key: cord-0954549-sfxq0y1y
authors: Córdova-Martínez, Alfredo; Caballero-García, Alberto; Roche, Enrique; Noriega, David C.
title: β-Glucans Could Be Adjuvants for SARS-CoV-2 Virus Vaccines (COVID-19)
date: 2021-11-30
journal: Int J Environ Res Public Health
DOI: 10.3390/ijerph182312636
sha: ca3f9e788d3c916b4f2b1cc634cbb83d1ca2ee8d
doc_id: 954549
cord_uid: sfxq0y1y

Waiting for an effective treatment against the SARS-CoV-2 virus (the cause of COVID-19), the current alternatives include prevention and the use of vaccines. At the moment, vaccination is the most effective strategy in the fight against pandemic. Vaccines can be administered with different natural biological products (adjuvants) with immunomodulating properties. Adjuvants can be taken orally, complementing vaccine action. Adjuvant compounds could play a key role in alleviating the symptoms of the disease, as well as in enhancing vaccine action. Adjuvants also contribute to an effective immune response and can enhance the protective effect of vaccines in immunocompromised individuals such as the elderly. Adjuvants must not produce adverse effects, toxicity, or any other symptoms that could alter immune system function. Vaccine adjuvants are substances of wide varying chemical structure that are used to boost the immune response against a simultaneously administered antigen. Glucans could work as adjuvants due to their immunomodulatory biological activity. In this respect, β-(1,3)-(1,6) glucans are considered the most effective and safe according to the list issued by the European Commission. Only glucans with a β-(1,3) bond linked to a β-(1,6) are considered modulators of certain biological responses. The aim of this review is to present the possible effects of β-glucans as adjuvants in the efficacy of vaccines against SARS-CoV-2 virus.

COVID-19 is caused by the SARS-COV-2 virus. Although most patients undergo mild symptoms, 20% develop severe symptoms. The disease is characterised by a primary pneumonia that evolves to acute respiratory distress syndrome (ARDS) in the most severe cases [1] . Despite the huge number of studies on SARS-CoV-2, there is no conclusive data regarding the best treatment for the disease [2] . Therefore, a treatment approved by the relevant regulatory health systems does not yet exist. Awaiting for the appearance of an effective treatment (single or combined), the current alternative is prevention and the use of vaccines against the virus.

Aside from the debate regarding the types and doses to be used to achieve the goal of immunisation, vaccination is the most effective strategy in the fight against the pandemic [3] . The main objective of preventive vaccination is the induction of a specific immune response against a pathogenic microorganism leading to protection against the infection and in the long term, eradication of the disease [4, 5] . mRNA vaccines, such as those developed phase that starts immediately after virus entry into the host, and a second specific (late) phase known as adaptive or acquired immunity [17] .

COVID-19 presents as an exacerbated immune response against SARS-CoV-2, resulting in systemic damage accompanied by inflammation [18, 19] that triggers a cytokine overproduction termed as "cytokine storm". This particular process plays a key role in the pathogenesis and severity of the disease [20] .

The onset of COVID-19 infection leads to an increase in the expression of proinflammatory cytokines, such as interleukin (IL)-1β, IL-2, IL-6, IL-8, tumour necrosis factor-α (TNF-α), and interferon (IFN) α and β, among others. The increase observed in these cytokines correlates to the severity of the infection [21] . In summary, the overproduction and expression of cytokines reflects the systemic damage caused by infection and may act as adaptive signalling in the response against SARS-CoV-2 [22] [23] [24] [25] . This entire response is undoubtedly exacerbated by the stress component of the situation, evidenced by glucocorticoid synthesis that has a direct impact on the immune system [26] .

Peripheral blood mononuclear cells include different types of lymphocytes (T cells, B cells and NK cells), dendritic cells (DCs), and monocytes [27] . DCs are antigen-presenting cells for T lymphocytes [28] . As COVID-19 infection progresses, neutrophil and lymphocyte depletion (neutropenia and lymphopenia) occur in severe stages [29] [30] [31] . SARS-CoV-2 invasion and/or replication could be favoured by increased apoptotic events on T-lymphocytes and the binding of SARS-CoV-2 spike protein to CD147, although this last point needs further investigation [22] . When disease severity increases, both the number and function of monocytes and DCs are altered [32] . DCs express MHC class I and II antigen-presenting molecules and are functionally the most potent inducers of antigen-presenting T cell activation and proliferation [33] . In addition, the glycan mannose present in many pathogens is recognised by DC-specific intracellular adhesion molecules (ICAMs) [34] . Therefore, an important element for the control of SARS-CoV-2 infection could be the inhibition and dissemination of pathogens in DCs.

In addition, NK cells act through membrane receptors to trigger the release of the hydrolytic/cytolytic content from their granules. The control of infection by NKs consists in the destruction of virus-infected cells, leading to a restriction of viral replication [35] [36] [37] . The production of certain cytokines, such as IFNs, IL-2, and IL-12, are associated with NK cell action [38] . IFNs activity increases the cytolytic capacity of active NK cells which in turn leads to IL-2 and IL-12 expression [39, 40] . IFNs interfere with the use of host cell resources by the virus, preventing replication and provoking cell death (apoptosis) [41] . In addition, it has been observed that NK cell depletion may favour pulmonary complications that occur in the most severe cases of COVID-19 [42] . Moreover, in models of respiratory infection, activated NK cells can deteriorate lung injury [43] . This suggests that therapeutic measures need to improve and enhance NK cell functionality. This could be a therapeutic alternative in severe cases of COVID-19 [43] .

In general, a key point to control the inflammatory process is the neutralisation of circulating TNF-α to membrane receptors [44] . We have observed this phenomenon when supplementing athletes with an immunomodulator during post-exercise recovery [44] [45] [46] [47] [48] . The neutralisation of pro-inflammatory cytokines (mainly TNF-α) and intermediates (nitric oxide/NO and hydrogen peroxide/H 2 O 2 ) is key to modulate inflammation, although an alternative to block TNF-α is the use of antibodies against it [49] . Most drugs also block bioavailable TNF-α, increasing susceptibility to co-infection or re-infection [50] . In addition, TNF-α can be released from macrophages via a β-glucan-mediated mechanisms. Lentinan (a β-glucan extracted from the mushroom Lentinula edodes) enhances the cytotoxicity of peritoneal macrophages against metastatic tumours [51] . Lentinan structure consists in β-1,3-linked glucose units that every five residues have two β-1,6-linked side chains. On the other hand, lentinan can cause inhibition of TNF-α and NO production in murine macrophages, through the inhibition of inducible nitric oxide synthase (iNOS) gene expression as well as TNF-α mRNA [52] .

So far, it seems that the most relevant antiviral defence is the action of IFNs. They recruit neutrophils, modulate inflammation and thus infection. Therefore, IFNs are placed as the first barrier against invasion by SARSCoV-2 [53, 54] . In these circumstances, IFNs would be able to block virus dispersion, giving the organism time to mount a more potent and specific immune response against SARS-CoV-2 [55, 56] . In the early stages of viral infection, IFN-I (α/β) act directly on NK cells by activating and enhancing cytotoxic function [57, 58] . It has been observed that patients with severe COVID-19 infection have lower IFN expression, which is associated to a decrease in the differentiation of CD4+ and CD8+ lymphocytes and NK cells [59] . In addition, high IL-6/IFN ratio could be a predictor of disease severity and thereby of lung damage associated to the "cytokine storm" [57, 60] . In this context of infection, structural and non-structural SARS-CoV2 proteins inhibit IFN-I release and secretion [61] [62] [63] . This blocks the antiviral and immunomodulatory activity of IFN-I, decreasing resistance to infection. Some of the adjuvant properties of glucans (commented later) against SARS-CoV-2 may lie along these lines of action.

β-glucans can be obtained from mould fungi, yeasts such as Saccharomyces cerevisiae, mushrooms such as Lentinus edodes, and some types of algae. Other sources include cereals, such as oats and barley, and to a lesser extent rye and wheat [64] . β-glucans are glucose polysaccharides forming part of the cellular wall of certain pathogenic fungi and bacteria. There is a wide variety of β-glucans, which differ in the position of the carbon bonds between the different monomers forming the glycoside chain. Bonds (1→3), (1→4), (1→6) have been identified between the D-glucose units. Depending on the source of extraction, one type of polysaccharide or another predominates in the β-glucans [65, 66] . Insoluble β-glucans (1,3 and 1,6) have the highest biological activity when compared to their counterparts soluble β-glucans (1,3 and 1,4). Therefore, differences between bonds and chemical structure in relation to solubility seem to be instrumental for the mode of action and biological activity [67, 68] .

In general, glucans are a group of substances with immunomodulatory biological activity and have been successfully used in clinical medicine and shown to improve health [8, 9] . Certain β-glucans have immunomodulatory effects, intervening in both innate and adaptive immunity. Basically, the proposed mechanisms to exert these effects are as follows ( Figure 1 ): (a) After oral administration, β-glucans are absorbed in the intestine and recognized by intestinal macrophages, which degrade them into smaller polysaccharides. They are then transported and released into the medulla and the mononuclear phagocytic system [69] . Subsequently, fragments of the β-glucans are released by macrophages and captured by neutrophils (granulocytes), monocytes and DCs, triggering the immune response; (b) An alternative mechanism of β-glucan uptake is through recognition by epithelial cells, such as M cells, cells of the lymphoid tissue associated with the intestine, macrophages, and DCs, introducing them into circulation [70] . 

From an immunological point of view, the innate immune system must display the capability to recognise and respond quickly to a pathogen. On the other hand, adaptive immunity uses generated receptors that recognize antigens that the host has previously encountered. The β-glucans are recognised by immune system cells via the following receptors: Dectin-1, CR3, Lactosylceramide, selected scavenger receptors, and the Toll like receptor (TLR) (Figure 1 ). The affinity of β-glucans for these receptors depends on their molecular weight, having higher affinity for receptors with high molecular weights [71] .

After the uptake and release of β-glucans in the marrow and mononuclear phagocyte system, they are recognised by granulocytes, monocytes, or macrophages and NK cells via receptors such as CR3. The binding of the polysaccharide to the receptor triggers different responses, such as phagocytosis and/or cytokine secretion (Figure 1) , thus activating innate immunity [72] . In addition, Dectin-1 (or b-glucan receptor) is a type II transmembrane protein receptor that binds β-(1,3) and β-(1,6) glucans. Dectin-1 binds β-glucans and triggers innate immune responses, including phagocytosis and the production of proinflammatory factors, directed towards the elimination of infectious agents [73] [74] [75] .

Monocytes/macrophages and neutrophils express Dectin-1 as well as DCs and a subpopulation of T cells, but to a lesser extent [76] . Dectin-1 binds polysaccharides containing β-(1,3) and/or β-(1,6) bonds. The signalling pathways activated by Dectin-1 involve the participation of NF-κB, the signaling adaptor protein CARD9, and nuclear factor of activated T cells NFAT [77] [78] [79] . This activation process culminates with the secretion of IL-6, IL-10, IL-12, and TNF-α.

The Dectin-1 receptor works together with TLR2 in macrophages and DCs, inducing the production of pro-inflammatory cytokines [80] . TLRs do not recognise glucans by themselves but enhance glucan signalling from Dectin-1 binding, resulting in NF-κB activation and cytokine production. Signalling from both receptors results in the phosphorylation of the ITAM (immunoreceptor tyrosine-based activation motif), leading to phagocytosis and activation of NADPH oxidase, ensuing the death of the invader microbe [81] . In addition, the SIGN-related 1 (SIGNR1) of DCs containing the ITAM-3 homologue motif, is another major macrophage mannose receptor that cooperates with Dectin-1 in the recognition of β-glucans and subsequent phagocytosis [82] .

On the other hand, TLR-4 blockade can inhibit the production of IL-10 and IL-12 induced by purified glucans from Ganoderma. This suggests a key role of TLR-4 signalling in glucan-induced DC maturation. This effect is also mediated by increased IκB kinase, NF-κB activity, and MAPK phosphorylation [83] .

Moreover, the adaptive immune response requires the combined action of T-cells and antigen-presenting cells. Presentation of MHC (major histocompatibility complex)-I antigens to cytotoxic CD8+ T cells is restricted to peptide fragments coming from intracellular pathogens after proteasome activity. The MHC-II endocytic pathway presents only proteolytic peptides from extracellular pathogens to CD4+ T-helper cells. β-glucans can use the MHC-II pathway to activate CD4+ T-cells [84] . In this context, β-glucans are processed into smaller carbohydrates that bind to MHC-II on antigen-presenting cells (DCs) for presentation to T helper cells.

Another mechanism of action of β-glucans is mediated by activated complement receptor 3 (CR3), located on NK cells, neutrophils, monocytes and certain lymphocytes. This pathway accounts for opsonic recognition of β-glucans, leading to phagocytosis and lysis of reactor cells. The β-glucans bind to the lectin domain of CR3, priming the binding of inactivated complement 3b (iC3b) on the surface of reactor cells. Neutrophils containing CR3 can trigger lysis of iC3b-coated tumour cells [72] . In a similar way, most human NK cells express CR3, and opsonisation of iC3b-coated NK cells has been shown to lead to increased lysis of the target [85, 86] .

It has been well stablished that macrophages play a key role in all phases of host defence in case of infection through a complete innate and adaptive immune response. Binding of the β-glucan to the receptor triggers different responses: phagocytosis and/or cytokine secretion, thus activating the innate immune system [69, 72] . Macrophages are also involved in the secretion of cytokines (IL-1, IL-6, IL-8, IL-12, TNF-α) and inflammatory mediators (NO and H 2 O 2 ) ( Figure 2) . Thus, the activation of macrophage functions by β-glucans can enhance host immune defence. Among the cytokines secreted, TNF-α, recognised as the first cytokine produced by activated macrophages, is an essential molecule in host defence. TNF-α activates inflammatory reactions by triggering the secretion of ILs, including IL-1 and IL-6. TNF-α increases NO release and activates innate and acquired immune responses, increasing immunoglobulin (Ig) production, activating the complement pathway and producing T and B cells. TNF-α also has an impact on neutrophil action [87] .

The binding of β-glucans to Dectin-1 elicits the secretion of cytokines such as IL-6, IL-10, IL-12, and TNF-α, which increases the body's response against antigens [67] . Certain studies have shown that some β-glucans are able to activate the complement system through the complement system receptor CR3, also known as CD11b/CD18. CR3 is expressed in myeloid cells, NK cells, and lymphocytes [69, 72, 88] . Once the β-glucans are recognised by CR3, the complement C3 pathway is activated, and the C3b fraction acts directly on macrophages, NK cells, and neutrophils, increasing phagocytosis and lysis of cells that are coated with iC3b (inactivated C3b) [69, 72, 88] . Therefore, β-glucans, through their action on different receptors (Dectin-1 and CR3) of the immune system, can trigger a variety of responses. These responses affect cells of the immune system, including macrophages, neutrophils, monocytes, NK cells, and DCs [89] . 

β-glucans may have broad anti-infective effects. In fact, β-glucan has been found to have a protective effect against influenza virus [90] . In swine influenza virus (SIV)induced pneumonia, β-glucans induced significantly higher levels of IFN-γ and NO in bronchoalveolar lavage fluid of treated pigs compared to the untreated group [90] . Another study in rats showed that treatment with β-glucans resulted in increased neutrophil migration to the site of inflammation and improved antimicrobial function [91] . Moreover, in patients undergoing major surgery, administration of β-glucans improves monocyte and neutrophil function, playing a key role in decreasing infectious complications [92] . Similarly, peri-operative administration of β-glucans also reduces by 39% severe postoperative infections [93] . Moreover, the β-glucan extract has recently been reported to show in vitro immunomodulatory and pulmonary cytoprotective effects, being indicated for COVID-19 immunotherapy [94] .

The key to immunomodulation is to adapt the host response. Otherwise said, how can the response be augmented or suppressed to obtain an optimal immune response? The advantages are: (i) enabling host defence mechanisms by enhancing the immune response and (ii) not involving the use of antibiotics, which is important taking into account the large number of pathogens that have developed resistance to antimicrobial agents [95] .

There are several types of endogenous immunomodulators, such as IFN-γ, colony stimulating factor (CSF), and macrophage and monocyte stimulating factor (GM-CSF). Some polysaccharides isolated from various botanical sources appear to possess relevant immunomodulatory properties and relatively low toxicity [81, 96] . As mentioned before, it has been observed that β-glucans can increase the cytotoxic activity of macrophages against tumour cells and microorganisms. This protective action is achieved by increasing reactive oxygen species (ROS) and NO production, as well as enhancing the production of cytokines and chemokines, such as TNF-α, IL-1β, IL-6, IL-8, IL-12, IFN-γ, and IFN-β2 [9, 25, 97] .

The role of glucans as immunomodulators has long been known. Glucans represent a type of immunostimulatory active molecules across the evolutionary spectrum, representing a conserved alternative in the direct innate immune response against pathogenic fungi [9, 97] . Thus, the components of the immune system are activated and modulated by β-glucans. It would therefore appear to be of interest as an ideal element to promote effective and long-lasting immunity.

A significant property in the immunological activity of β-glucans is their adjuvant action. In general, the immune system reacts with a better and greater response when β-glucans "prime" this system. For this reason, many studies have focused on the use of these compounds in conjunction with viral, bacterial and parasitic vaccines [90] .

During immune modulation, β-glucans are recognised through transmembrane receptors. Glucan-receptor binding stimulates glucan phagocytosis, the release of proinflammatory cytokines, chemokines, and antimicrobial proteins. In this context, it has been reported the potential performance of glucans for the preparation of delivery nanosystems as a platform for DNA vaccination [98] .

Current vaccines against SARS-CoV-2 are from Pfizer-BioNTech (SARS-CoV-2 mRNA vaccine), Moderna (SARS-CoV-2 mRNA vaccine), Janssen Pharmaceutical Companies of Johnson & Johnson (J&J's) (based on a replication-incompetent adenovirus serotype 26 (Ad26) vector, which encodes a SARS-CoV-2 spike protein), and Oxford/AstraZeneca (made from virus ChAdOx1) [99] [100] [101] .

Studies exploring the protective effects of β-glucans and its possible use as adjuvants in vaccines were conducted in the early 1990s. The β-glucan, like the tuberculosis vaccine (BCG), induces a TRIpartite Motif (TRIM) phenotype, involved in pathogen recognition and transcriptional regulation of innate immunity systems [102] [103] [104] . β-Glucans can produce long-lasting TRIM against a wide range of pathogens. In addition, β-glucans show additive and even synergistic effects with various agents [105] . The ability of (1→3), (1→6)-βglucans to activate cellular and humoral components of the immune system is well known. They enhance the antimicrobial activity of mononuclear cells and neutrophils and increase the function of macrophages. In addition, they stimulate monocyte and macrophage proliferation [95] . Upon exposure to β-glucans, innate immune cells are activated and there is an increase in cytokine production accompanied by changes in metabolic functions [106, 107] . Subsequently, if these cells are confronted with heterologous secondary stimuli, they are reprogrammed to produce a more potent immune response [108] [109] [110] (Figure 2 ).

As mentioned before, β-glucans have antiviral effects, helping to decrease the severity of infections. After exposure to an initial stimulus, the antiviral response could be due to the induction of immunity through TRIM, which triggers metabolic, mitochondrial, and epigenetic reprogramming, resulting in a memory phenotype of enhanced immune response [8, 90, 111, 112] .

Therefore, immunomodulators appear to be an effective tool to combat infectious diseases by boosting host defences. These can be used either preventively through vaccination or therapeutically. Currently, more and more vaccines are showing greater efficacy due in part to adjuvants. These are molecules that have little immunogenicity by themselves but help to boost and direct the immune response against an antigen [113] . In 1997, Adams, et al. [114] suggested that PGG-glucan (Betafectin), obtained from yeast, modulates the production of pro-inflammatory cytokines by lymphocytes and monocytes during sepsis. In studies in mice, it has been observed that those treated with PGG-glucan, when lymphocytes were removed, produced lower amounts of proinflammatory cytokines such as TNF-α. In addition, glucan treatment increased the level of cell apoptosis. Finally, rats infected with a lipopolysaccharide (LPS from E. coli) and treated with LAM (β-polysaccharide-(1→3)) displayed a decrease in TNF-α, nitrite and monocytes compared to non-treated rats. LAM also modulated intrahepatic immune cells, decreasing peroxidase-positive cells (corresponding to monocytes/neutrophils) and increasing the number of ED2-positive cells (mainly macrophages) [115] .

β-glucans activate the immune system and modify the cellular response. The binding of β-glucans to their receptors can elicit a cellular response through modulation of the activities of several extracellular messengers, such as cytokines and chemokines [116] . We believe that β-glucans orally administered may be useful as adjuvants, improving the effectiveness of various vaccines currently marketed against SARS-CoV-2 [117] . β-glucans show a clear immunomodulatory effect by improving the cellular pattern involved in the infectious process and decreasing the cytokines involved in the inflammatory course derived from COVID-19. The improvement of immune function is key in the mechanism of protection and elimination of intracellular infectious agents. Thus, oral β-glucans are promising molecules as vaccine adjuvants, as they alone can stimulate various immune pathways, including antibody production. β-glucans enhance the immunogenicity of hepatitis B vaccine, influenza vaccine, and vaccines against systemic aspergillosis and coccidioidomycosis. Thus, β-glucans (particularly β-(1,3)-(1,6)) are potentially useful as immune adjuvants to enhance the immune response, as has recently been observed in the vaccine against avian influenza subtype H5, with no adverse reactions [118] . 

China Novel Coronavirus Investigating and Research Team. A novel coronavirus from patients with pneumonia in China

Pharmacologic treatments for coronavirus disease 2019 (COVID-19): A review

The race for coronavirus vaccines: A graphical guide

COVID-19: Immunopathogenesis and Immunotherapeutics

Vaccines for COVID-19

COVID-19 vaccines: Where we stand and challenges ahead

SARS-CoV-2 vaccines in development

Beta glucan: Supplement or drug? From laboratory to clinical trials

Natural immunomodulators and their stimulation of immune reaction: True or false?

Vaccine adjuvants: Putting innate immunity to work

Summary of an international symposium on potentiation of the immune response to vaccines

Adjuvants-A classification and review of their modes of action

An update on vaccine adjuvants in clinical trial

Could the induction of trained immunity by β-glucan serve as a defense against COVID-19? Front

Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: A retrospective cohort study

Adjuvant potency of Astragaloside VII embedded cholesterol nanoparticles for H3N2 influenza vaccine

Alvárez de Mon, M. Inmunidad en el Deporte

The many faces of the anti-COVID immune response

Role of the immune response in COVID-19

Author correction: Pathological inflammation in patients with COVID-19: A key role for monocytes and macrophages

The cytokine storm and COVID-19

Infection of human lymphomononuclear cells by SARS-CoV-2

SARS-CoV-2 clearance in COVID-19 patients with Novaferon treatment: A randomized, open-label, parallel-group trial

AM3 inhibits HBV replication through activation of peripheral blood mononuclear cells

Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac

Isolated human peripheral blood mononuclear cell (PBMC), a cost effective tool for predicting immunosuppressive effects of drugs and xenobiotics

Molecular mechanisms of T cells activation by dendritic cells in autoimmune diseases

SARS-coronavirus replicates in mononuclear cells of peripheral blood (PBMCs) from SARS patients

DC/L-SIGNs of hope in the COVID-19 pandemic

Expression of lymphocytes and lymphocyte subsets in patients with severe acute respiratory syndrome

COVID-19 and myeloid cells: Complex interplay correlates with lung severity

Different types of in vitro generated human monocyte-derived dendritic cells release exosomes with distinct phenotypes

The physiological role of DC-SIGN: A tale of mice and men

Natural killer cell specificity for viral infections

AM3 modulates dendritic cell pathogen recognition capabilities by targeting DC-SIGN

NKG2A is a NK cell exhaustion checkpoint for HCV persistence

Regulation of human NK-cell cytokine and chemokine production by target cell recognition

Inmunoferon (Am3) enhances the activities of early-type interferon inducers and natural killer cells

A microplaque reduction assay for human and mouse interferon

Impaired interferon signature in severe COVID-19

Identification of druggable inhibitory immune checkpoints on Natural Killer cells in COVID-19

The promise and peril of natural killer cell therapies in pulmonary infection

Alvarez-Mon, M. Modulation of TNF-α, TNF-α receptors and IL-6 after treatment with AM3 in professional cyclists

Effects of AM3 (Inmunoferon®) on increased serum concentrations of interleukin-6 and tumour necrosis factor receptors I and II in cyclists

Inmunoferon ® , a glycoconjugate of natural origin, inhibits LPS-induced TNF-α production and inflammatory responses

Inmunoferon®, a glycoconjugate of natural origin, regulates the liver response to inflammation and inhibits TNF-α production by an HPA axis-dependent mechanism

New trends in biological aids to recovery after exercise: Immunomodulators

Immune response in COVID-19: Addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2

Therapeutic approaches for tumor necrosis factor inhibition. Braz

Pneumocystis carinii stimulates tumor necrosis factor-alpha release from alveolar macrophages through a beta-glucan-mediated mechanism

Ashida, H. β-Glucan from lentinus edodes inhibits nitric oxide and tumor necrosis factor-α production and phosphorylation of mitogen-activated protein kinases in lipopolysaccharide-stimulated Murine RAW 264.7 macrophages

Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity

Innate immunity to respiratory viruses

Coronavirus infections and immune responses

Interferon activation and innate immunity

Impaired type I Interferon activity and exacerbated inflammatory responses in severe COVID-19 patients

Natural killer cell responses during viral infections: Flexibility and conditioning of innate immunity by experience

Clinical and immunologic features in severe and moderate forms of coronavirus disease

High IL-6/IFN-γ ratio could be associated with severe disease in COVID-19 patients

Recent insights into emerging coronaviruses

Sars-CoV-2 envelope and membrane proteins: Structural differences linked to virus characteristics?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): An overview of viral structure and host response

Structural analysis of glucans

Effects of ß-glucans on the immune system

Medicinal mushrooms as a source of antitumor and immunomodulating polysaccharides

Beta-glucans: What types exist and what are their health benefits?

Immunomodulation and anti-cancer activity of polysaccharide-protein complexes

The effects of β-glucan on human immune and cancer cells

Possible mechanisms of action of mushroom-derived glucans on inflammatory bowel disease and associated cancer

Fungal β-glucans and mammalian immunity

Mechanism by which orally administered β-1,3-glucans enhance the tumoricidal activity of antitumor monoclonal antibodies in murine tumor models

The biological role of dectin-1 in immune response

The pattern recognition receptor dectin-1: From fungi to mycobacteria

Dectin-1: A signalling non-TLR pattern-recognition receptor

Lipopolysaccharide heterogeneity: Innate host responses to bacterial modification of lipid a structure

Dectin-1 stimulation by candida albicans yeast or zymosan triggers NFAT activation in macrophages and dendritic cells

Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity

Syk-dependent cytokine induction by dectin-1 reveals a novel pattern recognition pathway for C type lectins

Collaborative induction of inflammatory responses by dectin-1 and toll-like receptor 2

Beta-glucans as immunostimulant in vertebrates and invertebrates

The Role of SIGNR1 and the β-Glucan receptor (Dectin-1) in the nonopsonic recognition of yeast by specific macrophages

Polysaccharide purified from Ganoderma luciduminduced activation and maturation of human monocyte-derived dendritic cells by the NF-κB and p38 mitogen-activated protein kinase pathways

Polysaccharide processing and presentation by the MHCII pathway

Contribution of CR3, CD11b/CD 18 to cytolysis by human NK cells

The function of human NK cells is enhanced by β-glucan, a ligand of CR3 (CD11b/CD18)

Immunomodulating compounds in basidiomycetes

Immunostimulatory properties and antitumor activities of glucans

Polysaccharides inLentinus edodes: Isolation, Structure, Immunomodulating Activity and Future Prospective

Antiviral effect of saccharomyces cerevisiaebeta-glucan to swine influenza virus by increased production of interferon-gamma and nitric oxide

The effect of PGG-β-glucan on neutrophil chemotaxis in vivo

Randomized phase I/II trial of a macrophage-specific immunomodulator (PGG-glucan) in high-risk surgical patients

Effect of PGG-glucan on the rate of serious postoperative infection or death observed after high-risk gastrointestinal operations

β-Glucan extracts from the same edible shiitake mushroom Lentinus edodes produce differential in-vitro immunomodulatory and pulmonary cytoprotective effects-Implications for coronavirus disease (COVID-19) immunotherapies

Polysaccharide immunomodulators as therapeutic agents: Structural aspects and biologic function

Botanical polysaccharides: Macrophage immunomodulation and therapeutic potential

Effects of marine β−1,3 glucan on immune reactions

Polymeric nanoengineered HBsAg DNA vaccine designed in combination with β-glucan

The European medicines agency's EU conditional marketing authorisations for COVID-19 vaccines

Emergency use authorization of Covid vaccines-safety and efficacy follow-up considerations

Current status of COVID-19 (Pre)clinical vaccine development

Protective effect of glucan against systemic Staphylococcus aureus septicemia in normal and leukemic mice

Immunomodulation by a low-virulence, agerminative variant of Candida albicans. Further evidence for macrophage activation as one of the effector mechanisms of nonspecific anti-infectious protection

Non-specific beneficial effect of measles immunisation: Analysis of mortality studies from developing countries

Enhancement of murine alveolar macrophage functions by orally administered β-glucan

Beta-glucan enhancement of T cell IFNupsilon response in swine

Glucan-induced enhancement of host resistance to selected infectious diseases

Trained immunity: A smart way to enhance innate immune defence

The Set7 lysine methyltransferase regulates plasticity in oxidative phosphorylation necessary for trained immunity induced by β-glucan

Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity

extracted from oat, enhances disease resistance against bacterial and parasitic infections

β-Glucan-induced trained immunity protects against leishmania braziliensis infection: A crucial role for IL-32

Immunomodulatory effect of pleuran (β-glucan from Pleurotus ostreatus) in children with recurrent respiratory tract infections

PGG-Glucan activates NF-κB-like and NF-IL-6-like transcription factor complexes in a murine monocytic cell line

Dietary supplementation with laminarin, a fermentable marine β (1-3) glucan, protects against hepatotoxicity induced by LPS in rat by modulating immune response in the hepatic tissue

Baker's yeast beta-glucan supplement reduces upper respiratory symptoms and improves mood state in stressed women

Immunomodulators as adjuvants for vaccines and antimicrobial therapy

The adjuvant effect of sophy β-glucan to the antibody response in poultry immunized by the avian influenza a H5N1 and H5N2 vaccines

Acknowledgments: Caja Rural de Soria.

The authors declare no conflict of interest.