementary, and integrative medicine (TCIM) strategies appear to have sparked interest in the quest for conventional medical therapies for COVID-19. TCIM methods frequently emphasise prevention, and the immunesupporting benefits of several TCIM medicines are expected to help patients better fight against infection and after symptoms (Nugraha et al., 2020; Pergolizzi et al., 2021) . Natural products (medicinal plants/mushrooms) and their compounds could have the potential for prevention and treatment against COVID-19 since many phytocompounds have been recoganized as potential prophylactic and therapeutic agents for viral infections.

ACE2 has been discovered as a host cell surface receptor for the entrance of COVID-19 into humans, making it a promising target for novel treatments (Cheke et al., 2021) . Some popular plants, including cinnamon, pepper, olive, black nightshade, hawthorn, passion fruit, and grapes, were shown to have ACE2 inhibitory action and have been intensively explored with in silico, pre-clinical, and clinical models. Alkaloids, flavonols, flavonones, terpenes, limonoids, lignans, terpenoids, tannins, phenolic acids, and fatty acids are all examples of ACE2 inhibitors found in plant extracts (da Silva Antonio et al., 2020; Cheke et al., 2021; Abubakar et al., 2021; Joshi et al., 2021) .

In addition to using natural medicine to treat COVID-19, antiquated medicinal structures in Asia, such as Traditional Chinese Medicine (TCM) and Indian Ayurveda medicine, rely on the use of plants and therapeutic mushrooms in traditional medical systems and even regularly for various diseases such as influenza, hepatitis B, diarrhoea, throat infection, and also against various viruses such as hepatitis B, dengue, chikungunya, polio, and so on (Pergolizzi et al., 2021) .

Therefore, the purpose of this paper was to look into the anti-COVID-19 properties of regularly used and linked medicinal mushrooms. The mushrooms, which are extensively used in food and have numerous reports of improving immunity response, were used as a backdrop for this research since the primary concern from nCoV is the downregulation of the immune system and the overexpression of cytokines. As a result, in light of the COVID-19 study's focus on natural products, this evaluation suggests that mushrooms have the potential to be effective against nCoV based on existing scientific data. It also proposes that potential COVID-19 infection research targets for mushrooms should be researched and prioritized based on their antiviral, immunomodulatory, and other relevant properties. The selection criteria included PubMed/Google Scholar indexed studies or books on the immunomodulatory, anti-inflammatory, and antiviral activities of these mushrooms, as well as the primary term COVID-19.

Many medicinal mushrooms utilized in Traditional Chinese and Indian medical systems for over 2000 years have been discovered to have antiviral, immunomodulatory, and anti-allergic/anti-asthmatic effects (Patwardhan et al., 2005) . As well as, it have previously been reported to have anti-infectious, anti-inflammatory, anti-tumor, and immune-modulating properties and as a result, there is an increasing interest in the medicinal use of mushroom nutraceuticals (Pelizon et al., 2005; Akramien et al., 2007) .

Mushroom immunomodulators activate both the innate and adaptive immune systems.

By proliferating and activating innate immune system components such as natural killer (NK) cells, neutrophils, and macrophages, they increase the development and release of cytokines.

These cytokines subsequently promote B cell antibody production while also boosting T cell differentiation into T helper (Th) 1 and Th2 cells, which mediate cell and humoral immunity, respectively (Zhao et al., 2020).

Due to their large molecular weight, mushroom polysaccharides are unable to infiltrate immune cells and activate them directly. Dectin-1, Complement receptor 3 (CR3), Lactosylceramide (LacCer), and Toll-like receptor (TLR)2 are among the cell receptors implicated in polysaccharide stimulation. Polysaccharide effectiveness in these settings is determined by its affinity for immune cell receptors (Rangsinth et al., 2021) .

Since the dawn of time, mushrooms have been used to prevent and treat infection and sickness. The various reports on the immune-boosting abilities of a range of medicinal mushrooms may looked at the treatment of COVID-19 (Rangsinth et al., 2021) . According to Hetland et al. (2021) , basidiomycetes mushrooms may be effective as preventative or therapeutic add-on therapies in COVID-19 infection, as well as for the immunological overreaction and harmful inflammation associated with COVID-19 infection. Six lowtoxic/non-toxic chemicals in mushrooms demonstrated SARS-CoV-2 protease inhibitor action by Rangsinth et al., (2021) . Similarly, Chaga mushrooms (which grow largely on the bark of birch trees in Northern Europe, Siberia, Russia, Korea, Northern Canada, and Alaska) with a powerful enzymatic system and a strong defence system due to their parasitic way of life have demonstrated promising benefits in the decrease of COVID-19 related inflammatory responses in a study (Shahzad et al., 2020) .

Apart from this, the β-glucans from the edible shiitake mushroom have been found to protect against a wide range of viral infections and may assist to reduce the key cytokines implicated in the cytokine storm observed in severe COVID-19 instances. The beta-glucans, carbohydrates, found in the cell walls of saprophytes, lichens, and plants are most oftenly prescribed for heart disease and excessive cholesterol. According to recent study, medicinal mushrooms may aid with asthma and lung infections, meaning that they can also help with COVID-19. In this sense, medicinal mushrooms may have a preventive effect by strengthening the immune system's tolerance to COVID-19 (Murphy et al., 2020) .

According to Saxe, who led the MACH-19 trials with a combination of two mushrooms: turkey tail (Trametes versicolor) and agarikon (Fomitopsis officinalis), which are both accessible as over-the-counter supplements, the mushrooms offer physiologically plausible immune-modulating capabilities against SARS-CoV-2. Interacting to receptors on immune cells is one of the ways fungus interact as part of the gut microbiome. T lymphocytes, for instance, have receptors that bind mushroom polysaccharides. This is one route by which mushrooms might change the behaviour of our immune cells, which could help us to fight against SARS-CoV-2 (Slomski, 2021).

A wide rage of mushrooms have been reported with antiviral effects against various viruses as well as anti-inflammatory and immunomodulatory effects in various experiments. Table 1 shows the potential of medicinal mushrooms for the creation of broad-spectrum antiviral, anti-inflammatory, and immunomodulatory therapies, as well as the implications for COVID-19 therapy. Because of its nutritional and pharmacological characteristics, the sun mushroom Agaricus brasiliensis (synonyms: Agaricus blazei SS. Heinem) is frequently consumed, particularly as tea. Aqueous (AqE) and ethanol (EtOHE) extracts from the fruiting body of A. brasiliensis, as well as an isolated polysaccharide (PLS), were tested in HEp-2 cells for antiviral activity against poliovirus type 1. With selectivity lists (SI) of 5.4, 9.9, and 12.3, respectively, the quantity of plaques fell by half, 67 and 88 % when AqE, PLS, and EtOHE were administered shortly after infection immunization (time 0 h) (Faccin et al., 2007) .

Immunomodulatory and perhaps cancer-fighting activities of the extracts of Agaricus blazei mushroom have also been discovered. To assess leukocyte homing and enactment, mice were given (99m) Tc-radiolabeled leukocytes, which showed enhanced leukocyte migration to the spleen and heart of animals treated with A. blazei enhancements.

In the spleen, researchers detected increased initiation of neutrophils, NKT cells, and monocytes, as well as enhanced production of TNF-α and IFN-γ. Circulating NKT cells and monocytes were also more stimulated as a result of the enhanced gathering. The atherosclerotic sore patches in the aorta of mice were improved, with more macrophages and neutrophils counts. After 12 weeks of supplementation, A. blazei induced transcriptional activation of genes associated to macrophage initiation (CD36, TLR4), neutrophil chemotaxis (CXCL1), leukocyte adhesion (VCAM-1), and plaque vulnerability (MMP9) (Gonçalves et al., 2012) .

According to the literature, the related medicinal mushrooms, Agaricus blazei Murill, Hericium erinaceus, Grifola frondosa and Inonotus obliquus might have value as prophylactic or therapeutic add-on remedies in COVID-19 infection, particularly as countermeasures against pneumococcal superinfection, even when caused by multiresistant bacteria, and for the immune overreaction and damaging inflammation that occurs with COVID-19 attack (Shahzad et al., 2020; Hetland et al., 2021) .

Antrodia salmonea inhibit Angiotensin-Converting Enzyme 2 (ACE2) in Epithelial Cells which could be a potential compound against COVID-19 as prophylactic agents. Herein antcin-I show inhibitory effects on ACE2 in cultured human epithelial cells. As a result, there's a lot of curiosity about whether or if mushroom compounds can be used to combat the epidemic. Our goal was to write a short narrative assessment of the many sorts of mushrooms antiviaral and immunomodulatory effects and how they've been employed to against COVID-

The in-vitro cytotoxicity and hostile to HIV-1 activities of Cordyceps sinensis aqueous extract were investigated using the CCK-8 and TZM-bl pseudovirus tests. C. sinensis extract displayed anti-HIV-1 activities in vitro, while an aqueous extract from the fresh fungus inhibited opposite transcriptase more effectively. Furthermore, a significant relationship between the novel stroma concentrate and the Vif protein was observed.

According to the study, limiting converse transcriptase movement and partnering with Vif protein might impede the in vitro anti-HIV-1 effect of C. sinensis watery concentrates (Zhu et al., 2016) .

Grifola frondosa polysaccharide (GFP1) has a 1,6-d-glucan spine with a single 1,3-dfucopyranosyl side-spreading unit and was isolated from Grifola frondosa mycelia.

Enterovirus 71 is the germ that causes hand, foot, and mouth disease (EV71). GFP1 was evaluated for anti-EV71 action in cultivated cells, and it was discovered that EV71 viral replication was reduced, as well as viral VP1 protein articulation and genotoxicity. One of the most well-known medicinal fungus species, Ganoderma lucidum, has been used to treat a number of diseases. Triterpenoids and polysaccharides have been found as the main pharmacologically active components in G. lucidum (Boh et al., 2007) . Compounds The antiviral effects of two protein-bound polysaccharides were isolated from G. lucidum, a neutral protein-bound polysaccharide (NPBP) and an acidic protein-bound polysaccharide (APBP), were examined utilizing a plaque reduction test against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). APBP surpassed NPBP in terms of antiviral activity against HSV-1 and HSV-2 at a 50 percent effective concentration (EC 50 of 300-520 µg/mL). APBP blocked HSV-1 and HSV-2 binding to Vero cells at doses of 100 and 90 µg/mL, respectively, and both forms of HSV were prevented from entering Vero cells (Eo et al., 2000) .

In the face of inexorable hematopoietic putrefaction infection (IHNV), the antiviral activity of Lentinan (LNT-1), a powder made from Lentinus edodes mycelia (shiitake) mushroom, was investigated. According to the results, LNT-1 has a sub-atomic burden of 3.79 ×10 5 Da and has a β-(1 3)-glucan backbone with β-(1 6)-glucosyl side-branching units terminated by mannosyl and galactosyl residues. LNT-1 demonstrated antiviral efficacy against INHV, and its main antiviral mechanisms were due to the immediate inactivation and viral replication limitation, according to the research (Lee et al., 2009; Rincão et al., 2012) .

The anti-herpes simplex Virus-1 activity was found in the aqueous extracts of Fomes fomentarius (EC 50 , 11.22 mg/mL; SI > 4.46), Phellinus igniarius (EC 50 , 9.71 mg/mL; SI > 5.15), and P. pini (EC 50 , 7.16 mg/mL; SI > 6.98) (Doğan et al., 2018) .

In another in vitro study in MDCK cells, the antiviral activity of higher mushroom mycelia was examined against influenza A (serotype H1N1) and herpes simplex infection type 2 (HSV-2), strain BH. Whereas another experiment in RK-13 cells reported, Pleurotus ostreatus, Fomes fomentarius, Auriporia aurea, and Trametes versicolor viable against HSV-2 strain BH, with comparable levels of flu suppression. In this study, A. aurea exhibited resistance to the flu and antiherpetic workouts. The high regenerative file (324.67) of T.

versicolor 353 mycelium suggests that it might be a potential material for the pharmaceutics as an antiviral and antiherpetic specialist with low toxicity (Krupodorova et al., 2014) .

In a rat experiment, an antiviral protein derived from Grifola frondosa (GFAHP) inhibited HSV1 multiplication in vitro and lowered the severity of the viral infection (Gu et al., 2007) . HSV1 infection was similarly inhibited by polysaccharides from Agaricus blazei Murill in HEp2 cell cultures (Minari et al., 2011; Yamamoto et al., 2013) . By reducing infection attachment, segment, and cell to cell transmission, A. blazei mycelium polysaccharide decreased ocular, cutaneous, and vaginal (HSV2) illnesses in mice, as indicated by plaque reduction (Cardozo et al., 2013) . Surprisingly, this was caused by a blockage of early viral penetration (Minari et al., 2011) . In vitro assays, G. frondosa polysaccharide was found to inhibit replication of enterovirus 71 (EV71), the major causative for foot, hand, and mouth infection, smother viral protein articulation and induce apoptosis replication, viral enzyme, viral protein production, and cellular proteins, they claim to improve immunity against HSV-1, HSV-2, influenza A virus, HIV, HCV, FCV, and EV71.

Polysaccharide, lectin, lentin, and laccase from P. abalonus, P. citrinopileatus, L. edodes, and T. giganteum had IC 50 of 0.1-2.2 M against HIV-1. While, anti-HIV drugs like AZT, dideoxycytidine, and dideoxyinosine have IC 50 of 0.03-0.5 M, 0.5-1.5 M, and 2-10 M against HIV-1, respectively. As a result, mushrooms-derived compounds may be used as antiviral agents (Adotey et al., 2011; Wang et al., 2011; Collins & Ng., 1997; Li et al., 2008; Ngai & Ng, 2003; Wang & Ng, 2000; Wang & Ng, 2004; Wang et al., 2007; Lv et al., 2009; Eguchi et al., 2017; Seo & Choi, 2021) .

Mushroom compounds' antiviral mechanisms have been well established against enveloped viruses; however, non-enveloped viruses like NoV and enteroviruses are yet to be investigated. Therefore, bioactive metabolites from mushrooms might be employed as antiviral options against DNA and RNA viruses like nCoV causing COVID-19 (Seo & Choi, 2021) . The more details of the antiviral studies' results are depicted in Table 1 .

Immunomodulators are important components in advanced health and wellness industries, matching the invulnerable framework's role as the principal infection-prevention barrier. In clinical practice, they are usually classed as immunological suppressants, immune stimulants, or immune adjuvants. For healthy persons, they are also utilized as prodrugs or preventive medication. Over 50 mushrooms have been recognized as containing natural mixes that are invulnerable to handle and have extraordinarily extended subatomic weight and structure. Almost no mushrooms with immunomodulator properties have workouts that improve both inborn and flexible invulnerable frameworks. They increase cytokine articulation and emission, malignant development, and incurable disorders by multiplying and activating inborn safe framework components such as Natural Killer (NK) (Hazama et al., 1995; Liu, 2002; Szallasi et al., 1999; Lee et al., 1996; Sato et al., 2002; Ali et al., 1996; Saito et al., 1998; Mothana et al., 2003; Smania et al., 2003; Zhang et al., 2002) .

These compounds were described and their structures depicted in Figure 2 .

These compounds promote B cell growth for antibody production while also inciting T cell dissociation to T partner cells, which combat cell and humoral invulnerability independently. Immune-modulatory lectins, immunological-modulatory terpenes and terpenoids, immune-modulatory polysaccharides, and fungal immune-modulatory proteins are the four primary categories of mushroom immune modulators (FIPs) that have been proven to effectively reduce cytokine production (Zhao et al., 2020).

TML-1 and TML-2, two lectins isolated from Leucocalocybe mongolica (syn.

Tricholoma mongolicum), showed anticancer and immune-modulating activities through raise the production of macrophage-activating factors and so impede the proliferation of mouse lymphoblast-like (p815) mastocytoma cells by increasing nitrite and tumour necrosis factor (TNF-α). Interferon (IFN-γ) and other cytokines, such as interleukin (IL-1β) and transforming growth factor (TGF), are influenced by up-regulation of inducible nitric oxide synthase (NOS) (Zhao et al., 2020) . Even at extremely low doses, the lectin from Grifola frondosa has been demonstrated to have a significant cytotoxic impact on HeLa cells in vitro. Ricin-B-like lectin, a 15.9-kDa homodimeric lactose-binding lectin, isolated from Clitocybe nebularis with anti-proliferative action against human leukemic T cells by binding to carbohydrate receptors (Pohleven et al., 2009 ), causes the maturation and activation of dendritic cells (DCs), as well as the activation of many pro-inflammatory cytokines (Pohleven et al., 2012) .

LNT-1, Lentinan powder made from Lentinus edodes mycelia (shiitake) mushroom, caused a significant decrease in the outflow of pro-inflammatory cytokines like TNF-α, IL-2, and IL-11, as well as an increase in the expression of antiviral, antiproliferative, and immunomodulatory cytokines like IFN-1 and IFN-γ (Lee et al., 2009; Rincão et al., 2012) .

The usual safe response, as previously stated, is a crucial determinant in the severity of COVID-19 disease and infection result. Therefore, the effects of LNT-1 could be evaluated against this disease, since SARS-COV-2 patients have high levels of flaming cytokines (Chaisuwan et al., 2021) .

Similarly in another study using peptidomannan extracted from Cordyceps militaris, the mice infected with influenza A virus (H2N2) were administered orally and intraperitoneally with peptidomannan, which enhanced survival and elevated IFN levels in the blood (Suzuki et al., 1979) . In mouse lung tissue, it also reduced lung consolidation and virus titer. In vitro, however, peptididomannan had no impact on the virus. According to the study results, peptidomannan seemed to reduce viral infection via immunological strengthening (Hwang et al., 2014).

Modified terpenes (terpenoids or isoprenoids) are discovered in macrofungi with biological properties that might be employed in medicine. Ganoderma sp. mushrooms, such as G. lucidum and G. applanatum, are known for high quantities of triterpenoids such as lanostane, which possesses immunomodulating and anti-infective activities (Chakraborty et al., 2019) . Whereas, the triterpenoids from G. lucidum and G. lingzhi may aid to minimize drug-induced nephrotoxicity and inflammation. The activation of the nuclear factor (NF-κB) pathway and mitogen-activated protein kinases has been shown to possess antitumor, immune-modulatory, and/or anti-infective properties of G. lucidum, G. lingzhi, and G. applanatum (Jeong et al., 2008; Ina et al., 2013) .

Their diversified behaviors, on the other hand, suggest that they have a lot of promise for research and clinical treatment applications, despite the fact that their behavior processes and structure-activity correlations are still little understood. Some G. lucidum terpenes have been demonstrated to protect against medication nephrotoxicity and inflammation, hinting that they might be used in medicine (Zhao et al., 2020).

In recent times Yin et al. (2021) They have immunomodulatory effects as well, although with a delayed immune system activation mechanism. Low molecular weight polysaccharides, on the other hand, may enter immune cells and activate them as a result of their simple structural shape, hence regulating immunity (Barbosa et al., 2021) .

The amount and length of short branched chains in mushroom polysaccharides may have a significant influence on their bioactivity in the immune system. In immunologically active polysaccharides, the degree of branching number (DB) is generally between 20% and 40%. The polysaccharide fraction of G. frondosa extract with the best immunomodulatory activity was discovered to have a molecular weight of around 800 kDa (Adachi et al., 1990) .

Although a high DB number is normally linked with enhanced activity, in certain situations, debranching polysaccharides may also boost their bioactivity. The activity of a largely debranched pachymaran from Poria cocos, for example, was greater than the natural form (Chihara et al., 1970) . Even with the well-studied lentinan, maximal immunemodulating and anticancer activities were attained at a DB of 32 percent, and there was a negative relationship between biological activity and DB levels between 32 and 40 percent 

The viral load in COVID-19 (severe coronavirus disease) by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection peaks early and past after symptom onset.

COVID-19 is marked by altered innate and adaptive immune responses, as well as an atypical cytokine profile and multiorgan system dysfunction that persists long after the virus has been eradicated. As a consequence, a treatment strategy based primarily on antivirals may be inefficient, and antiviral medicines may not be therapeutic later in the disease.

Immunomodulatory approaches being studied include corticosteroids, cytokine and anticytokine medications, small molecule inhibitors, and cellular therapies (Mingyi et al., 2019).

In a randomized, controlled study, dexamethasone was the only medication that showed a survival advantage for COVID-19 patients. However, it is unknown which patients may benefit the most and if long-term dangers, such as secondary infections, will be present. Various research discussed here showed that mushroom polysaccharides may improve the function of immunological organs and cells, hence boost immunity (Zhang et al., 2020).

As a consequence, discovering a natural immunoregulator in mushrooms to improve immunity is a current scenario. Besides the specific polysaccharides, mushroom biomolecules have previously been shown to have antiviral and anti-inflammatory properties, making them promising candidates for new antiviral therapeutics (Figure 1) . As a consequence, natural compounds with the potential to be effective innovative COVID-19 therapies may seem to be attractive sources (Orhan & Deniz, 2020) . (Yan, 1988; Liu et al., 2001; Gao et al., 2002; Hsu et al., 2008) . In individuals with recurrent genital herpes, supplementing with Coriolus extract resulted in enhanced invulnerability and fewer days off, and clinical research have demonstrated that Coriolus, Reishi, and mixed mushroom polysaccharide derivatives all help to prolong the freedom of high-risk HPV strains (Kawana & Hashido, 1988; Donatini, 2014; Couto & da Silva, 2008) .

In an in vivo study, using mushroom extracts to guard against influenza antibodies increased protective invulnerability, while FVe, a protein from Enokitake (Flammulina velutipes), was shown to fundamentally prolong the anti-tumour protection afforded by HPV-16 vaccination in another sample (Ichinohe et al., 2010; Ding et al., 2009) . Several mushrooms have chemicals with direct antiviral action, and two in particular stand out for their potential advantages in the present epidemic.

Cordycepin (3'-deoxyadenosine) from Cordyceps organisms has been proven to limit viral replication in a number of investigations (Qin et al., 2019) . It also has a powerful calming movement and has been demonstrated to successfully protect the lungs from severe harm caused by the sort of provocative insusceptible response observed in more extreme COVID-19 virus illnesses (Lei et al., 2018) . At dosages of 10, 30, and 60 mg/kg/day, Ophiocordyceps sinensis was shown to protect mice against severe lung damage, with higher doses giving more substantial protection (Fu et al., 2019) .

Reishi triterpenes have also been demonstrated to have a considerable mitigating impact, inhibiting viral replication and reducing viral replication. Angiotensin-converting enzyme activity has been reported to be inhibited by triterpenes and proteins from Reishi, blocking the conversion of ACE-1 to ACE-2, the sort of chemical via which COVID-19 reaches cells. Although mushrooms clearly aid in the development of our immune systems and the prevention of infection, they are not a cure (Morigiwa et al., 1986; Ansor et al., 2013) .

Finally, some interesting mushrooms studied here (Agaricus subrufescens, Agaricus blazei Murill, Cordyceps sinensis, Ganoderma lucidum, Grifola frondosa, Hericium

Trametes versicolor) also showed pleiotropic effects that could provide a multimodal approach to COVID-19 management through antiviral, anti-inflammatory, and immunomodulatory effects as they had reduced the cytokines production which is considered as most fatal in COVID-19. As a result, dietary supplements and nutraceuticals based on ethnomycological mushroom expertise have showed promise in preventing and treating the present epidemic (Slomski, 2021).

Based on prior experiences with coronavirus outbreaks, seasonal epidemics produced by other viruses, and the efficiency of natural products in the treatment of HIV, HCV, and Influenza, mushrooms and their phytoconstituents might be developed as a possible medication candidate against COVID-19 (Shahzad et al., 2020) . Despite this, there isn't enough proof of direct antiviral actions specific to the COVID-19 virus. As a result, further study into the anti-viral property with anti-inflammatory and immunomodulatory effects, as well as the quality and safety of herbal drugs, is required to identify their role in COVID-19 therapy. Mushroom derived biochemical compounds must have anti-inflammatory, antioxidant, antiviral, and immunomodulatory effects to be an effective therapy in the treatment of COVID-19. Despite the renin-angiotensin system being involved in COVID-19, with ACE-2 as the main target, to be an effective therapy in the treatment of COVID-19 (Brendler et al., 2021; Rangsinth et al., 2021; Attah et al., 2021) .

• Mushrooms are mostly employed as nutritional supplements or functional meals at the moment. However, special precautions should be taken in terms of preparation, application, dose, and harmful consequences.

• In addition, to establish the mushroom's impact against coronavirus infection, preclinical and clinical laboratory experiments, standardization, and scientific validation must be considered with legal authorization.

• Establishing the safety of medicinal mushroom-derived food items for therapeutic use via the development of clinical study approaches.

• Strengthening the reverse pharmacology process by identifying the primary molecule using cutting-edge technologies.

The continued proliferation of COVID-19 necessitates the public exposure of alternate therapeutic procedures. Natural remedies have been utilized in a variety of methods since ancient times. They've been dubbed "intense clinical specialists" against a broad spectrum of viral diseases because to their antiviral capabilities. The body's protective frameworks help to fight against infections and pathogens development as well as a number of other disorders. Many allopathic medications are available to assist us to improve our immune systems, but we all know that they come with a lengthy list of negative effects and are costly. As a consequence, we seek for other sources such as Traditional Chinese Medicine and Ayurvedic products containing medicinal mushrooms, which offer a healthy environment for the body while also strengthening the immune system without producing any negative side effects. Several studies have shown that those with excellent immunity have a greater recovery rate in the event of a COVID-19 pandemic. Phytochemicals found in medicinal mushrooms include terpenoids, alkaloids, flavonoids, phenols, tannins, polyphenols, polysaccharides, proteins, lipids, and peptides, all of which have potent antiviral properties in terms of preventing viral invasion, penetration, replication, expression, assembly, and release. Furthermore, since the illness's emergence, restorative medicinal mushrooms and their culinary elements have emerged as the most promising options for preventing or treating infection and disease transmission. Regardless, they are now being evaluated in vitro in order to acquire quick verification of COVID-19 patients' positive strength.

In the present paper, which explained the possible role of natural definitions to treat COVID-19, we outlined the progressing preliminaries of medicinal mushrooms and their biomolecules against this hazardous sickness. Nonetheless, the assays for determining COVID-19 resistance by several medicinal mushroom taxa are inadequate or not pointed out but they are in one or other way effective for its symptoms. Regardless, research is beginning to identify their potential benefits, and we hope that future studies will be undertaken in a more thorough manner. Several researchers are continuing to work on these investigations in order to produce a viable antidote for this virus. Combining these studies with persuasive creativity and study, protein denaturation of receptor proteins and parts of certain proteases chemicals may be regarded in the future as a manner of proving their involvement in obstructing the life pattern of this infection. 

The authors declare no conflicts of interest 

Polysaccharides obtained from natural edible sources and their role in modulating the immune system: Biologically active potential that can be exploited against COVID-19

Discovery of Ganoderma lucidum triterpenoids as potential inhibitors against Dengue virus NS2B-NS3 protease

Ganoderma lucidum and its pharmaceutically active compounds

Botanical drugs and supplements affecting the immune response in the time of COVID-19: Implications for research and clinical practice

COVID-19: immunopathology and its implications for therapy

In vivo anti-herpes simplex virus activity of a sulfated derivative of Agaricus brasiliensis mycelial polysaccharide

SARS-CoV-2 variant classifications and definitions

The Antiviral Activity of Bacterial, Fungal, and Algal Polysaccharides as Bioactive Ingredients: Potential Uses for Enhancing Immune Systems and Preventing Viruses

Bioactive polysaccharides from natural sources: A review on the antitumor and immunomodulating activities

Antioxidant activities of polysaccharides from Lentinus edodes and their significance for disease prevention

Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies

Coriolus versicolor supplementation in HPV patients

Origin and evolution of pathogenic coronaviruses

An inflammatory cytokine signature predicts COVID-19 severity and survival

Coadministration of the fungal immunomodulatory protein FIP-Fve and a 1

COVID-19-navigating the uncharted

Protective effect of Cordyceps sinensis extract on lipopolysaccharide-induced acute lung injury in mice

Reishi Mushroom) extract in patients with chronic Hepatitis В

Pro-inflammatory effects of the mushroom Agaricus blazei and its consequences on atherosclerosis development

Antcins from Antrodia cinnamomea and Antrodia salmonea Inhibit Angiotensin-Converting Enzyme 2 (ACE2) in Epithelial Cells: Can Be Potential Candidates for the Development of SARS-CoV-2 Prophylactic Agents

Isolation, identification and function of a novel anti-HSV-1 protein from Grifola frondosa

WHO discontinues hydroxychloroquine and lopinavir/ritonavir treatment arms for COVID-19

Clinical effects and immunological analysis of intraabdominal and intrapleural injection of lentinan for malignant ascites and pleural effusion of gastric carcinoma

Can medicinal mushrooms have prophylactic or therapeutic effect against COVID-19 and its pneumonic superinfection and complicating inflammation?

Natural products as potential leads against coronaviruses: could they be encouraging structural models against SARS-CoV-2?

Ayurveda and traditional Chinese medicine: a comparative overview

Immunomodulatory activities associated with β-glucan derived from Saccharomyces cerevisiae

Traditional, Complementary and Integrative Medicine Approaches to COVID-19: A Narrative Review

Natural product emerging as potential SARS spike glycoproteins-ACE2 inhibitors to combat COVID-19 attributed by in-silico investigations

Recent efforts for drug identification from phytochemicals against SARS-CoV-2: Exploration of the chemical space to identify druggable leads

Natural products modulating angiotensin converting enzyme 2 (ACE2) as potential COVID-19 therapies

Natural products' role against COVID-19

Purification, characterization and cloning of a ricin B-like lectin from mushroom Clitocybe nebularis with antiproliferative activity against human leukemic T cells

Bivalent carbohydrate binding is required for biological activity of Clitocybe nebularis lectin (CNL), the N, N′-Diacetyllactosediamine (GalNAcβ1-4GlcNAc, LacdiNAc)-specific lectin from Basidiomycete C. nebularis

Therapeutic potential and biological applications of cordycepin and metabolic mechanisms in cordycepin-producing fungi

Effectiveness of Remdesivir, Lopinavir/Ritonavir, and Favipiravir for COVID-19

Treatment: A Systematic Review

Mushroom-derived bioactive compounds potentially serve as the inhibitors of SARS-CoV-2 main protease: An in silico approach

Polysaccharide and extracts from Lentinula edodes: structural features and antiviral activity

Erinacine E as a kappa opioid receptor agonist and its new analogs from a basidiomycete, Hericium ramosum

Dehydrotrametenolic acid induces preadipocyte differentiation and sensitizes animal models of noninsulin-dependent diabetes mellitus to insulin

Antcins from Antrodia cinnamomea and Antrodia salmonea Inhibit Angiotensin-Converting Enzyme 2 (ACE2) in Epithelial Cells: Can Be Potential Candidates for the Development of SARS-CoV-2 Prophylactic Agents

Antiviral Bioactive Compounds of Mushrooms and Their Antiviral Mechanisms: A Review

The Antiviral, Anti-Inflammatory Effects of Natural Medicinal Herbs and Mushrooms and SARS-CoV

 Gu et al., 2006