How Herbal Medicines Reprogramme Innate Immunity

“That which does not kill us makes us stronger”. Friedrich Nietzsche (1)

Geert Vanden Bossche (GVB) states that the innate immune system is equipped with potent humoral and cellular effectors including, innate antibodies and natural killer (NK) cells, that can abrogate (prevent) viral infection, and that these innate cells are a crucial component of the humoral (antibody-mediated) immune system (2). If you have previously contracted coronavirus disease 2019 (COVID-19/C-19), the positive news is that we now know that innate immunity can be ‘imprinted’ by past experiences. These ‘trained’ innate immune cells can create a ‘memory’ of a pathogen to allow a more coordinated immune response to a second challenge. Natural medicines can train your innate immunity to stop severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection in its tracks. In this article I would like to discuss how plant-derived compounds known as phytochemicals can epigenetically and metabolically reprogramme innate immune cells to create a ‘memory’ of a pathogen. Before discussing how these phytochemicals work, I will review innate immunity.

Innate immunity

Antiviral innate immunity to SARS-CoV-2 and C-19

As SARS-CoV-2 is (or was) a novel virus, an effective adaptive response would not be expected to occur until 2-3 weeks after viral exposure. As the first line of defence, immediate innate cellular responses are crucial in combating SARS-CoV-2, and in viral infection regulation, disease progression and prognosis. Infection control in asymptomatic patients or patients with mild C-19 disease is likely due to a robust innate immune response.

Innate antibodies are the antibodies we are born with

Innate antibodies are also known as natural antibodies (NAbs). NAbs are immunoglobulins (Igs) that are present before the body encounters a foreign antigen. NAbs act as the first line of defence against infection to allow time for the body to mount a specific antibody response. NAbs are a crucial non-redundant component of the humoral immune system, also called antibody-mediated immunity. The humoral immune system is the branch of the adaptive (acquired) immune system (3, 4). B-1 cells are the main producer of NAbs. B-1 production peaks during late embryonic development. By comparison, B-2 cells are generally considered to mediate adaptive immunity (5, 6). IgM Abs are the major component of the NAbs and are the first class of Abs produced during a primary Ab response (7). The interaction between NAbs and lectins allows NAbs to act as a bridge between innate and adaptive immunity (8).

Vaccinal antibodies outcompete innate antibodies

GVB describes the importance of this IgM-mediated effect. In a Voice for Science and Solidarity (VSS) article entitled ‘The alleged ‘case’ for experimental C-19 vaccination of children is merely based on silo mentality and immunological ignorance’. GVB explains that the fundamentals of immunology teach that highly antigen-specific Abs (IgGs) bind their epitopes with higher affinity than multispecific innate Abs (IgMs). GVB says that as IgMs bind to the SARS‑CoV‑2 spike (S) protein using the same type of multivalent interaction as vaccinal anti-S (Abs), it is reasonable to assume that even non-neutralising vaccinal Abs will have the capacity to compete with innate Abs for binding to SARS‑CoV‑2. Essentially GVB is saying that even non-neutralising vaccinal Abs can outcompete innate Abs for binding to SARS‑CoV‑2, thus completely compromising innate (natural) Abs (IgMs) (2). This is the danger humanity faces, particularly as innate Abs have a critical role in protecting children.

Vaccinating during a pandemic drives variants and increases the risk of ADE

In ‘Omicron a wolf in sheep's clothing’ GVB describes an additional danger whereby the continued mass vaccination programme during a pandemic will increase immune pressure and drive variants capable of potentiating antibody-dependent enhancement (ADE) in vaccinees (people receiving the vaccine) (9). In ‘The Coming Crisis?’ GVB explains the mechanism behind immune pressure. As the vaccines do not prevent SARS-CoV-2 infection, vaccinees, should they come in contact with the virus, have a high viral load. Concomitantly, vaccinees have vaccinal Abs and, due to ‘antigenic sin’ (the ability to rapidly recall and boost original vaccinal Abs), the vaccinated also have high Ab levels. It is this combination of a high viral load and high vaccinal Abs that creates the immune pressure that drives natural selection and viral mutations. By contrast, the unvaccinated, should the virus evade innate immune defences, also have a high viral load, however as viral transmission occurs well before a robust humoral response, there is no B cell response. Furthermore, GBV explains another protective mechanism in the unvaccinated whereby de novo priming of anti-SARS-CoV-2 Abs towards the circulating variant prevents natural selection and adaptation of more infectious variants (10).

Epigenetic and metabolic reprogramming and trained immunity

Trained immunity involves epigenetic and metabolic reprogramming of the innate immune cells. This results in enhanced recognition of common pathogen-related rather than antigen-specific signals by innate immune cells and may thereby improve the host’s first line of defence against subsequent infections to improve host survival (11). Whilst diverse stimuli exist, the stimulus in the case of this pandemic is the pathogen-associated molecules on the SARS-CoV-2 virus. This stimulus induces long-lasting training, impacting future responses, even to distinct stimuli (12). Epigenetic and metabolic reprogramming are key regulatory mechanisms of trained immunity. Epigenetic reprogramming is the process by which our genotype interacts with the environment and is achieved through diet, weight management, physical activity, avoiding pollutants, and managing stress. Metabolic reprogramming may involve glucose, fatty acid, and amino acid metabolism, inflammation, proliferation, DNA methylation, and reactive oxygen species (ROS). Both metabolism and epigenetics act equally to support trained immunity, and a continuous interplay between them exists. This is termed metabolo-epigenomics or immunometabolism (13, 14). Both epigenetic and metabolic factors can lead to therapies to train immunity (15). GVB clearly states that the process of epigenetic changes (training) is compromised in the vaccinated (9).

The effector cells of innate immunity

Cellular components include natural killer (NK) cells, mast cells, eosinophils, basophils; and phagocytic macrophages, neutrophils, osteoclasts and dendritic cells (DCs) (16). Antiviral innate immunity has several humoral components that recognise cell surface glycans e.g., mannose-binding lectin, interferons (IFNs), chemokines, and NAbs (mainly IgM, but also IgA and IgG). NK cells abrogate replication at an early stage of infection through cytotoxic action on target cells and cytokine production (17). The SARS-CoV-2 S protein is recognised in a glycan-dependent manner by multiple innate immune receptors (18).

Interferons

Viral recognition by the innate immune system rapidly initiates the production of IFNs. IFNs ‘interfere’ with viral replication to protect cells from virus infection. Importantly, IFNs trigger the release of the aforementioned innate immune cells (19). For many respiratory viruses, including SARS-CoV-2, IFN types I and III (so-called ‘innate’ IFNs), appear to play a role in limiting infection. In innate immunity, IFN type I [IFN-alpha/ IFN-beta (IFN-α/β)] constitutes the first defence line in response to viral infection. IFN type I signalling activates both innate and adaptive immune responses. IFN types I and III [INF-lambdas (IFN-λs)] are produced in cells following interaction between microbial by-products and proteins known as cellular pattern recognition receptors [(PRRs) discussed shortly]. This interaction activates two intracellular signalling cascades; nuclear factor-kappa B (NF-kB) and IFN regulatory factor (IRF), proteins that regulate INF transcription. NF-κB is known as the master regulator of innate immune responses and is vital in orchestrating the inflammatory response to pathogens by innate immune cells. IFN type II [IFN-gamma (IFN-γ)] is the primary activator of macrophages, NK cells and neutrophils, and is critical to both innate and adaptive immunity (20, 21).

SARS-CoV-2 infection causes an imbalance of IFN type I responses and increases inflammation in C-19. Delayed and inadequate IFN production makes viral detection and elimination difficult, causing the virus to replicate in large amounts, further aggravating inflammation and oxidative stress (22). Elderly patients have a significant decline in the ability to produce adequate IFN upon SARS-CoV-2 infection. Additionally, elderly patients often have comorbidities, further exacerbating inflammation and oxidative stress (23).

Pattern recognition receptors

As mentioned, innate immunity relies on pattern recognition receptors (PRRs). PRRs recognise specific molecular patterns called pathogen- or microbe-associated molecular patterns (PAMPs or MAMPs) that are found on all microorganisms, and danger-associated molecular patterns (DAMPs) that are released from dying cells. PRR activation by PAMPs, MAMPs and DAMPs triggers innate immune responses and produces multiple IFNs and proinflammatory cytokines (9). The majority of microbial patterns are glycans (11). NAbs are directed at these self-(like) glycans (24). Many PRRs exist including toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors, nucleotide-binding oligomerization domain- (NOD-) like receptors (NLRs), C-type lectin receptors, and DNA sensors. TLRs and RIG-I-like receptors (RLRs) are the two major receptors responsible for detecting RNA virus infection and activating antiviral IFN (SARS-CoV-2 is an RNA virus) (25). SARS-CoV-2 infection activates PRRs on pulmonary epithelial cells, endothelial cells, macrophages, DCs, and other immune cells to produce cytokines (26). TLR4 is of particular importance as it regulates trained immunity (27).

Pathophysiology of SARS‑CoV‑2

Certain individuals contracting SARS-CoV-2 display a well-coordinated immune response and recover easily, whilst others display a dysfunctional immune response leading to serious complications including acute respiratory distress syndrome (ARDS), sepsis, multiple organ failure (MOF), and associated with morbidity and mortality. Studies in patients with a dysfunctional immune response reveal there is a massive cytokine and chemokine release, referred to as the ‘cytokine storm’. These patients release extreme levels of proinflammatory interleukin-6 (IL-6), IL-1, tumour necrosis factor [TNF-alpha (TNF-α)] and IFN (28). Treatment strategies to calm the cytokine storm can reduce the state of hyperinflammation and the sequelae thereof (29). Numerous phytochemicals found in herbal medicines (HMs) can modulate the immune response, and inhibit inflammation to prevent the cytokine storm.

The role of ACE2 in the cytokine storm and innate immunity

Angiotensin-converting enzyme 2 (ACE2) can tilt the balance between pro and anti-inflammatory immune responses. ACE2 is expressed in alveolar epithelial cells, endothelial cells, macrophages, neutrophils, DCs, and lymphocytes in lung tissue, thus lung tissue is particularly vulnerable to SARS-CoV-2 invasion. SARS-CoV-2 uses ACE2 to overcome the barrier and bind to host cells in the alveoli, resulting in decreased ACE2 and increased blood angiotensin II (Ang II). Ang II results in bronchial smooth muscle contraction, increased pulmonary vascular hyperpermeability, alveolar epithelial cell apoptosis (programmed cell death), and the release of numerous inflammatory cytokines and chemokines, potentially leading to ARDS (26). ARDS is both a product of the cytokine storm following SARS-CoV-2 infection and exacerbates the cytokine storm (30, 31). Ang II induces NF-κB and p38 mitogen-activated protein kinase (p38 MAPK)to produce numerous inflammatory factors, activating the inflammatory response and triggering a massive accumulation of macrophages and neutrophils in the lungs which exacerbates lung damage. MAPK signalling has several roles in innate immune responses. Macrophages and neutrophils release proinflammatory IL-1β, IL-6, TNF-α and the chemokines CXCL8, and CXCL10. This promotes DCs and maturation, activation and migration of CD4+ and CD8+ T cells. It is the overproduction of these proinflammatory mediators that ultimately contribute to the cytokine storm and ARDS.

ACE regulates cellular immune responses through a calcineurin-dependent pathway, which activates T cells and is a new immunologic target for SARS-CoV-2 (32, 33). The calcineurin-dependent pathway also plays a key role in regulating innate immune responses (34). Additionally, whilst ACE2 binds Ang II and is normally known for its role in blood pressure regulation, it has recently been identified as a key player in the conventional renin-angiotensin system (RAS) that promotes inflammation, oxidative stress and apoptosis, and these prolonged immunological effects may weaken innate and adaptive immunity. Changes in ACE2 levels are associated with many diseases and hyperinflammatory states (35, 36). By activating the innate immune response, ACE2 is a therapeutic target to treat C-19 (26).

Herbal medicines epigenetically and metabolically reprogramme innate immunity

Epigenetic reprogramming of innate immunity involves regulating the genes that induce or suppress inflammatory signalling, such as pro-inflammatory chemokines and cytokines; dysregulation of which is responsible for the cytokine storm (37). Different epigenetic modifications control the gene expression of many of these regulators. The remarkable impact of epigenetic changes in inducing or suppressing inflammatory signalling is increasingly being recognised. Several studies have highlighted the interplay of histone modification, DNA methylation, and post-transcriptional proinflammatory microRNAs (miRNAs)-mediated modifications in inflammatory diseases (38).

Histone modification

Numerous phytochemicals have been shown to regulate epigenetic mechanisms and inhibit aberrant inflammation. One study found that 99% of 200 government approved traditional Chinese medicine (TCM) formulas are histone-modifying agents (including through histone acetylation, a critical epigenetic modification etc.) and that 36% of the 3,294 TCM medicinals interact with human histone-modifying enzymes (39).

DNA methylation

Several studies show that numerous phytochemicals [resveratrol, curcumin, genistein and epigallocatechin-3-gallate (EGCG) can inhibit DNA methyltransferases (DNMT) activity or downregulate DNMT expression, and modulate DNA methylation (40).

MicroRNAs-mediated modification

It has recently been shown that phytochemicals, including resveratrol, EGCG, curcumin, quercetin, 3,3′-diindolylmethane (DIM), sulforaphane, genistein, boswellic acid, silymarin, β-Sitosterol-d-glucoside etc., may regulate the expression of miRNAs to exert their anticancer effects by altering miRNA expression (41).

PRR antagonism/agonism

Natural PRR antagonists are a potential therapeutic agent in chronic inflammatory diseases. Phytochemicals have been studied as possible immunomodulating agents due to their multiple and pleiotropic (produce more than one) effects. Phytochemicals have been shown to inhibit PRRs, including TLRs, by recognising PAMPs and activating innate immune responses for host defence (42). On the contrary, TLR agonists are a class of agents which have been shown to trigger the phenomenon of trained immunity through metabolic reprogramming and epigenetic modifications (43). Many phytochemicals including curcumin, naringenin, piperine, baicalin, paeoniflorin, oxyberberine, eriodictyol etc. have been demonstrated to target TLR4 (44). An article published in Frontiers in Immunology in March 2021 describes how phytochemicals modulate the TLR4/NF-κB pathway by regulating the expression of proinflammatory miRNAs, especially those upregulated after NF-κB activation (38). Again, NF-κB is the master regulator of innate immune responses and TLR4 regulates trained immunity (21, 27). These phytochemicals will be discussed further in ‘Herbal Medicine to Train Innate Immunity: Part I’.

Metabolo-epigenomics

As described, the interplay between metabolism and epigenetics to support trained immunity is termed metabolo-epigenomics or immunometabolism. Metabolic reprogramming of monocytes (differentiate into macrophages and DCs) and trained immunity, in particular, has been studied (15). Two sides to innate immunity and macrophages have been found; training (functional, metabolic and epigenetic adaptation of innate immunity) and tolerance (prevention of an immune response against a particular antigen) (45). Whilst both metabolic and epigenetic reprogramming are key regulatory mechanisms of trained immunity, many of these mechanisms are still poorly understood at the biochemical level. To understand the epigenetic regulatory mechanisms of trained immunity, one also needs to understand the role of specific metabolites and metabolic networks involved (14).

During infection innate effector cells require large amounts of energy in the form of adenosine triphosphate (ATP). Glycolysis and fatty acid oxidation (FAO) are the main sources of ATP, although carbohydrates, fats and proteins drive ATP synthesis (37). Flavonoid-mediated immunomodulation of human macrophages involves key metabolites and metabolic pathways including glycolysis, amino acid metabolism, tricarboxylic acids (TCA) cycle and oxidative phosphorylation (OxPhos). Studies on macrophages exposed to phytochemicals have explored these metabolites and metabolic pathways. Flavonoids influence different metabolic pathways to have a broad range of metabolic effects on pro-inflammatory macrophages. Three flavonoids (quercetin, naringenin and naringin) were tested and the metabolic effects common to all flavonoids were restricted to decreased lactate and ATP levels. Quercetin and naringenin promoted a decrease in succinate, alanine, creatine and phosphocreatine (fuel sources for mitochondria to produce ATP) whereas naringenin and naringin-treated macrophages displayed increased glutamate and adenosine diphosphate (ADP) levels. Whilst an increased intracellular ADP: ATP ratio is recognised as an indicator of cell death, this study showed that, despite the relative decrease in ATP and the concomitant increase in ADP, the viability of macrophages incubated for 24 h with flavonoids was not compromised (46).

Beneficial gut microbiota

Gut microbiota (GM) can influence the generation of innate memory. Some intestinal genes related to innate immunity are influenced by microbiota through DNA methylation (47). As mentioned, innate immunity relies on self-(like) PRRs. The intestine maintains control over the intestinal microflora utilising the innate immune response with TLR involvement (48). Beneficial gut microbiota (BGM) as a source of PAMPs, is recognised by PRRs on innate immune cells, thus a potential role exists for GM to induce and regulate innate immune memory. Training of PRRs expressing innate cells with gut microbial/non-microbial ligands is a required protective mechanism (49). PRR and PAMP interaction is pivotal as it triggers the sequence of signalling events and epigenetic rewiring that not only play a fundamental role in modulating the activation and function of the innate cells, but also to convey memory response (49). Many herbal medicines (HMs) increase BGM.

The first pathway

The first pathway is that the GM ‘digests’ HMs into absorbable active small molecules, which enter the body and induce physiological changes. The TCM formula Shi Quan Da Bu Tang (Ten Significant Tonic Decoction) can alter the expression of heat shock protein (HSP) genes in the intestine and liver. This formula is known as Juzentaihoto in traditional Japanese Kampo medicine. HSPs are known as the ‘intestinal gatekeeper’ and protect intestinal epithelial cell function (50, 51). HSPs also stimulate innate and acquired immunity (52).

The second pathway

The second pathway is that HMs regulate the composition of the GM and its secretions to induce physiological changes. For example, Indian mulberry (Morinda officinalis/ Ba Ji Tian) can reduce the abundance of the pathogenic GM, and increase the abundance of BGMs such as Lactobacillus and Bifidobacterium. Liquorice (Glycyrrhiza glabra/ Gan Cao) also promotes increases in Lactobacillus and Bifidobacterium. Southern ginseng (Gynostemma pentaphyllum/ Jiao Gu Lan) may effectively increase BGM levels, reduce sulphate-reducing bacteria levels, and inhibit several pro-inflammatory cytokines. Garlic (Allium sativum L./ Da Suan), southern ginseng and astragalus (Astragalus membranaceus/ Huang Qi) have been used to increase the levels of Lactobacillus in the small intestine of chickens(53). The traditional Japanese Kampo HM formula Bofutsushosan increases the abundance of BGM. Bofutsushosan is also known as Fang Feng Tong Sheng San in TCM. The formula consists of schizonepeta, (Shizonepetae spica/ Jing Jie Sui), liquorice root (Glycyrrhiza uralensis / Gan Ciao), ephedra (Ephedra sinica/ Ma Huang), and forsythia fruits (Forsythiae fructus/ Lian Qiao). Other TCM formulas including, Bawei Xileisan, Wuji Wan, and Gegen Qinlian, also increase the abundance of BGM. The phytochemical rhein, derived from rhubarb (Rheum palmatum/ Da Huang) increases BGM (53).

Polysaccharides (complex carbohydrates), comprise starches and dietary fibres. Plant polysaccharides benefit the growth, promotion and proliferation of intestinal epithelial cells. Many HMs contain polysaccharides which cannot be ‘digested’ by ordinary digestive enzymes, thus Bifidobacterium and Bacteroides secrete hydrolases and reductases, such as d-glucosidase, β-glucuronidase, and β-glucosidase, which assist carbohydrate and protein breakdown. These digestive enzymes convert molecules in HMs into smaller units through oxidation, reduction, and acetylation (53). Polysaccharides assist in stimulating the fermentation rate and increasing the production of short-chain fatty acids (SCFAs), which benefit the differentiation and proliferation of intestinal epithelial cells (54). HMs are an important source for SCFA production, and HMs have been demonstrated to modulate GM composition and regulate SCFA production (55). Butyrate is a SCFA produced by the GM. Recently, butyrate has gained attention as a powerful immune modulatory metabolite in vitro and in vivo. This has been linked to its potent activity as a histone deacetylase (HDAC) inhibitor. Via (histone deacetylase 3) (HDAC3) inhibition, butyrate preconditioning of macrophages enhances their anti-bacterial properties, which enhances glycolysis and mammalian target of rapamycin (mTOR) functions, facilitating an inflammatory response (56). HMs can also play a role by regulating other GM secretions including hippurate, trimethylamine oxide (TMAO) and lipopolysaccharide (LPS) (38).

Conclusion

Coronaviruses have evolved multiple means to evade host antiviral immune responses (14). A distinguishment must be made between immune-modulating mechanisms that can mitigate infection and disease and immune effector mechanisms that neutralise (kill) the virus or kill virus-infected cells. All antiviral mechanisms are prone to immune escape, especially when operating during a pandemic, unless they are non-selective (e.g., NAbs and NK cells). Whilst ‘training’ of innate immunity is only achieved by exposure of innate IgM-producing B cells to these self-like glycan patterns at the surface of the virus, the full benefit of training can only be exploited by a fully functional innate immune system. This can be achieved by optimising health and properly educating (i.e., functional reprogramming) innate immune cells to ensure their improved adaptation to the pathogen. Whilst a greater understanding at a biochemical level needs to be had, HMs have been shown to both epigenetically and metabolically reprogramme innate immunity, not only due to their phytochemical content, but also because they feed BGM which acts as a source of PAMPs to train innate immunity. As GVB warns, the danger humanity faces is that innate immunity may be wiped out by C-19 vaccines. The positive news is that dietary and lifestyle changes can contribute to a fully functioning immune system, so that when our innate cells are exposed to the virus again, they can get the full benefit of training. Look out soon for a follow-on articles in VSS entitled, ‘Herbal Medicine to Stimulate Innate Immunity: Part I and II’. In good health be.

Abbreviations

Angiotensin-converting enzyme 2 (ACE2)

Angiotensin II (Ang II)

Beneficial gut microbiota (BGM)

Coronavirus disease 2019 (COVID-19/C-19)

Dendritic cells (DCs)

DNA methyltransferases (DNMT)

Epigallocatechin-3-gallate (EGCG)

Heat shock proteins (HSPs)

Herbal medicine (HM)

Immunoglobulin (Ig)

Interferon-beta (IFN-β)

Interleukin-6 (IL-6)

Lipopolysaccharide (LPS)

Mitogen-activated protein kinase (MAPK)

MicroRNAs (miRNAs)

Natural antibodies (NAb)

Natural killer (NK) cells

Nuclear factor-kappa B (NF-κB)

Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2)

Short-chain fatty acid (SCFA)

Spike (S)

Toll-like receptors (TLRs)

Traditional Chinese medicine (TCM)

Tumour necrosis factor (TNF)-alpha (TNF-α)

References

1.         Wohns RNW. Editorial. What doesn’t kill you makes you stronger. Neurosurgical Focus FOC. 2020;49(5):E4.

2.         Bossche GV. The alleged ‘case’ for experimental C-19 vaccination of children is merely based on silo mentality and immunological ignorance Belgium2021 Dec [Available from: The alleged ‘case’ for experimental C-19 vaccination of children is merely based on silo mentality and immunological ignorance | Voice for Science and Solidarity.

3.         Holodick NE, Rodríguez-Zhurbenko N, Hernández AM. Defining Natural Antibodies. Frontiers in immunology. 2017;8.

4.         Reyneveld GI, Savelkoul HFJ, Parmentier HK. Current Understanding of Natural Antibodies and Exploring the Possibilities of Modulation Using Veterinary Models. A Review. Frontiers in immunology. 2020;11.

5.         Montecino-Rodriguez E, Dorshkind K. B-1 B cell development in the fetus and adult. Immunity. 2012;36(1):13-21.

6.         Baumgarth N, Tung JW, Herzenberg LA. Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion. Springer Semin Immunopathol. 2005;26(4):347-62.

7.         Boes M. Role of natural and immune IgM antibodies in immune responses. Mol Immunol. 2000;37(18):1141-9.

8.         Panda S, Ding JL. Natural Antibodies Bridge Innate and Adaptive Immunity. The Journal of Immunology. 2015;194(1):13.

9.         Bossche GV. Omicron a wolf in sheep's clothing Brussels, Belgium: Voice For Science and Solidarity; 2022 Feb 17 [Available from: Omicron a wolf in sheep's clothing | Voice for Science and Solidarity.

10.       Bossche GV. The Coming Crisis? Q&A with Geert Vanden Bossche #4 Belgium: Geert Vanden Bossche; 2021 [Available from: Q&A #4: The Coming Crisis? | Voice for Science and Solidarity.

11.       Baum LG, Cobb BA. The direct and indirect effects of glycans on immune function. Glycobiology. 2017;27(7):619-24.

12.       Eades L, Drozd M, Cubbon RM. Hypoxia signalling in the regulation of innate immune training. Biochemical Society Transactions. 2021;50(1):413-22.

13.       Riksen NP, Netea MG. Immunometabolic control of trained immunity. Mol Aspects Med. 2021;77:100897.

14.       Fanucchi S, Domínguez-Andrés J, Joosten LAB, Netea MG, Mhlanga MM. The Intersection of Epigenetics and Metabolism in Trained Immunity. Immunity. 2021;54(1):32-43.

15.       Sun L, Yang X, Yuan Z, Wang H. Metabolic Reprogramming in Immune Response and Tissue Inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology. 2020;40(9):1990-2001.

16.       Aristizábal B GÁ. Innate Immune System. In: Aristizábal B GÁIisIAJ, Shoenfeld Y, Rojas-Villarraga A, et al.,, editor. Autoimmunity: From Bench to Bedside. Bogotá, Columbia: El Rosario University Press; 2012.

17.       Boechat JL, Chora I, Morais A, Delgado L. The immune response to SARS-CoV-2 and COVID-19 immunopathology – Current perspectives. Pulmonology. 2021;27(5):423-37.

18.       Gao C, Zeng J, Jia N, Stavenhagen K, Matsumoto Y, Zhang H, et al. SARS-CoV-2 Spike Protein Interacts with Multiple Innate Immune Receptors. bioRxiv. 2020.

19.       contributors W. Interferon. Wikipedia2018.

20.       Robb RJ, Hill GR. The interferon-dependent orchestration of innate and adaptive immunity after transplantation. Blood. 2012;119(23):5351-8.

21.       Dorrington MG, Fraser IDC. NF-κB Signaling in Macrophages: Dynamics, Crosstalk, and Signal Integration. Frontiers in immunology. 2019;10.

22.       Zhang J, Zhao C, Zhao W. Virus Caused Imbalance of Type I IFN Responses and Inflammation in COVID-19. Frontiers in immunology. 2021;12.

23.       Bartleson JM, Radenkovic D, Covarrubias AJ, Furman D, Winer DA, Verdin E. SARS-CoV-2, COVID-19 and the aging immune system. Nature Aging. 2021;1(9):769-82.

24.       Bovin NV. Natural antibodies to glycans. Biochemistry (Mosc). 2013;78(7):786-97.

25.       Kasuga Y, Zhu B, Jang K-J, Yoo J-S. Innate immune sensing of coronavirus and viral evasion strategies. Experimental & Molecular Medicine. 2021;53(5):723-36.

26.       Qu L, Chen C, Yin T, Fang Q, Hong Z, Zhou R, et al. ACE2 and Innate Immunity in the Regulation of SARS-CoV-2-Induced Acute Lung Injury: A Review. Int J Mol Sci. 2021;22(21).

27.       Bhattarai S, Li Q, Ding J, Liang F, Gusev E, Lapohos O, et al. TLR4 is a regulator of trained immunity in a murine model of Duchenne muscular dystrophy. Nature Communications. 2022;13(1):879.

28.       Ragab D, Salah Eldin H, Taeimah M, Khattab R, Salem R. The COVID-19 Cytokine Storm; What We Know So Far. Frontiers in immunology. 2020;11.

29.       Peter AE, Sandeep BV, Rao BG, Kalpana VL. Calming the Storm: Natural Immunosuppressants as Adjuvants to Target the Cytokine Storm in COVID-19. Frontiers in Pharmacology. 2021;11(2305).

30.       Ni W, Yang X, Yang D, Bao J, Li R, Xiao Y, et al. Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Crit Care. 2020;24(1):422.

31.       Wang J, Yang X, Li Y, Huang J-a, Jiang J, Su N. Specific cytokines in the inflammatory cytokine storm of patients with COVID-19-associated acute respiratory distress syndrome and extrapulmonary multiple-organ dysfunction. Virology Journal. 2021;18(1):117.

32.       Hallaj S, Ghorbani A, Mousavi-Aghdas SA, Mirza-Aghazadeh-Attari M, Sevbitov A, Hashemi V, et al. Angiotensin-converting enzyme as a new immunologic target for the new SARS-CoV-2. Immunol Cell Biol. 2021;99(2):192-205.

33.       Nataraj C, Oliverio MI, Mannon RB, Mannon PJ, Audoly LP, Amuchastegui CS, et al. Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway. J Clin Invest. 1999;104(12):1693-701.

34.       Vandewalle A, Tourneur E, Bens M, Chassin C, Werts C. Calcineurin/NFAT signaling and innate host defence: a role for NOD1-mediated phagocytic functions. Cell Commun Signal. 2014;12:8-.

35.       Crowley SD, Rudemiller NP. Immunologic Effects of the Renin-Angiotensin System. J Am Soc Nephrol. 2017;28(5):1350-61.

36.       Peters EMJ, Schedlowski M, Watzl C, Gimsa U. To stress or not to stress: Brain-behavior-immune interaction may weaken or promote the immune response to SARS-CoV-2. Neurobiol Stress. 2021;14:100296.

37.       Vachharajani V, McCall CE. Epigenetic and metabolic programming of innate immunity in sepsis. Innate Immun. 2019;25(5):267-79.

38.       Saleh HA, Yousef MH, Abdelnaser A. The Anti-Inflammatory Properties of Phytochemicals and Their Effects on Epigenetic Mechanisms Involved in TLR4/NF-κB-Mediated Inflammation. Frontiers in immunology. 2021;12.

39.       Hsieh HY, Chiu PH, Wang SC. Histone modifications and traditional Chinese medicinals. BMC Complement Altern Med. 2013;13:115.

40.       Dammann RH, Richter AM, Jiménez AP, Woods M, Küster M, Witharana C. Impact of Natural Compounds on DNA Methylation Levels of the Tumor Suppressor Gene RASSF1A in Cancer. Int J Mol Sci. 2017;18(10).

41.       Kang H. MicroRNA-Mediated Health-Promoting Effects of Phytochemicals. Int J Mol Sci. 2019;20(10).

42.       Zhao L, Lee JY, Hwang DH. Inhibition of pattern recognition receptor-mediated inflammation by bioactive phytochemicals. Nutr Rev. 2011;69(6):310-20.

43.       Owen AM, Fults JB, Patil NK, Hernandez A, Bohannon JK. TLR Agonists as Mediators of Trained Immunity: Mechanistic Insight and Immunotherapeutic Potential to Combat Infection. Frontiers in immunology. 2021;11.

44.       Dai W, Long L, Wang X, Li S, Xu H. Phytochemicals targeting Toll-like receptors 4 (TLR4) in inflammatory bowel disease. Chinese Medicine. 2022;17(1):53.

45.       Zubair K, You C, Kwon G, Kang K. Two Faces of Macrophages: Training and Tolerance. Biomedicines. 2021;9(11).

46.       Mendes LF, Gaspar VM, Conde TA, Mano JF, Duarte IF. Flavonoid-mediated immunomodulation of human macrophages involves key metabolites and metabolic pathways. Sci Rep. 2019;9(1):14906.

47.       Pan X, Gong D, Nguyen DN, Zhang X, Hu Q, Lu H, et al. Early microbial colonization affects DNA methylation of genes related to intestinal immunity and metabolism in preterm pigs. DNA Res. 2018;25(3):287-96.

48.       Santaolalla R, Abreu MT. Innate immunity in the small intestine. Curr Opin Gastroenterol. 2012;28(2):124-9.

49.       Negi S, Das DK, Pahari S, Nadeem S, Agrewala JN. Potential Role of Gut Microbiota in Induction and Regulation of Innate Immune Memory. Frontiers in immunology. 2019;10:2441.

50.       Kato M, Ishige A, Anjiki N, Yamamoto M, Irie Y, Taniyama M, et al. Effect of herbal medicine Juzentaihoto on hepatic and intestinal heat shock gene expression requires intestinal microflora in mouse. World J Gastroenterol. 2007;13(16):2289-97.

51.       Liu H, Dicksved J, Lundh T, Lindberg JE. Heat Shock Proteins: Intestinal Gatekeepers that Are Influenced by Dietary Components and the Gut Microbiota. Pathogens. 2014;3(1):187-210.

52.       Colaco CA, Bailey CR, Walker KB, Keeble J. Heat Shock Proteins: Stimulators of Innate and Acquired Immunity. BioMed Research International. 2013;2013:461230.

53.       An X, Bao Q, Di S, Zhao Y, Zhao S, Zhang H, et al. The interaction between the gut Microbiota and herbal medicines. Biomedicine & Pharmacotherapy. 2019;118:109252.

54.       Zhang B, Liu N, Hao M, Zhou J, Xie Y, He Z. Plant-Derived Polysaccharides Regulated Immune Status, Gut Health and Microbiota of Broilers: A Review. Front Vet Sci. 2021;8:791371.

55.       Feng W, Ao H, Peng C. Gut Microbiota, Short-Chain Fatty Acids, and Herbal Medicines. Frontiers in Pharmacology. 2018;9.

56.       Liu H, Wang J, He T, Becker S, Zhang G, Li D, et al. Butyrate: A Double-Edged Sword for Health? Adv Nutr. 2018;9(1):21-9.