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Article

Published by The Vampire Network on the 6th of January2017

Sialic Acid: Significance to Vampirism

All nucleated cells are covered with a dense and complex coat of sugar chains (glycans) or protein-sugar chains (proteoglycans) (1). Sialic acids are nine-carbon acidic sugar in which the individual sugar moieties (monosaccharides) are linked together to form multi-sugar chains (polysaccharides) that occur at the end of most sugar chains attached to the surfaces of cells (2). They comprise a family of 43 naturally occurring derivatives. One branch of the sialic acid family are the N-acetylneuraminic acids, which are the most widespread form of sialic acid and almost the only form found in humans (2). However, different forms of sialic acids are found in other animal species and in human pathologies (ex. cancer). Furthermore, sialic acids can be modified on many of the nine carbon moieties resulting in remarkable structural diversity. These altered forms may confer altered function (2, 3).

Sialic acid is synthesized endogenously (by the cells of the individual organism itself) from simple sugars (glucose and fructose) and the essential amino acid glutamine in a complex multi-step enzymatic reaction (2). The rate-limiting enzyme in the synthesis of sialic acid in humans and all mammals is UDP-Nacetylglucosamine-2-epimerase, which is expressed in the liver. Its expression is low at birth and early in development. Consequently, studies have shown that sialic acid must be supplemented from external sources early during postnatal life (2). Failure to do so has been associated with cognitive retardation and increased susceptibility to infection as well as faulty development of the immune system (2).

Sialic acid is expressed in nearly all bodily tissues, organ systems and secretions where it plays major roles in their function. Several of these and their significance to vampirism are highlighted in this review.

Brain

Sialic acid concentration is highest in the brain, where it plays a critical role in both neuronal structure and neurotransmission (2). In the brain, higher levels of sialic acid increase cognition, performance and learning. High sialic acid levels are associated with ability to learn and synthesize new information rapidly and formation of accurate short- and long-term memory; whereas, low sialic acid levels correspond with neuronal degeneration, loss of cognition and major developmental problems.

Polysialic acid (polymers of sialic acid) is essential for appropriate brain development, and polymorphisms in human genes responsible for its biosynthesis are associated with major developmental disorders (ex. Salla disease, a debilitating nervous system disorder marked by hypotonia, ataxia, delayed motor development that may be accompanied by seizures, and death at an early age), as well as psychiatric disorders (schizophrenia, autism, and bipolar disorder) (2). In further support of importance of adequate levels of sialic acid during brain development, infants reared on formula replacement, which contains little usable sialic acid, vs. breast milk show a significantly higher percentage of developmentally-induced mental retardation and/or delayed development, as well as psychiatric disorders (2). Whereas, sialic acid directly regulates gene expression in many viruses and bacteria (ex. Streptococcus pneumoniae) (4), in humans, this direct gene regulatory activity has so far been confirmed only in the brain, where sialic acid regulates genes involved in neuronal development (5).

Polysialic acid also plays a role in adult brain plasticity, including neuronal regeneration (15). High levels of sialic acid increase axon (body of a neuron) stability and allow for neuronal regeneration (15). In contrast, several diseases which present as progressive neuronal degeneration characterized by loss of cognitive function and memory, including Alzheimer’s and Huntington’s disease, are caused, at least in part, by dysregulation of axon-myelin interactions induced by low levels of sialic acid (6, 7).

Whereas the above effects are largely attributed to structural modulation of neurons by sialic acid, sialic acid is also involved in modulation of nerve cell excitability, i.e. neurotransmission (2). Sialic acid is critically involved in the transport of neurotransmitters at nerve termini as well as their binding to their respective receptors. For example, sialic acid is directly involved in the operation of the carrier proteins which transport GABA (8) and is found in inhibitory interneurons characterized by the presence of GABA (9). Sialic acid is also involved in the uptake mechanism of both serotonin and dopamine; however, its expression is much lower than around GABAnergic neurons leading to milder effects (9, 10, 11). These observations are consistent with the idea that sialic acid is a negative regulator of interneuron excitability and promotes inhibitory, GABA-mediated, signaling (9). Formation of memory and learning depends on sialic acid-containing neuronal gangliosides (molecules the chemical structure of which contains sialic acid, a lipid and a sugar), where sialic acid regulates neuron-neuron interaction, neuronal membrane flexibility and calcium-sensitive events all of which control neurotransmission involved in memory formation (9).

Finally, sialic acid levels have also been connected with intelligence. Sialic acid concentration in the human brain is 2-8 times higher than in other mammals (ex. sialic acid concentration in the brain of a 2-year old chimpanzee is ~1/3 that in a human child of the same age) (2). In humans, higher brain levels of sialic acid correlate with higher IQ scores (2).

Significance to vampirism

There is significant evidence that in vampires, GABA-mediated neurotransmission is most prominent. As described above, sialic acid is a critical cofactor for effective GABA-mediated neurotransmission. This is consistent with the idea that high levels of sialic acid in vampires may contribute to vampires’ (on the population level) “cold” personality, tendency to prefer reason over emotion, ability to learn and synthesize new information rapidly and above average IQ scores while preventing long-term memory loss and promoting neuronal regeneration to support longevity.

But, sialic acid is also thermo- and UVA/UVB-sensitive (its expression and/or form are modified by temperature and sunlight exposure). Sialic acid is increased in the brain and the circulation in response to UVA/UVB radiation markedly above levels seen normally in humans, which is associated with protein aggregation similar to that seen in dementia and Alzheimer’s disease (12). On the other hand, a mutation in an enzyme which is required to make sialic acid results in temperature-sensitive paralysis (13, 14). These observations are consistent with the idea that abnormalities in sialic acid content (abnormally high or low levels) may be, at least in part, responsible for the vampire’s sunlight sensitivity/intolerance and related symptoms ranging from decreased overall cognitive function and torpor to muscle weakness and paralysis. Many vampires feel generally better in the autumn and winter (in the Northern hemisphere) when daylight is shorter and it is cooler outside.

The immune system

Sialic acid plays a major role in the activation of the immune system in response to pathogens. Mammalian breast milk, not coincidentally, contains very high levels of sialic acid and breastfeeding (vs. replacement formulas) has been associated with a lower incidence of morbidity and mortality, especially of infectious disease. Accordingly, sialic-acid-containing oligosaccharides from human milk have been shown to prevent rotavirus and cholera toxin infections associated with infant diarrhea, as well as Escherichia coli strain infections associated with neonatal meningitis and sepsis. High levels of sialic acid in breast milk act as “decoys” for bacteria, viruses and other pathogens while the infant’s immune system is not yet developed and endogenous sialic acid production is still low (2).

A major way in which sialic acids control immune system responses is through regulation of complement activation. The complement system is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic immune cells to clear pathogens and damaged cells from the organism by promoting inflammation, and attacking the pathogen's plasma membrane. The complement system consists of a number of small proteins found in the blood, in general synthesized by the liver, and normally circulating as inactive precursors (pro-proteins). When stimulated by one of several triggers, proteases in the system cleave specific proteins to initiate an amplify cascades of further cleavages. The end result is stimulation of phagocytes to clear foreign and damaged material. A protein called C3 is a key component of the complement activation cascade. It is cleaved into C3a and C3b; C3b then binds to the surface of the pathogen, which is necessary for further activation of the cascade. Sialic acid interacts with C3b. However, the affinity of sialic acid for C3b is determined by modifications of sialic acid itself. The basic nine-carbon structure of sialic acid can be modified at the 4, 5, 7, 8, and 9 positions to generate a large amount of structural diversity. For example, modification at position 9 (9-O-acetylation) reduces its affinity for C3b and complement activation, resulting in the organism’s tolerance of the pathogen, i.e. lack of attack on and destruction of the pathogen (15). Alternative modifications produce opposite effects.

Trafficking of white blood cells (leukocytes) to sites of infection is another important early step in mounting an effective immune response. Sialic acid binds molecules expressed on the surface of endothelial cells (P-selectins), which line the insides of blood vessels. This binding and consequent extravasation of leukocytes into surrounding tissue is critical for their delivery to sites of infection (3). Thus, sialic acids are powerful anti-microbials, capable of orchestrating a coordinated immune system attack.

In addition, sialic acids are key regulators of “self” vs. “non-self” recognition, which is critical for proper development of the immune system. Consequently, the role for sialic acid in autoimmune disease is well-recognized. Siglecs are inhibitory receptors expressed on immune cells that bind to sialic acid-containing oligosacharydes and mediate inhibitory signaling in B-cells thus protecting the organism from autoimmunity (6). An alteration in sialic acid structure would prevent sialic acid-Siglec interaction, thus allowing for autoimmunity to develop. Interaction between sialic acid and factor H of the complement cascade also determines “self” recognition and prevents complement cascade activation (1, 3). Thus, sialic acid both activates the immune system and is a critical participant in the “education” of that immune system.

The sialic acid-Siglec and sialic acid-factor H interactions have been used by pathogens to avoid detection by the host’s immune system. Although non-vertebrates do not normally express sialic acid, several bacteria and viruses (including influenza viruses) have learned to synthesize mimetics of sialic acid, and avoid early detection by the immune system using this form of molecular mimicry (1, 3). Not only are they able to avoid detection by the immune system, but they can also engage Siglec and consequently depress the overall immune response (1, 3). In response, modifications in circulating components of the complement system, which are able to recognize these “fake” sialic acids have been detected (3).

Significance to vampirism

We hypothesize that in the early stage of vampiric transformation molecular mimicry of the recipient’s sialic acid allows vampire foreign antigens to escape detection by the recipient’s immune system. An immune reaction eventually does follow, but it is too weak and too late to effectively fight the transformation, and the recipient’s immune system is overwhelmed and eventually destroyed to be replaced by the new, revised, immune system.

Incidence of auto-immune diseases (most of them anemias) is markedly elevated among vampires. It is hypothesized that this is linked to alterations of the immune system during the process of the vampiric transformation. In the process of re-building the new immune system which tolerates changes in the surface receptors on altered blood and tissue cells, errors are made, and some cells of the recipient are recognized as “non-self” resulting in autoimmunity. The structure of sialic acid has been shown to be readily modifiable with the consequence of either promoting or suppressing immunogenicity as described above; and thus, fulfills all requirements of a surface molecule which may mediate such a process. Interestingly, modifications in sialic acid structure (alpha 2,3- vs. alpha 2,6-linked N-acetyneuraminic acid) have been associated with cold-antibody autoimmune hemolytic anemia (IAHA) in humans (16). The incidence of IAHA among vampires is ~12% vs. 0% (2.6 per 100,000 people) among non-vampires. Recently, sialic acid has been shown to play a direct role in many autoimmune diseases. Efficacy of intravenous immunoglobulin G (IVIG) therapy, the newest promising therapy for many forms of autoimmune disease, depends on sialylation of the Fc region of the administered IgG antibodies so that they are not immediately destroyed by the host’s immune system (17, 18).

On the other hand, when living an optimal lifestyle (limited sun exposure and adequate nutrition), vampire immune systems are better equipped for fighting infection, resulting in vampires rarely suffering from infectious disease. The properties of sialic acid and its interacting proteins described above also easily account, at least in part, for this phenomenon. For example, the vampire complement system might be better at detecting “fake” sialic acid on invading pathogens, thus mounting an earlier and more effective immune response. Or, modified sialic acids on vampire immune cells enable them to bind to endothelial receptors more effectively, thus arriving at sites of infection faster. Early response is the most important aspect of limiting disease progression. During periods of influenza epidemics, many vampires report starting to feel the symptoms of the flu which vanish within 12-24 hours (vs. 7-10 day average for non-vampires), which is consistent with early and vigorous activation of the immune system vs. lack of susceptibility to infection by the influenza virus. Alternatively, it is possible that altered RBCs of vampires express altered forms of sialic acids which serve as decoys, much like mucins (described below). RBCs represent ~50% of total blood volume and could act as “viral traps”. A sialic acid–binding virus such as influenza, if it managed to make its way past mucins and into the bloodstream, would immediately encounter the extensive cell surface of erythrocytes that it can bind to but in which it cannot replicate, and the infection would be effectively limited.

Finally, the sunlight and temperature-sensitivity of sialic acid when correlated with physical symptoms observed in vampires makes it a uniquely suitable candidate for modulation of the immune system in vampires. In vampires, summer and increased sunlight exposure universally bring on worsening of chronic autoimmune conditions such as IAHA, as well as declined resistance to infectious disease. Given the role sialic acid plays in the regulation of the immune system this is not unexpected. Whole body exposure to ultraviolet light (UV) causes systemic immunosuppression (19). UVA/UVB slows down migration and function of so called antigen presenting cells (APCs). The job of these cells is to recognize foreign pathogens, ingest them (phagocytosis), then present parts of their proteins on their surface for T-cells and B-cells to learn that any cell with these proteins expressed on its surface is foreign and needs to be eliminated. This "teaching" of T- and B-cells happens in the lymph nodes and the spleen. If it takes the APCs too long to get there, the pathogen overwhelms the body’s defenses before the immune system can launch an attack, allowing the immune system to be overwhelmed and opening the door for other opportunistic infections (including many bacterial infections, ex. pneumoniae) (19). The function of T-cells themselves can be similarly compromised by UV light (20).

Blood (other than immune cells/system)

Differently modified forms of sialic acid on the surface of red blood cells (RBCs, erythrocytes) have been shown to correspond with different human blood types (A, B, AB and O) (21). Furthermore, the ABO antigens stabilize the sialic acids expressed on RBCs (22).

Significance to vampirism

Sialic acid is thermo- and photo-sensitive. UVA/UVB radiation increases plasma sialic acid levels. However, 90+% of the increased sialic acid is derived from just two proteins, hemopexin and haptoglobin (23). These two proteins bind free heme released from RBCs during their destruction; once formed the heme-protein complexes are destroyed in the spleen. Hemopexin and haptoglobin levels are one of the diagnostic features of hemolytic anemia. While, idiopathic autoimmune hemolytic anemia (IAHA) has not specifically been linked with “photosensitivity” (sensitivity to sunlight), sunlight has been shown to induce hemolysis in many studies (24). In burn victims, sialic acids are modified and also become key players in the destruction (hemolysis) of erythrocytes (RBCs) (25).

A fundamental as yet unanswered question is why vampires need to consume blood repeatedly and often. The natural life-span of RBCs is 100-120 days, but most vampires require blood much, much more often than that. Not all vampires have hemolytic anemias, and even in the ones who do, the autoantibodies generated against the individual’s own RBCs should not attack those of the donors. We hypothesize that the vampires’ immune system does however detect the donor RBCs as foreign and does attack. Some bacteria have learned to highjack RBCs and their sialic acids for quick transport across the body and to avoid detection by the immune system. Mycoplasma pneumoniae, the causative agent of “walking pneumonia”, is one example. But, much like IAHA, M. pneumoniae infections typically result in production of high titers of autoantibodies against RBCs (IgM) and RBC destruction because the altered sialic acids on the surface of these highjacked RBCs are recognized by the human immune system as foreign (26, 27). We believe that the vampire’s immune system similarly recognized human sialic acid as foreign and that this explains the accelerated destruction of the vampire’s own as well as any donor’s RBCs.

Also, vampire blood typically cloths faster. An alteration in sialic acid binding to thrombocytes could, at least in part, account for this phenomenon. In humans, a rare mutation in the inhibitory complement regulator factor H, which prevents sialic acid from binding to this molecule and is expressed on platelets to prevent the binding of complement and its activation, results in binding of the complement C3b and C5b subunits, which leads to formation of blood cloths (28). This, or similar mutations may be present in vampires.

Saliva and mucus

Sialic acid is a significant component in all salivary mucins. In fact, the name sialic acid is derived from the Greek 'sialos' meaning saliva. The concentration of mucins in saliva and other mucus membrane secretions increases in response to infection forming thick mucus. Mucin structure consists of a protein core with attached oligosaccharide (multiple sugar polymers) side chains, which may constitute up to 75% of the total mucin molecule. The final carbohydrate in these chains is most often sialic acid (2). Bacteria, viruses, and other pathogens use cell surface carbohydrates as sites for recognition and binding to their target host cell, the first step in infection. Sialic acid is capable of effecting molecular mimicry of these oligosaccharide side chains on mucins so that they resemble the receptors for these pathogens on actual membranes of cells of mucosal membranes which they typically infect. Thus, sialic acid enables the host organism to use mucus as decoy. Consequently, these pathogens attach to mucus instead of their target cells, and are washed away, out of the body (2).

Significance to vampirism

As stated previously, vampires rarely contract infectious diseases. In part, this is related to the more efficient immune system (see above). Sialic acids, their total content and form in saliva also play a major part in defense against pathogens as described above.

In addition, a feature of the vampire’s saliva is thought to be its ability to prolong blood clotting time. The composition of the vampire’s saliva has been analyzed in some detail and discovered to contain an increase in plasminogen activator (PA), which cleaves and activates a protease called plasmin which degrades thrombin. Thrombin is a major component of blood cloths. Formation of thrombin (and fibrin) cloths is regulated by sialyation. In addition, glycosylation of PA affects the functional activity of the protein. A certain amount of sialic acids attached to the backbone of the PA protein are necessary for its activity; however, addition of excessive sialylation interferes with its interaction with plasmin and prevents thrombolysis (29). Thus, sialic acid also likely plays a significant role in this feature of vampirism.

Skin

Sialic acid is a major component of skin. One of its major functions is in wound healing via regulating the inflammatory response which participates in wound healing. Wound healing is delayed and impaired in diabetes resulting in major consequences including secondary infection and amputation. Poor wound healing is associated with ongoing inflammation, defective clearance of apoptotic cells, increased risk of secondary infection, and poor genesis of new blood vessels (angiogenesis). Sialic acid is involved in all of these processes. While circulating levels of sialic acid are increased in diabetes, related to characteristic vascular pathology (30), sialic acid-dependent regulation of local inflammation involved in wound healing is more intricate. For example, phagocytic capacity of dendritic cells and macrophages is improved or reduced by certain forms of sialic acid vs. others (31). This property is essential for clearing of apoptotic cells. The forms of sialic acid expressed in diabetics, for example, reduce the phagocytic capacity of dendritic cells and macrophages (31). Poor angiogenesis is considered the primary contributor to poor wound healing in diabetics. Expression of sialic acids on cells which line the newly forming blood vessels is necessary to support their maintenance; however, this is decreased in diabetic wounds (32).

Significance to vampirism

The critical role of both quantity and correct forms of sialic acid in wound healing is obvious. In addition, sialic acid has been shown to stimulate proliferation of neuronal and muscle cells. These cell types do not normally proliferate in adult animals (31, 33, 34). Thus, it seems entirely possible that further evolved vampire-specific forms of sialic acid or simply an increase in its levels may foster accelerated wound healing often observed in vampires.

On the other hand, sialic acid may play a role in the vampire’s sun intolerance, including its skin manifestations. Photoallergy refers to immunologically mediated photosensitivity reactions, both immediate (antibody-mediated) and delayed (cell-mediated) hypersensitivity. Unlike phototoxicity which manifests as severe and immediate sunburn, photoallergy resembles a skin allergic reaction characterized by a rash (dermatitis) on predominantly light-exposed areas, which may appear immediately or hours after sun exposure (35) and is a reaction experienced by many vampires. Sialic acids, through their interactions with Siglec-8 on eosinophils, basophils and mast cells (major cell types involved in allergic reactions) are key determinants of allergic reactions (36); it is likely that they also participate as key players in the photoallergy component of the vampire’s sunlight sensitivity. Interestingly increased sialic acid levels correlate with increased oxidative stress, and large increases in oxidative stress have been recorded in vampires upon sunlight exposure (vs. humans, see article entitled “Sun Sick: Exacerbated Effects of the Sun’s UV Radiation in Vampires”).

Muscle

The role of sialic acid in skeletal muscle physiology is multi-fold. Polymers of sialic acid are critical for muscle development and regeneration (34). However, during the entire lifespan, skeletal muscle is continuously remodeled (increased/decreased in size/mass). Sialic acid plays a role in this remodeling. Sialidases are enzymes which remove sialic acid from the cell surface. They play a variety of functions by removing sialic acids from a variety of cell types. In skeletal muscle, they work within different subcellular compartments to ensure the proper turn-over of glyocoproteins by catalyzing the removal of sialic acids residues. They have been shown to increase insulin sensitivity by regulating the signaling pathway for glucose uptake into skeletal muscle, production of extracellular matrix important for muscle cell attachment, hypertrophic muscle growth, and even activate resident stem cells to promote muscle cell division and regeneration (37).

While dymanic turn-over of sialic acid is a part of normal muscle remodeling, decreased sialic acid content on the surface of muscle cells is a sensitive indicator of muscle damage (38). In a Phase II clinical trial, extended-release sialic acid supplements stabilized muscle strength in patients with a rare hereditary, progressive, adult-onset muscle disease (GNE myopathy (GNEM)). Patients with GNEM have mutations in a gene controlling a key enzyme in the synthesis pathway for sialic acid resulting in low levels of sialic acid in skeletal muscle. They typically experience distal muscle weakness, which progresses to lower and upper extremities (33). Thus, elevating levels of sialic acid can increase muscle strength and endurance.

Significance to vampirism

Increased muscle strength and endurance are often associated with vampirism. Alterations in isoforms of contractile proteins and their regulators, and more efficient energy (ATP) usage, which could explain those characteristics have been observed in vampires. It is possible that increased levels of sialic acid could also contribute. On the other hand, expression of skeletal muscle-specific sialidases in particular cellular compartments could be altered.

Vision

Mutations in sialic acid which affect its interaction with factor H of the complement system have been shown to contribute to age-dependent macular degeneration (3). Decreasing concentrations of sialic acids have been related to aging of the eye, particularly of the lens (39). In addition, exogenous application of sialic acid-containing gangliosides influences excitability of retinal neurons (2), raising the possibility that apart from affecting the structure and function of the eye itself, sialic acid may also affect vision on the level of neurotransmission.

Significance to vampirism

One of the characteristics of vampirism is enhanced nighttime vision, which comes at the expense of reduced daytime visual acuity. Sialic acids are sensitive to sunlight (UVA/UVB rays). Although a specific relationship between sun-sensitive alterations in sialic acids and visual impairment has not yet been described, because of sunlight-sensitive alterations in sialic acids and their consequences in other organ systems (see brain, skin), we suspect that such a relationship may, in part, account for daytime visual impairment and sun-induced damage to the eyes of vampires.

Conclusion

Our observations, accumulated data and current scientific literature suggest that sialic acid levels may be elevated in vampires or that the form (structure) of sialic acids may be altered. Current research in humans suggests that normal levels of sialic acids must be maintained for proper development and function of all organ systems, whereas, too low or too high levels are associated with pathology and/or cellular damage (including UV-induced damage). Low sialic acid expression on surfaces of many cells, including RBCs, are also indicative of aging (7). In contrast, abnormally high levels of sialic acid on cell surfaces have been documented on cancer cells (40), which are while clearly pathological within the human organism, biologically immortal, and do offer some insight into molecular mechanisms of extended cellular life span. Sialic acid levels are also elevated in cells and tissues exposed to hypoxia (41), a state entered by the entire vampire organism during periods of blood starvation. Thus is it tempting to conclude that sialic acid levels may simply be elevated in vampires.

On the other hand, the notion that there might be structural changes in sialic acids in vampires is supported by: 1) the observed variety of forms of sialic acids in humans, and 2) the fact that the genes for sialic acid (and its interacting sugars and proteins, ex. Siglec) represent some of the most human-specific genetic changes in all of evolution. 20% of the genes which encode for these molecules are human-specific even though sialic acids are expressed in all vertebrates. This extremely high human-specificity on the genetic level correlates with evolution of human-specific diseases which are linked to their mutations (1). Thus, a similar vampire-specific evolution of sialic acid forms is not inconceivable.

In conclusion, sialic acid possesses all the necessary characteristics of a molecular biopolymer which explain the physiological adaptations of the entire vampire organism. It is UV-sensitive. Its evolution is species-specific, but its molecular structure offers sufficient structural diversity to allow for altered and species-specific function. It is expressed in nearly all tissues; importantly in ones which we know are altered in vampires, and it plays a major role in the regulation of the immune response, which is the major and initiating factor in vampiric transformation. As such, it may be the key to unlocking the “mystery” of vampirism.

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