patrick.net

Great review of innate immunity. IMHO, pattern recognition receptors are the bomb!
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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).

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