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Medicinal fungi are not only crude extracts, but also that some single components, such as proteins, polysaccharides and terpenoids, can effectively combat viral infection. Some of these medicinal fungi also have inhibitory effects on a variety of viruses. The complex components are closely related to its multi-target and multi-link action mechanism. Some medicinal fungi, including Poria cocos and Polyporus umbellatus, have been widely used in clinical practice. Because of the special properties of medicinal fungi, it is better than that of traditional medicine, which is more beneficial to be used as a kind of health food.
- antiviral
- medicinal fungi
- viruses
1. Introduction
In today’s world, the outbreak of many infectious diseases has posed a serious threat to human life and health. As early as thousands of years ago, the outbreak of smallpox had caused tens of thousands of human deaths [1]. The outbreak of SARS-CoV-2 has now pushed mankind to the edge of the cliff. The outbreaks of most of these infectious diseases are related to viral infection. At this stage, the greatest threat to humanity is the RNA viruses, because they are very easy to mutate in the process of replication and reverse transcription [2]. This makes the prevention and treatment of RNA viruses very difficult. Classic antiviral drugs such as interferon and ribavirin are effective against most viruses in vitro, but usually not for patients, and because of a series of problems such as drug resistance and the high price of existing medicine [3][4][3,4]. More suitable antiviral drugs need to be found quickly.
Medicinal fungi are widely used all over the world. In Pakistan, nearly 23 species of medicinal fungi are used to treat colds, cough, influenza, asthma and other diseases [5]. The United States has added Ganoderma lucidum to the American Herbal Pharmacopoeia and Treatment Program [6]. The medicinal use of medicinal fungi also has a long history in China, which was recorded in Shennong Ben Cao Jing as early as 2000 years ago [7]. It can be used to treat or prevent diseases and has significant biological activity and medicinal value. A series of substances such as proteins, polysaccharides, and alkaloids can be produced in the mycelium, fruiting body, or spores, which has health effects on the human body [8]. Its antiviral, anticancer, and anti-inflammatory effects have attracted more and more attention in recent years [9][10][11][9,10,11]. Because of the special properties of medicinal fungi, their toxicity is much less than that of chemical drugs. During these years, some fungi have gradually developed into medicinal and edible fungi. Medicinal fungi are gradually welcomed by people, greatly improving people’s acceptance.
2. Antiviral Activity
Medicinal fungi can fight viruses in a variety of ways (Figure 1). At present, most existing antiviral drugs are effective mainly through the inhibition of the replication of the viruses in the body. Because medicinal fungi contain complex components, the synergistic effect of multiple components on the viruses in the body will often have an unexpected effect (Figure 2).
Figure 1.
Medicinal fungi antiviral actions.
Figure 2.
Antiviral mechanism of medicinal fungi in vivo.
2.1. Human Viruses
2.1.1. SARS-CoV-2
Novel coronavirus disease 2019 (COVID-19) is an enveloped positive-stranded single-stranded RNA coronavirus of the betacoronaviridae family [12][107]. The high mutation rate of the RNA virus brings a serious challenge to the fight against the virus. From the beginning of Alpha, Beta, and Delta to today’s Omicron, more highly infectious variants have emerged one after another, resulting in a more powerful and contagious virus, making it more difficult to detect and control [108]. [13]Therefore, we urgently need to develop new antiviral drugs to deal with this disease.
In a cell-based anti-SARS-CoV-2 test, several polysaccharides containing L-fucose isolated and characterized from Ganoderma lucidum were tested. It was found that the L-fucose–containing polysaccharides fraction 3 (RF3) had excellent antiviral activity (2 μg/mL) and was still effective at 1280 times dilution without cytotoxicity [14][12]. The impairment of the ACE/ACE2 ratio in coronavirus diseases is related to the pathological mechanism of COVID-19. ACE inhibitory proteins can be isolated from different medicinal fungi, including Ganoderma lucidum, Grifola frondosa, Agrocybe species, Auricularia auricula, Hericium erinaceus, Hypsizygus marmoreus, Pleurotus cystidiosus, P. eryngii, P. flabellatus, P. florida, P. sajor-caju, Schizophyllum commune, Tricholoma giganteum, and Volvariella volvaceae. In addition to peptides and proteins, ACE inhibitory triterpenes were extracted from Ganoderma lucidum. The ACE inhibition of these mushrooms can indirectly restore the ACE/ACE2 ratio, thus providing COVID-19’s treatment effect [15][13]. Antcins, a steroid compound in Taiwan’s endemic medicinal fungus Antrodia cinnamomea, has ACE2 inhibitory effect and can be used as new anti-ACE2 agents to combat SARS-CoV-2 infection [16][14].
2.1.2. Influenza Virus (IV)
IV belong to Orthomyxoviridae and have segmented single-stranded RNA genomes, which are usually divided into A, B, and C types. Influenza A virus is the most popular virus in the world [17][109]. The outbreak of the H1N1 virus in 2009 is one of the most serious cases in recent years [18][110]. At present, most influenza viruses spread seasonally. The most effective way to treat the influenza virus is to be vaccinated. However, the strong mutation ability of the virus leads to the need for vaccination year by year, which causes great inconvenience to people [19][111]. A compound Cryptoporic acid E (CAE), extracted from Cryptoporus volvatus, could inhibit the replication of the influenza virus and reduce the RNA level of the influenza virus [20][22]. The water extract from Cryptoporus volvatus fruiting body is also effective against H1N1 infection. The results showed that it could reduce the level of virus in cells, which may be related to the targeted inhibition of virus entry into cells by its water extract. In animal studies, the extract can completely protect mice from virus infection at high doses [21][23]. Cordyceps militaris also has a good curative effect APS could significantly reduce the titer of the virus in the lungs of mice, enhance the immune level and reduce the mortality after intranasal administration [22][24].2.1.3. Enterovirus 71(EV71)
EV71, a single-stranded RNA virus of about 7500 nucleotides, belongs to the Enterovirus genus of the Picornaviridae family [23][113]. EV71 virus infection can cause hand, foot, and mouth disease (HFMD) as well as serious neurological diseases, posing a serious threat to children under six years of age [24][114]. A new heteropolysaccharide GFP1 was extracted and purified from Grifola frondosa mycelia. The results of cell experiments in vitro showed that GFP1 inhibited the cytopathic effect (CPE) induced by EV71 in a dose-dependent manner. GFP1 inhibited the synthesis of EV71 virus RNA in Vero cells in a dose-dependent manner. The expression of EV71 virus polyprotein was analyzed by western blot. The results showed that GFP1 inhibited the expression of viral VP1 in EV71 infected cells and reduced the apoptosis induced by the EV71 virus by reducing the level of caspase-3 activation [25][30].2.1.4. Human Immunodeficiency Virus (HIV)
In the early 1980s, human immunodeficiency virus type 1 (HIV-1) retrovirus was identified as the pathogen of acquired immunodeficiency syndrome (AIDS) [26][115]. The genome of HIV consists of two identical positive strands of RNA, with a total length of about 9.7 kilobase pairs. Antiretroviral therapy (ART) for HIV-1 infection is the main treatment for AIDS at present, which significantly reduces the morbidity and mortality associated with HIV/AIDS, but the problem of drug resistance still needs to be solved [27][116]. A novel serine protease cordysobin was purified from the Cordyceps sinensis fruiting bodies. The protein has obvious inhibitory activity on HIV-1 reverse transcriptase. The IC50 value is 8.2 × 10−3 μM [28][33]. The anti-HIV activity was also found in the water extracts from different parts of wild Cordyceps sinensis in vitro. The results showed that the five kinds of water extracts had a dose-dependent inhibitory effect on the HIV-1 virus. Further studies showed that their antiviral effect may be related to the activity of HIV-1 reverse transcriptase [29][34].2.1.5. Human Papilloma Virus (HPV)
HPV is a DNA virus with a double-stranded, closed, circular genome and an unenveloped icosahedral capsid of about 8 kb. HPV infection can lead to a variety of cancers, including cervical cancer, penile cancer, anal cancer, vaginal cancer, vulvar cancer, and oropharyngeal cancer [30][117]. HPV vaccination and regular physical check-ups are the main ways to prevent HPV infection [31][118]. In a clinical trial, Trametes versicolor and Ganoderma lucidum fruiting bodies powder were put into capsules for oral HPV patients, and 87.8% of the patients were cured after treatment. This confirmed the curative effect of the two kinds of fungi and laid the foundation for further research [32][52]. In a preliminary study of asymptomatic women, the use of a vaginal gel based on Trametes versicolor for 12 days significantly improved the composition of vaginal microbial communities, helping to improve the state of cervical epithelium and vaginal health [33][53].2.1.6. Dengue Virus (DENV)
DENV is an arbovirus that mainly relies on Aedes aegypti mosquitoes as a vector to transmit to humans. It has four different serotypes: DENV-1, DENV-2, DENV-3, and DENV-4. Among them, DENV-2 is the most widely spread [34][35][120,121]. Dengue fever is a global public health threat, infecting 100 to 400 million people every year, with tropical and subtropical regions being the most affected [36][122]. The treatment of Aedes aegypti mosquitoes with Beauveria bassiana spores can significantly inhibit the replication of the dengue virus in the midgut of mosquitoes, which is partly related to the immune activation of effector genes controlled by Toll and JAK-STAT pathways [37][54]. Panya et al., found that cordycepin can inhibit the replication of DENV and reduce the RNA level of the virus in Vero cells. Its antiviral effect is related to the replication of virus RNA in the later stage of virus infection [38][55].2.1.7. Hepatitis Viruses (HV)
Corbrin capsule prepared from Cordyceps sinensis extract can reduce the apoptosis of renal tubular epithelial cells induced by HBX protein caused by hepatitis B virus infection. The mechanism is to inhibit the apoptosis of HK-2 cells enhanced by HBX by inhibiting the PI3K/Akt/Bcl-2 pathway [39][60]. The GF-D extracted from Grifola frondosa by Gu et al., has an inhibitory effect on HBV, and has a synergistic effect with human interferon α-2b in cell experiments. The antiviral mechanism of GF-D may be that it directly interferes with HBV replication at the level of DNA polymerase [40][61]. In another study, a large number of clinical data show that Polyporus umbellatus polysaccharides (PUPS) alone or in combination with interferon and other drugs can treat hepatitis caused by HBV [41][62].
Matsuhisa’s team found that Lentinula edodes mycelia solid culture extract (MSCE) and its main active component low-molecular-weight lignin (LM-lignin) could inhibit the entry of HCV pseudovirus (HCVpv) into cells, and LM-lignin inhibited HCVpv entry at a concentration lower than MSCE [42][67]. A kind of Cordyceps militaris (CM) capsule can inhibit HCV RNA replication in vitro. Further study showed that cordycepin is the main activity component of CM anti-HCV. The effect of cordycepin is related to its inhibition of NS5B polymerase activity [43][68].
2.1.8. Herpes Viruses (HV)
A novel Grifola frondosa protein GFAHP can inhibit HSV-1 replication in vitro. The IC50 value is 4.1 μg/mL and the therapeutic index is more than 29.3. In vivo experiments show that GFAHP can alleviate the inflammatory response of mice and reduce the production of virus in vivo [44][69]. A Lentinus edodes mycelia extract JLS-S001 also can significantly inhibit the infection of HSV-1 to cells. This may be related to the fact that JLS-S001 blocks HSV-I replication at the later stage of the virus replication cycle [45][70].
Cordycepin can inhibit virus infection by affecting the synthesis of virus protein by acting on the gene of EBV, and resist the proliferation of tumor cells caused by EBV infection, and has certain anti-tumor activity [46][76]. Terpenoids in Ganoderma lucidum may be used as a potential EBV antigen inhibitor. Iwatsuki et al., studied the inhibitory effect of 17 terpenoids on EB virus early antigen (EBV-EA).