Rationalization of Mushroom-Based Preventive and Therapeutic Approaches to COVID-19: Review

Abstract

Since December 2019, a de novo pattern of pneumonia, later named coronavirus disease 2019 (COVID-19), has caused grave upset throughout the global population. COVID-19 is associated with several comorbidities; thus, preventive and therapeutic strategies targeting those comorbidities along with the causative agent, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), seem imperative. In this state-of-the-art review, edible and medicinal mushrooms are featured in the treatment of SARS-CoV-2, COVID-19 pathomanifestations, and comorbid issues. Because this is not an original research article, we admit our shortcomings in inferences. Yet we are hopeful that mushroom-based therapeutic approaches can be used to achieve a COVID-free world. Among various mushroom species, reishi or lingzhi (Ganoderma lucidum) seem most suitable as anti-COVID agents for the global population.

Full text

Rationalization of Mushroom-Based Preventive and
Therapeutic Approaches to COVID-19: Review
Mohammad Azizur Rahman,a,* Mohammad Saidur Rahman,b,c Nurul Mostafa Bin Bashir,a
Rajib Mia,a Abul Hossain,a Shajib Kumar Saha,a Akther Jahan Kakon,d & Nirod Chandra Sarkerd
aDepartment of Biochemistry and Molecular Biology, Jahangirnagar University, Savar, Dhaka 1342, People’s Republic
of Bangladesh; bDepartment of Chemistry, Jahangirnagar University, Savar, Dhaka 1342, People’s Republic of
Bangladesh; cOperational Integrity, SGS Bangladesh Limited, Dhaka 1205, People’s Republic of Bangladesh;
dMushroom Development Institute, Department of Agricultural Extension, Ministry of Agriculture, Government of the
People’s Republic of Bangladesh, Dhaka, People’s Republic of Bangladesh
*Address all correspondence to: Mohammad Azizur Rahman, Department of Biochemistry and Molecular Biology, Jahangirnagar University,
Savar, Dhaka 1342, People’s Republic of Bangladesh; Tel.: +00880201727195484; Fax: +880-2-7791052, E-mail: azizbmb@juniv.edu
ABSTRACT: Since December 2019, a de novo pattern of pneumonia, later named coronavirus disease 2019 (COVID-19),
has caused grave upset throughout the global population. COVID-19 is associated with several comorbidities; thus, pre-
ventive and therapeutic strategies targeting those comorbidities along with the causative agent, severe acute respiratory
syndrome coronavirus-2 (SARS-CoV-2), seem imperative. In this state-of-the-art review, edible and medicinal mush-
rooms are featured in the treatment of SARS-CoV-2, COVID-19 pathomanifestations, and comorbid issues. Because this
is not an original research article, we admit our shortcomings in inferences. Yet we are hopeful that mushroom-based
therapeutic approaches can be used to achieve a COVID-free world. Among various mushroom species, reishi or lingzhi
(Ganoderma lucidum) seem most suitable as anti-COVID agents for the global population.
KEY WORDS: ACE, ACE2, compromised immunity, immunomodulation, COVID-19, medicinal mushrooms, Gano-
derma lucidum, protease inhibitor, SARS-CoV-2
ABBREVIATIONS: ACE, angiotensin-converting enzyme; AD, Alzheimer’s disease; ADAM, a disintegrin and metalloprotein-
ase; ALI, acute lung injury; Ang, angiotensin; ARDS, acute respiratory distress syndrome; AT1R, angiotensin receptor type 1;
CD, cluster of differentiation; COVID-19, coronavirus disease 2019; CVD, cardiovascular disease; DC, dendritic cell; FIP, fungal
immunomodulatory protein; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulat-
ing factor; HIV, human immunodeciency virus; IFN, interferon; IL, interleukin; IP, IFN-γ–induced protein; MasR, muscarinic
receptor; MCP, monocyte chemotactic protein; MIP, macrophage inammatory protein; NF-κB, nuclear factor κB; NK, natu-
ral killer; NO, nitric oxide; PRR, pattern recognition receptor; RAS, renin angiotensin system; RTI, respiratory tract infection;
S protein, spike protein; SARS, severe acute respiratory distress syndrome; SARS-CoV-2, severe acute respiratory distress syn-
drome coronavirus-2; Th, helper T cell; TMPRSS2, transmembrane protease serine 2; TNF, tumor necrosis factor; TRIM, trained
immunity; WHO, World Health Organization
I. INTRODUCTION
Following the breakout of the novel coronavirus disease 2019 (COVID-19) in December 2019 in Wuhan,
China, the virus is still shaking the global health care sector, economies, education, politics, as well as
the global population. COVID-19 is caused by severe acute respiratory syndrome coronavirus-2 (SARS-
CoV-2). Although the initial signs and symptoms of COVID-19 in patients are fever, dry cough, and
dyspnea, pneumonia in adverse states leads to severe acute respiratory syndrome (SARS) and death.1 De-
velopment of antiviral agents against SARS-CoV-2 has become a global urgency and the development of
different therapeutic strategies continues worldwide.2 Unfortunately, to date there is hardly any single or
combined medicotherapy available that could be prescribed to patients with COVID-19. The world has
painstakingly awaited a vaccine against this pandemic, and vaccine distribution began in some parts of the
world at the end of 2020. Because vaccine development requires a longer clinical trial period, the search
for a currently usable medicotherapy that can withstand, albeit slow down, COVID-19 pathogenesis has
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gained momentum. In this context, nutraceutical or functional food–based approaches would benet hu-
mans highly.3 COVID-19 has manifested several comorbidities such as compromised immunity, depleted
nutritional status, hypertension, cardiovascular diseases (CVDs), lipid prole, diabetes, noncommunicable
diseases like Alzheimer’s disease (AD), and old age.4 Thus, integrative treatment strategies aimed directly
at SARS-CoV-2 infection along with amelioration of these comorbidities seem pertinent.5 The combina-
tion of both Eastern and Western medicotherapeutic approaches would greatly aid the COVID-19 affected
population in overcoming this global crisis.5 Inclusion of alternative and traditional medicine in COVID-19
treatment also seems benecial.6–8 In this context, edible and medicinal mushrooms are excellent as func-
tional food–based and traditional medicotherapeutic agents against SARS-CoV-2 pathogenesis.9,10 Thus, by
pinpointing the SARS-CoV-2–related antiviral, immunomodulatory, nutritive, and COVID-19 comorbidi-
ty-ameliorating effects of different mushroom species, this review rationalizes the usage of mushrooms as
a defense in the war against COVID-19.
II. MOLECULAR MECHANISM OF SARS-COV-2 PATHOGENESIS
SARS-CoV-2 possesses four structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid
(N) proteins (Fig. 1). Binding of SARS-CoV-2 to the host cell receptor is S protein mediated.11 Entry of
coronavirus into host cells requires S protein priming by cellular proteases such as transmembrane protease,
serine 2 (TMPRSS2).12 S protein is cleaved by proteases into S1 and S2 subunits (Fig. 2). Initially, through
the receptor binding domain in the S1 subunit, the S protein binds to the ACE2 receptor of the host.11 Then,
the S2 subunit fuses with the cell membrane and viral entry occurs, followed by attachment of the viral ge-
nome (ssRNA) with the host’s ribosomes and translation (Fig. 2).11 Later, proteolysis of two coterminal and
large polyproteins into smaller components facilitates folding and packaging into virions.11 Virions exert
both cytocidal and immunomodulatory effects on host cells (Fig. 2). Cytopathic effects (apoptosis and cell
lysis) and syncytia formation, especially in the lungs, also occur.
SARS-CoV-2 pathogenesis involves both innate and adaptive immune responses (Fig. 2). Cytokines,
produced by innate (macrophages, dendritic cells [DCs], natural killer [NK] cells) and adaptive (B and
T lymphocytes) immune cells, are important components of inammatory responses to viruses. Pattern
recognition receptors (PRRs) of innate immune cells recognize and bind pathogen-associated molecular
patterns of the invading virus that trigger inammatory responses yielding inammatory cytokines (Figs.
2 and 3).13,14 Interleukin (IL)-1, tumor necrosis factor (TNF)-α, and IL-6 are the most important proinam-
matory cytokines of the innate immune response (Figs. 2 and 3).13,14 Circulatory levels of other elevated
FIG. 1: Structure of SARS-CoV-2
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proinammatory cytokines found in patients with COVID-19 are IL-1b, IL-7, IL-8, IL-9, broblast growth
factor, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor
(GM-CSF), interferon (IFN)-γ, IFN-γ–induced protein (IP)-10, monocyte chemotactic protein (MCP)-1,
macrophage inammatory proteins (MIP)-1A and MIP1-B, platelet-derived growth factor, and vascular
endothelial growth factor (Figs. 2 and 3).13,14 The state of transient increased levels of circulatory proinam-
matory cytokines is referred to as the “cytokine storm” (Figs. 2 and 3). The cytokine storm triggers an inux
of immune cells (macrophages, neutrophils, and T cells) to the infection site, which associates perturbed
FIG. 2: Molecular mechanism of SARS-CoV-2 pathophysiology. CatB/L, cathepsin B/L.
FIG. 3: SARS-CoV-2 pathophysiology
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endothelial cell-to-cell interactions and damage of the vascular barrier and capillaries (Figs. 2 and 3).15 Al-
veolar damage, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and ARDS-mediated
hypoxia are the most notorious effects of the cytokine storm that culminate in the death of persons with
SARS-CoVID-19 infection (Figs. 2 and 3).15
III. PERTURBED ACE/ACE2 RATIO AND COVID-19 PATHOPHYSIOLOGY
Renin angiotensin system (RAS) dysregulation has been considered as a pathophysiological factor of
COVID-19–led ALI and ARDS. In RAS, angiotensin-converting enzyme (ACE) converts angiotensin
(Ang) I to AngII and ACE2 converts AngII to angiotensin 1-7 (Ang1-7) (Fig. 4A). ACE2 is expressed
highly in alveolar epithelial cells, vascular endothelial cells, cardiomyocytes, intestinal epithelial cells,
and renal proximal tubular cells.16 AngII, through agonism at AngII receptor type 1 (AT1R), mediates va-
soconstrictive, proinammatory, and pro-oxidative effects (Fig. 4B and 4C).17 On the other hand, Ang1-7,
binding at the muscarinic receptor (MasR), provides anti-inammatory, antioxidative, and vasodilatory
FIG. 4: ACE/ACE2 ratio in normal physiology and SARS-CoV-2 pathophysiology. ACEI, angiotensin-converting
enzyme inhibitor; ARB, angiotensin receptor binding domain.
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effects (Fig. 4D).18 Thus, the ACE2/Ang1-7/MasR and ACE/AngII/AT1R triads exert opposite effects (Fig.
4D and 4E). In patients with COVID-19, binding of SARS-CoV-2 to ACE2 attenuates ACE2 activity and
shifts the ACE/ACE2 ratio disproportionately such that signaling of the ACE/AngII/AT1R triad predom-
inates, resulting in overproduction of vasoconstrictor Ang and lowered production of vasodilator Ang1-7
(Fig. 4D and 4E). Signaling through AT1R, AngII acts as a proinammatory cytokine (Fig. 4D and 4E).16
Further activation of nuclear factor κB (NF-κB) and a disintegrin and metalloprotease ADAM17 by the
AngⅡ-AT1R axis triggers production of the mature form of epidermal growth factor receptor ligands and
TNF-α as well as the gp130-mediated activation of STAT3.19 Consequently, activation of the IL-6 amplier
leads to a hyperinammatory state with increased pulmonary vascular permeability (Figs. 2–5).20 Severe
immune injury occurs from hyperactivation of T cells producing proinammatory helper T cell Th17 and
highly cytotoxic cluster of differentiation CD8+ T cells and rapid activation of CD4+ T lymphocytes into
pathogenic Th1 cells and inammatory CD14+ CD16+ monocytes (Fig. 5).21,22 Elevated levels of plasma/
serum cytokines and chemokines such as IL-2, IL-7, G-CSF, GM-CSF, IP-10, MCP-1, MIP-1a, and TNF-α
lead to the cytokine storm described earlier (Figs. 2–5).14,15
IV. MUSHROOMS IN MAINTAINING ACE/ACE2 BALANCE
Because the impaired ACE/ACE2 ratio has been linked with the COVID-19 pathomechanism, treatment
strategies targeting this ratio have received immense attention.23 ACE inhibitory proteins have been iso-
lated from different edible and medicinal mushrooms, of which the most notable are Ganoderma lu-
cidum, Grifola frondosa, Agrocybe species, Auricularia auricula-judae, Hericium erinaceus, Hypsizygus
marmoreus, Pleurotus cystidiosus, P. eryngii, P. abellatus, P. orida, P. sajor-caju, Schizophyllum com-
mune, Tricholoma giganteum, and Volvariella volvaceae.24–29 In addition to peptides and proteins, ACE
inhibitory triterpenes have also been extracted from G. lucidum.30 The ACE inhibitory effect of these
mushrooms can restore the ACE/ACE2 ratio indirectly and would thus provide a COVID-19-ameliorat-
ing effect.23 In addition, by allowing less conversion of AngI to AngII through ACE inhibition, usage of
mushrooms seems apt in COVID-19 therapeutics. As chemically synthesized ACE inhibitors have side
effects such as dry cough, an alternative medicinal approach incorporating mushrooms seem promising.31
On the other hand, increasing ACE2 levels would also increase the susceptibility of SARS-CoV-2 bind-
ing to host cells, making the process a double-edged sword. Thus, further research is warranted in this
aspect.
FIG. 5: Hyperactivation of T cells generating a series of Th cells and proinammatory cytokines. TGF, tumor growth
factor; Treg, regulatory T cell.
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V. ANTIVIRAL PROPERTIES OF MUSHROOMS
Mushroom extracts and biocomponents can impede viral multiplication through their inhibitory roles to-
ward virus adsorption and entry into host cells, viral replication, and nucleic acid synthesis.32 Viral proteases
are important for replication and proteolytic cleavage-led production of infectious viral particles. Inhibitors
of those proteases are of paramount choice in antiviral drug development. The U.S. Food and Drug Admin-
istration has permitted the use of human immunodeciency virus (HIV)-1 protease inhibitors (tipranavir,
saquinavir, ritonavir, nelnavir, lopinavir, indinavir, darunavir, atazanavir, and amprenavir) for treatment
against SARS-CoV-2.33 In addition, RNA-dependent RNA polymerase inhibitors (remdesivir and favilavir)
have been applied as a COVID-19 treatment in different countries.34 Different protease inhibitors have
been isolated from edible and medicinal mushrooms such as G. lucidum, G. colossum, G. sinense, Lignosus
rhinoceros, A. polytricha, Russula paludosa, Cordyceps militaris, and Agaricus bisporus.35–45 Ganomycin I
and ganomycin B from G. colossum are reported to have anti–HIV-1 protease with half maximal inhibitory
concentration values of 7.5 and 1.0l μg/ml, respectively.39 Ganoderone A, ganoderol B, lucialdehyde B,
lucidadiol, lucialdehyde, amantadine sulfate applanoxidic acid G, and ergosta-7,22-diene-3b-ol isolated
from G. pfeiffery have shown antiviral effects against inuenza A virus.46 Compared to others, Ganoderma
species seem promising in protease inhibition–based antiviral therapeutic approaches. Up to the present
day, biocomponents derived from Ganoderma (ganocompounds) have been found effective in thwarting
HIV-1 protease, which corroborates utilization of ganocompounds against SARS-CoV-2. Cordycepin
(3′-deoxyadenosine), isolated from C. militaris, exerts an antiviral effect through a protein kinase inhib-
itory mechanism.47 Also, its inhibitory role toward RNA synthesis has been implicated in inuenza virus
multiplication.48 The epigenetic mode of antiviral effects has also been linked with cordycepin.49
VI. IMMUNOMODULATORY ROLE OF MUSHROOMS
COVID-19 manifests a multitude of illnesses, some of which are symptomatic while others are asymptom-
atic.50 Among them, immunological deregulation (i.e., the cytokine storm) is the most notable manifestation
of COVID-19.50 Thus, modulation of the compromised immune system has become the focal point in com-
bating COVID-19. Immunomodulation is the regulatory process that maintains a balanced immune system:
it does not allow all immune cells to be active altogether. In this regard, food and nutraceutical-based ap-
proaches boosting immune defense and modulating compromised immunity seem apt as a defense against
COVID-19.51 Immunomodulators are biocomponents able to lower immune stimulation (immunosuppres-
sant), promote innate immune response (immunostimulants), or enhance vaccine efcacy (immunoad-
juvants).52 Mushroom-based immunomodulators can be classied into four categories: lectins, proteins,
polysaccharides, and terpenoids.52 Fungal immunomodulatory protein (FIP)-fve isolated from Flammu-
lina velutipes could suppress replication of respiratory syncytial virus, a bronchiolitis agent. FIP-fve also
lowered IL-6 expression and inammation through inhibition of NF-κB translocation.53 Trained immunity
(TRIM) is a modied and epigenetic innate immune response that is capable of producing antibody-free
memory to the pathogen and lasts for several months.54 β-D-glucan has been implicated in enhancing TRIM
through epigenetic mechanisms and metabolic regulation.55 Respiratory tract infection (RTI), especially
lung infection, is a grave concern of COVID-19 manifestations. Mushroom-derived β-glucan has been
found to ameliorate both upper and lower RTIs and boost immunity.56–58 Common cold or u-like symp-
toms are the general features of COVID-19. Oral administration of β-D-glucan was shown to lower the
level of common cold events by one-fourth, as evidenced in randomized, double-blind, placebo-controlled
studies.59,60 These effects have been deemed to arise through TRIM effects of β-D-glucan.61 The β-D-glucan
level is reported to be 54.0, 50.5, 34.3, and 32.8 g/100 g of dry weight of G. lucidum, Trametes versicolor,
G. frondosa, and C. militaris, respectively.62 Hot water extract of G. lucidum has been found to alleviate
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inuenza in H1N1 and H5N1 virus-induced inuenza model rats.63 Although the exact mechanism of anti-
viral effect is not yet known, overall enhanced immunity seems apt. This enhancement might occur either
through direct immune stimulation or through TRIM. Thus, usage of β-D-glucan as both a therapeutic and
prophylactic agent seems apposite.
Corticosteroids prescribed against severe ALI and ARDS hamper host antiviral immunity; thus, their
usage against SARS-CoV-2 seems unwise.64 Also, proximal immune response inhibition through IFN-re-
lated PRR activation would deregulate the host immune system.65 Therefore, immunomodulatory treatment
strategies targeted at proinammatory and Th2 cytokine (IL-1, IL-4, IL-6, IL-8, IL-21, TNF-α, oxygen
radicals) production seem apt.66 Various anti-inammatory biocomponents such as polysaccharides, ter-
penoids, phenolics, glycerides, and other low molecular weight substances have been isolated from Basid-
iomycetes mushrooms.9,10,66 β-D-glucan extracted from Lentinus edodes is found to reduce inammation
in human alveolar epithelial A549 cells, as evidenced by reduced cytokine-induced NF-κB activation and
attenuated proinammatory cytokine production (TNF-α, IL-8, IL-2, IL-6, IL-22) oxidative stress-induced
early and late apoptosis.67 Thus, modulation of the cytokine storm through β-glucan–mediated controlled
expression of pro- and anti-inammatory cytokines could aid in withstanding COVID-19 pathogenesis.66,67
Mushroom biocomponents (polysaccharides such as α- or β-glucans, proteins, or glycoproteins) exert im-
munomodulatory pursuits through regulation of cytokine (IL-10, IL-12p70, and IL-12p40) production by
DCs; production of TNF-α, IL-1, IL-6, IL-8, IL12p40, and nitric oxide (NO); expression of inducible nitric
oxide synthase by macrophages; and activation of NK cells.68 Most of these effects have been reported for
G. lucidum, Phellinus linteus, A. blazei, and G. frondosa.68 Basidiolipids from Agaricus species of mush-
rooms have been found to have immunoadjuvant activity.69 Through enhanced production of IFN-γ (inducer
of DC maturation) and TNF-α (stimulator of IL-2 production), A. bisporus increased NK cell activity in
mice.70 NF-κB and AP-1 signaling has been associated with the anti-inammatory potential of P. ostrea-
tus.71 Novel lentinal (LNT-1) extracted from L. edodes signicantly downregulated expression of proin-
ammatory cytokines (TNF-α, IL-2, IL-11) and upregulated that of immunomodulatory, anti-inammatory,
and antiproliferative cytokines such as IFN-1 and IFN-γ.72 DCs are potent antigen-presenting cells capable
of activating naïve T cells (Fig. 5). Protein-bound polysaccharide K derived from Coriolus versicolor aids
in the maturation of DCs along with overcoming the defective phagocytosis of DCs.73,74 Inammatory ame-
lioration of Inonotus obliquus polysaccharides is linked with JAK-STAT signaling pathway inhibition and
the associated release of Th subsets, especially CD4+ T cells.75 Downregulation of IL-1, IL-6, IL-8, IL-17,
MMP-9, NO, TNF-α, and IFN-γ and upregulation of IL-2 and IL-10 by G. lucidum as well as downregula-
tion of IL-8, NF-κB, TNF-α, and MCP-1 by G. frondosa have been observed.76
VII. MUSHROOMS IN AMELIORATION OF COVID-19 COMORBIDITIES AND AS A
NUTRITIONAL SUPPLEMENT FOR PATIENTS WITH COVID-19
Most patients with COVID-19 are aged > 65 years. Some people in this age range suffer from AD. AD,
CVD, diabetes mellitus, hypercholesterolemia, and hypertension are common comorbidities of COVID-19.
Patients with COVID-19 and comorbidities require nutritional supplementation in support of their ght
against SARS-CoV-2 and diminished homeostasis.77 As a functional food, both edible and medicinal
mushrooms are highly effective in supplementing nutritional deprivation.78–83 Polysaccharides (especially
β-D-glucan), polyphenols, triterpenes, proteins, vitamins, and minerals present in mushrooms would sup-
port treatment of patients with COVID-19 and comorbidities.83 As the preparation of mushroom powder
is simple and does not require sophisticated handling and preservation processes, supplying mushroom
powder to patients with COVID-19 and comorbidities around different parts of the globe would also be
less cumbersome for aid agencies. Thus, we recommend quick actions in preparing mushroom-based food
items for COVID-19 sufferers and request that the World Health Organization (WHO) and other health care
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management agencies take the necessary steps to disseminate a mushroom-based therapeutic and preven-
tive approach against SARS-CoV-2.
VIII. CONCLUSIONS
Different aspects of biomedical, biopharmaceutical, nutritional, immunological, and antiviral approaches
link both edible and medicinal mushrooms in treatment to combat COVID-19. The contents of proteins,
triterpenes, viral replication inhibitory proteins, and immunomodulatory polysaccharides like β-D-glucan
found in mushrooms as well as nutritional supplements place mushrooms in superb stead in this global
crisis. Among different mushroom species, G. lucidum stands out as the best in terms of COVID-19 pre-
ventive and curative agents. However, we must disclose that appropriate clinical studies are quintessential.
Thus, we request that the WHO and health care agencies provide necessary measures in formulating mush-
room-based anti-COVID preventive and therapeutic strategies.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the researchers and institutions associated with research on SARS-
CoV-2 and mushrooms for providing the necessary information and gures. No nancial assistance was
obtained in conducting this research or preparation and publication of this review.
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