Mushrooms have been used as both food and medicine since antiquity. One of my favorite poems, discovered in an ancient Egyptian temple, illustrates this history: “Without leaves, without buds, without flowers, yet from fruit; as food, as tonic, as medicine: the entire creation is precious.” At a time when viral epidemics are inevitable and the current COVID-19 pandemic has presented in most of the world, antiviral therapies are possibly being investigated now more than ever before. This paper explores the use of medicinal mushrooms as antivirals in in vivo (human and animal) and in vitro (petri dish) experiments and how these experiments may inform us on the utilization of these fungi as antiviral therapies.
Medicinal mushrooms are known as biological response modifiers. This physiologic modification is largely a result of the interaction of various mushroom constituents, primarily polysaccharides, with the immune system. Therefore, to understand the role that medicinal mushrooms play as antiviral agents, it is imperative to understand the happenings of the immune system in response to a viral pathogen and the interplay between mushrooms, their constituents, and this system. Unlike pharmaceutical antivirals, the actions of medicinal mushrooms are not straightforward, and there is no absolute rule that mushrooms stimulate or depress immunity. Mushrooms contain many constituents and are dynamic in their interplay with the human body.
Overview of anti-viral immunity
The initial immune response to a new pathogen is facilitated by the innate immune system (innate meaning inborn or natural). This is our first response to non-self organisms, and requires no other stimulation than the pathogen itself. It is the response that is ready to go at all moments in the day and persistently protects the human body from infection. It is easy to imagine that an altered or defective innate immune response can have a detrimental effect on the ability to fight disease.
The innate immune response to a virus is multidimensional. There is a massive amount of cell-to-cell communication and different chemicals (called cytokines) are released to make this communication possible. Once an epithelial cell (cells that make up the surface of different body tissues like skin, lungs, etc) is infected with a virus, Type 1 Interferon (Interferon-α, a cytokine) is released and has three major functions: to induce resistance to viral replication in all cells, to increase expression of ligands for receptors on natural killer (NK) cells, and to activate NK cells to kill virus infected cells. NK cells are lymphocytes (a small white blood cell that is found primarily in the lymphatic system) that defend against viral infections and tumor cells via cytokine stimulation and direct killing of infected cells. NK cells provide such a vital role in antiviral immunity that people deficient in NK cells suffer from persistent viral infections. These functions of NK cells are important in regards to understanding medicinal mushrooms and their role in antiviral immunity.
Imagine the immune response to a newly inhaled viral particle. This virus enters the healthy person’s lungs and invades the lung epithelium. Once an epithelial cell is infected, it releases Type 1 Interferon, which turns circulating NK cells into cytotoxic effector NK cells (NK cells primed to seek out and kill virally infected cells). The cytotoxic effector NK cells promptly start the process of seeking out infected cells and the innate immune response commences. At the same time, there are resident macrophages in the respiratory epithelium and throughout the body. These macrophages (“big eaters”), are also major players in the innate immune response. Their role is to consume these virus particles and produce chemicals (cytokines and chemokines) that attract and engage more NK cells and also T cells. An important cytokine engaged in this process is interleukin-12 (IL-12), which stimulates NK cells to not become cytotoxic, but rather effector NK cells. Unlike cytotoxic effector NK cells, these effector NK cells stimulate an inflammatory response via Type 2 Interferon (IFN-γ), at the site of infection. This inflammatory cascade consists of IL-1, IL-6, TNF-α, and IL-12, and is essential for viral eradication. It is only when this response is out of control that it becomes problematic and detrimental to the host.1,2,3,4 If this initial response is not primed for viral combat, viral particles continue to proliferate and infect more healthy cells. It is in this phase that medicinal mushrooms can have a great impact to prevent viral infections from taking over the host.
|IFN-α||Virus infected epithelium||Circulating NK cells –>Cytotoxic effector NK cells|
|IL-12||Macrophage post virus consumption||NK cells –> effector NK cells|
|IFN- γ||Effector NK cells||Macrophages –> inflammatory cytokines (TNF-α, IL-2, IL-1, IL-6)|
|TNF- α||Macrophages||Induces blood vessels more permeable, enabling effector cells to enter infected tissue|
|IL-1||Macrophages||Induces blood vessels more permeable, enabling effector cells to enter infected tissue|
|IL-6||Macrophages||Induces fat and muscle cells to metabolize, make heat and raise temperature of infected tissue|
|IL-12||Macrophages||Recruits and activates NK cells –> secrete more cytokines that strengthen macrophage response to infection|
|IL-10||Toxic substances secreted by macrophages–> TH2||Suppress macrophage activation|
|IL-4||Toxic substances secreted by macrophages–> TH2||Suppress macrophage activation|
COVID-19 is an excellent example of these two main immune responses.5 The first stage of infection is the less severe incubation phase. The previously mentioned immune response is imperative to eliminate the virus and keep disease from progressing to later, more severe stages. It is in the incubation stage that immune-stimulating therapies are most indicated. In more severe stages, the protective immune response is impaired and the virus will spread and destroy healthy cells. Because damaged cells induce inflammation, immune stimulation is less indicated and it is more favorable to treat with anti-inflammatory therapies. It is at this stage of disease, characterized by severe lung inflammation, that life-threatening respiratory disorders occur and the feared cytokine storm is initiated. The cytokine storm is an influx of inflammatory cytokines. It is an overdramatic immune response that is harmful to the host and can often lead to acute respiratory distress syndrome. The inflammatory cytokines that are so important for stage one of the disease ( IL-1, IL6, TNF-α, and IL-12) are now abundant, destructive and out of control.6,7
The two phase division of the immune response is very important . The first immune response is protective and a response that can be altered through diet and lifestyle: our base response when initially combating infection. As mentioned previously, this is the phase where medicinal mushrooms are most indicated. They are primers of the first response to viral particles.
Antiviral immunity in healthy adults
The most informative studies exploring the interaction of medicinal mushrooms and the immune response are done on healthy human adults. In these studies it is ideal to see cytokine and NK cell levels before and after mushroom intake in healthy people to get a good idea of how exactly the mushrooms are priming our innate response. There are not many studies of this kind, but there are a few.
Healthy Korean men who took 1.5g/day of powdered extract of Cordyceps militaris brown rice culture for four weeks had their blood analyzed before and after treatment. Levels of NK cells, IFN-y and IL-12 were examined in blood samples before and four weeks after therapy began. There was a significant increase in NK cells and IFN-y and no difference in IL-12.8 Cordyceps sinensis mycelium extract, in combination with the endoparasitic fungus that commonly exists with C. sinensis, Paecilomyces hepialid, also had immune-stimulating activity in healthy adults. In this study, people were given 1.43g/day and after eight weeks the cytotoxic activity of NK cells was significantly higher than at baseline (before therapy.)9 Wild fruiting bodies of Cordyceps species are incredibly expensive and are therefore rarely, if ever used in research. However, It is likely that cultivated fruiting bodies have similar medicinal qualities.10,11,12
Another study with 52 healthy males and females aged 21-41 consumed either 5g or 10g of Lentinus edodes (shiitake mushroom) daily for four weeks. Eating the Shiitake for four weeks led to increased proliferation of NK cells and IgA, decreased CRP (a marker of inflammation), and an increase in IL-4, Il-10, TNF-α and IL-1. Serving size had no impact on cytokine levels, except that two servings of Shiitake increased serum IL-4.13 Shiitake is a good example of the dynamic effects that some mushrooms have on the immune system. Shiitake both increased inflammatory cytokines (IL-1, TNF-α) and anti-inflammatory cytokines (IL-10 and IL-4) simultaneously, illustrating the use of the term immunomodulatory: it is neither a pure stimulator nor a depressor of the immune system. This may mean that immune modulating mushrooms are safe and effective to take during both phases of the viral immune response, and in fact, may have inhibitory effects during the cytokine storm of acute respiratory distress syndrome.
Grifola frondosa (Maitake) also exhibits this modulating activity. G. frondosa fruiting body extract produced both immune stimulatory IL-2, TNF-α and IFN-γ and suppressive IL-10 in breast cancer survivors taking 5-7g/kg per day of mushrooms extract for three weeks.14
The combination formula of Trametes versicolor(Turkey tail) and Salvia miltiorrhiza (Red sage root, or Dan Shen) given at 50mg/kg and 20mg/kg respectively for four months showed significant immunomodulatory effects in healthy adults. There was a significant increase in PBMC (peripheral blood mononuclear cells – NK, B and T cells) gene expression of IL-2 receptor, increase in T helper cells and the ratio of T helper cells to cytotoxic T cells. There is also a significant increase in IFN-γ.15 There is little information in western herbal and mycological medicine about the use of plant and mushroom combination formulas. Dan Shen is known to ‘move the qi of the blood’ and in combination with the immune stimulating activity of Turkey tail, has promise as a very useful combination for immune therapy.
Not all fungi are created equally as immune modulators. When the β-glucan isolate, lentinax, from L. edodes mycelium was administered to healthy adults, there was no difference seen in NK cells and inflammatory cytokines between treatment and control groups.16 This juxtaposes the previous Shiitake study where the subjects consumed whole mushrooms and did have immune stimulatory effects. Contrary to what has been suggested in in vitro research 17,18 a mushroom that showed no benefit in vivo was Agaricus blazeii. Healthy elderly women consumed 300mg of A. blazeii fruiting body extract three times daily for 60 days, and there was no change in levels of IFN-γ, IL-6 and TNF-α after administration.19 Perhaps the dose was too low in this study, further research is needed.
|Mushroom||Cytokine response||Immune response (simplified)||Phase of viral response most applicable|
|Grifola frondosa (Maitake)||IL-10
IL-2, TNF-α, IFN- γ
|Possibly severe phase
|Lentinus edodes (Shitake)||IL-4, IL-10
|Possibly severe phase
|Cordyceps spp.||IFN- γ||Pro-inflammatory||Prevention/incubation|
|Trametes versicolor (Turkey tail) with Salvia miltiorrhiza (Red sage)||IL-2, IFN- γ||Pro-inflammatory||Prevention/incubation|
Mushrooms as immune-modulators
The increases seen in IL-10 and IL-4 after Maitake, Shiitake, and Cordyceps mycelium intake are important as they relate to TH2 immune responses. TH2 responses are anti-parasitic and anti-allergic, but through the lens of viral immunity and inflammation, are anti-inflammatory. In fact, IL-10 is considered an anti-inflammatory master regulator. 20,21,22,23 IL-10 is essential for defending the host from tissue destruction during acute phases of immune responses, though it is not as desirable in the initial phase of infection, where a higher TH1 (inflammatory) response is required. At this stage, IL-10 can downregulate antigen presentation in macrophages and dendritic cells and can lead to chronic infection.24 During the later stages of infection, however IL-10 levels can determine host survival and higher concentrations of IL-10 have been associated with better outcomes in patients with acute respiratory distress syndrome.25
This is immune modulation. As depicted, mushrooms are neither solely inflammatory, nor anti-inflammatory, and so should be utilized as such. The safety of medicinal mushroom use at different phases of the immune response is debatable. It is most likely that if mushrooms and mushroom extracts are consumed as preventative medicine, and the immune response is primed, the host won’t succumb to infection in the first place. There is some concern that if IL-10 is too high during the initial phase, the infection will become chronic, but since the mushrooms are simultaneously stimulating inflammatory cytokines, this isn’t likely.
|Associated cytokines||IL-2, IL-12, IFN-γ, TNF-α||IL-4, IL-10, IL-5, IL-6, IL-13, IL-9|
Mushroom Derived β-glucans and the Immune Response
The most studied immune-stimulating constituents derived from medicinal mushrooms are 1,3/1,6-β-glucans. β-glucans, or polysaccharides, are present in all mushrooms as they are an integral component of the mushroom cell wall. Macrophages in the gut have specific receptors for β-glucans, most significantly Dectin-1, complement receptor 3 and TLR-2.26,27 When β-glucans bind to these receptors, an immune response is initiated. Because of this, in most studies, polysaccharides have been deemed the ‘active’ constituents in regards to immune activation. Therefore, isolation and administration of these compounds is most commonly seen in the literature.
Pleuran, a polysaccharide derived from Oyster mushrooms
There are a number of human trials exploring the use of pleuran, a polysaccharide extracted from Pleurotus ostreatus (Oyster mushroom) as a therapeutic agent in respiratory infections. As respiratory infections are most commonly of viral origin,28 it seems appropriate to discuss this research here. In a double-blinded, placebo-controlled, randomized multicentric study, 175 children treated with pleuran experienced a significant reduction in the frequency of recurrent respiratory tract infections.29 These findings agreed with a Spanish study investigating 166 children aged one to ten years old who were also treated with pleuran for recurrent respiratory infection.30
Advantageous respiratory effects of pleuran are also observed in adult athletes. A study of 50 athletes treated with pleuran over a three month period found a significant reduction in the frequency of upper respiratory tract infections compared to athletes treated with placebo. Blood samples of the athletes showed significantly higher levels of circulating NK cells in the pleuran group as compared to the placebo group.31
Oyster mushrooms contain almost 33% polysaccharides,32 so we can deduce from these studies that consuming whole Oyster mushrooms and/or Oyster mushroom aqueous extracts could be beneficial for the prevention of respiratory infections.
Immune-stimulating polysaccharides in late stage cancer patients
The polysaccharides isolated from Ganoderma lucidum, also known as ‘Ganopoly’, were administered at 1800mg three times daily in late stage cancer patients, and there was a significant increase in NK cells, IL-1, IL-6 and IFN-γ after administration.33 Another isolate, polysaccharide krestin (PSK), is a protein-bound polysaccharide derived and isolated from Trametes versicolor. In a phase one clinical trial, breast cancer patients consumed 6 or 9g of PSK for six weeks, leading to an increase in CD8 T cells and NK cells.34 Another isolated polysaccharide, Maitake D fraction (derived from the fruiting body of G. frondosa), was administered to patients with stage 2-4 cancer aged 46-84 at doses between 40 and 150mg twice daily. IL-2 and NK cell activity was detected through peripheral blood draw and both were significantly increased after administration35 The research on isolated, mushroom-derived polysaccharides was intended to prove anti-cancer activity, but because of the close similarities of anti-cancer and antiviral immunity,36 it also suggests that polysaccharides support antiviral immunity in late stage cancer patients.
In vivo healthy animal trials
Polysaccharides from G. lucidum, L. edodes and G. frondosa administered to healthy mice significantly increase macrophage phagocytosis and NK cell activity.37 Other studies have demonstrated similar immune-enhancing effects on healthy mice with G. frondosa and L. edodes extracts exhibiting increases in IL-12, IL-6, and IFN-γ. In this study, the combination of the G. frondosa and L. edodes extracts have a stronger effect than either extract alone.38 Maitake D fraction increases IL-12 and IFN-γ in healthy mice along with a significant decrease in IL-4 and IL-10.39 C. militaris extract also increases IL-12 and TNF-α cell activity in H1N1 infected mice.40
In vivo animal cancer models
A number of in vivo animal trials explore different mushroom extracts with similar immune effects. Many of these animal studies are cancer models, so they will be mentioned briefly. Agaricus hot water extracts increase IFN-γ, IL-6 and IL-1,41,42 Reishi polysaccharide and triterpene extracts increase inflammatory NFkB, TNF- α, IL1-b, IL-2, IFN-γ 43,44,45,46 Maitake extract increases IL-12, IFN-γ and TNF-α, IL-147,48 and PSK increases IL-12.49 Ganoderma polysaccharides increase NK cells and cytotoxic T cells, IL-1, IL-6 and IL-1.50,51
Because these are cancer models, so it is not completely clear if the same effects would take place in healthy animal models, though we can deduct from other experiments using healthy volunteers and healthy animals that it is likely that similar immune effects would occur.
In vitro antiviral activity
There are a number of fungal constituents that have antiviral activity in-vitro, including polysaccharides, indole alkaloids, terpenoids, polyketides and lignan derivatives. Agaricus subfruescens and Grifola frondosa act directly on viral particles, β-glucan protein from A. subfruescens inhibits viral adsorption into the cell, polysaccharides from A. subfruescens and polysaccharopeptide from T. versicolor inhibit viral replication, and triterpenes from Ganoderma spp directly kill virus proteins.52
The fruiting body ethanol-water extract of T. versicolor extract increases the TH1-related cytokines IL-2, IL-12, IL-18 and IFN-γ.53,54 As most of the research done on T. versicolor is with an isolated constituent, PSK, it is significant that this study, which used whole fruiting body extract, exhibits immune stimulating qualities.
Maitake fruiting body extract does not show direct antiviral activity to influenza A but does exhibit antiviral activity through macrophage activation and an increase in TNF-α production. 55
L. edodes mycelium directly inhibits influenza virus growth at early phases of infection, possibly during the entry process of viral particles to host cells. The in vivo administration stimulated an increase in innate immunity as well, suggesting that Shiitake mycelium has antiviral effects through both inhibition of initial viral replication and immune stimulation.56
A little known mushroom, Cryptoporus volvatus, the Cryptic Globe Fungus, has shown anti-viral activity through multiple mechanisms. Aqueous extracts of the fruiting body inhibit porcine respiratory syndrome virus infection by repressing viral entry, viral RNA expression, possibly viral protein synthesis, cell-to-cell spread, and the release of virus particles from the host cell. C. volvatus also inhibits influenza virus replication in vitro and in vivo.57,58,59
The aqueous extract of Phellinus igniarius, or Fire Sponge, shows virucidal activity against influenza A and B viruses, including 2009 pandemic H1N1, human H3N2, avian H9N2, and oseltamivir-resistant H1N1 viruses. The study concludes that this extract may interfere with one or more early events in the viral replication cycle, including viral attachment to the target cell. 60
In vitro research is what propels in vivo research forward, but it is important to take this information with a grain of salt and understand this is what may happen in the human body, and not necessarily what will happen.
A highly valued antiviral action in pharmaceuticals is neuraminidase inhibition. This is the mechanism of the commonly known antivirals Tamilflu and Rilenza. Neuraminidase is found on the surface of influenza viruses and allows viruses to be released from the host cell so they can then infect other healthy human cells. Neuraminidase inhibitors have been shown to improve the outcome of patients with leukemia and influenza. 61 Medicinal mushrooms and their constituents have been shown to have neuraminidase inhibitory activity in vitro and in vivo. Ganoderic acids, triterpenes found in Ganoderma species, have broad spectrum inhibition against influenza neuraminidases, specifically H5N1 andH1N1.62,63 Both the fruiting body and mycelial extracts of Phellinus spp. have neuraminidase inhibiting actions as well. 64,65,66 While there is still more research needed in this area, it is possible that Reishi and Phellinus species could be beneficial in treating viruses that utilize neuraminidase.
This paper focuses on mushrooms as antiviral therapies for enveloped, influenza-like viruses, but there is in vitro evidence to suggest medicinal mushrooms have antiviral activity towards many different viruses.67,68 Ganoderma lucidum has shown to be active against enterovirus, 69 human papillomavirus (HPV),70,71 herpes simplex virus (HSV)72,73,74,75 hepatitis B (HBV)76 and Epstein Barr virus (EBV).77 Cordyceps militaris has anti-hepatitis C (HCV) activity.78 Trametes versicolor is active against human immunodeficiency virus HIV.79.80 Grifola frondosa is active against HSV-181 and HBV.82 Inonotus obliquus has anti-HSV, 83,84 anti-HCV 85and anti-HIV86 activity and Lentinula edodes has anti-HBV 87 and anti-HSV 88 activity. Although not explored in this paper, these antiviral actions are interesting and worth considering for further dissection in future research.
Having a basic understanding of our complex immune system is important in understanding the role that mushrooms play as antivirals. As we have seen, mushrooms are immune modulators and can stimulate inflammatory and anti-inflammatory responses simultaneously. Mushrooms are most likely to be useful as preventative medicine before infection occurs, though if there is an initial infection, Cordyceps, Maitake, Shiitake, Turkey tail and Oyster mushroom may prevent infection from becoming more severe. If infection does become severe, the mushrooms that also stimulate IL-10 – Maitake, Cordyceps and Shiitake, could also be beneficial. In the wake of the current viral pandemic, these mushrooms should be further explored and utilized as medicine. Further research is essential in elucidating their potential effects.
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