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Acetaldehyde and tryptophan starvation
Explores the impact of acetaldehyde on the antimicrobial defense system tryptophan starvation with implications for autoimmune diseases
Date: 11/25/2012 3:12:46 PM ( 12 y ) ... viewed 13227 times Is it not astounding that C. albicans can produce counterfeit immunoregulatory molecules such as resolvin E1 and prostaglandin E2 that are indistinguishable from those made by the body itself?
• See "The Artful Dodger" http://curezone.com/blogs/fm.asp?i=2007179
This yeast species has established a niche in reality that it controls extremely well to provide for its needs. It is rarely found in the environment outside of a mammalian host and even when it is, it can usually be traced back to contamination or contact. It positions itself in nutrient-rich zones just waiting to be fed and emits molecules to manipulate the immune system's response or non-response to its presence as it sees fit. Its long history of interaction with the specific mammalian cell types that it encounters in its chosen habitat is reflected by a staggering list of point-counterpoint scenarios [1]:
• suppression of lymphocyte maturation and function [2]
• cell-wall-mediated inhibition of phagocytosis by macrophages [3]
• degradation of immunoglobulins, complement and extracellular matrix by multiple secreted aspartyl proteases [4]
• emission of tissue-invasive phospholipases [5]
• reduction of reactive oxygen species production by macrophages and neutrophils [6]
• inhibition of release of nitric oxide from macrophages [7]
• aberrant acidic lysosomal compartmentalization after phagocytosis [8]
• white-opaque phase variant suppression of neutrophil-chemotactic peptides [9]
• selective induction of apoptosis (cellular suicide) in a variety of cells including neutrophils [10], macrophages [11], and human sperm cells (infertility) [12]
• tetrad of mechanisms (induced endocytosis, direct invasion, intercellular junction passage, leukocyte transport) for penetration of endothelial or epithelial barriers [13], including the blood-brain barrier [14]
• cell wall remodelling to suit environmental substrate [15]
• utilization of multiple alternate non-fermentable carbon sources in glucose-poor conditions [16]
• subversion of nutritional (iron-limiting) immunity by active acidification of local environment [17] to liberate essential iron from transferrin [18], ferritin [19], and hemoglobin
• adaptive prediction for coping with changing environmental stressors [20]
• formation of mixed colony biofilms with organisms such as Staphylococcus epidermidis with mutually advantageous resistance to antimicrobial agents [21]
Consideration of this list brings to mind an image, not of a benign hitch-hiker making a quiet home for itself, but rather:
The toothy yeast cell is laughing at us because while we were ignoring it as a "harmless" commensal, it was slowly but surely making us sick. Now that we understand a bit more about the profile of this perpetrator and what it is capable of doing, perhaps we can look for an answer to the question posed previously about why C. albicans releases toxic acetaldehyde into its environment, instead of reducing it to alcohol or oxidizing it to acetate.
• See "C. albicans Fermentation Process" http://curezone.com/forums/fm.asp?i=1986782
Tryptophan starvation is an antimicrobial technique used by the body to rid itself of invasive organisms [22]. It is especially effective against microbes, such as Toxoplasma gondii, that require tryptophan as an essential amino acid scavenged from host cells [23].
The tryptophan starvation sequence is initiated by interferon-gamma released by various immune system cells when they encounter a problem. For example, oral epithelial cells, a part of the innate immune system barriers to infection, can respond to C. albicans growth by secreting interferon-gamma [24]. Interferon-gamma induces the production of the enzyme indoleamine 2,3-dioxygenase (IDO) in many cell lines. This enzyme is the rate-limiting step in the catabolism of the amino acid tryptophan into N-formyl-kynurenine:
The antiparasitic and cytotoxic efficacy of tryptophan starvation at inducing apoptosis (cellular-suicide) has been demonstrated in morphologic studies with DNA analysis in ME180 (human epidermoid carcinoma) cells [25].
T helper cells (Th cells) are a type of white blood cell of the body's adaptive immune system, involved in maximizing the cidal activity of phagocytes. Th17 cells are a subset of this class that produce interleukin 17 (IL-17), an immunostimulatory cytokine that possesses multiple proinflammatory functions, such as recruiting neutrophils, activating neutrophil/macrophage phagocytosis activity, and inducing ß-defensin release. Th17 and IL-17 are regarded as an important component in host defense against fungal infections [26]. In response to this threat C. albicans can downregulate the secretion of host IL-17 by inhibiting the IDO catabolism of tryptophan [27], actively shifting the balance of tryptophan metabolism and thwarting the tryptophan-starvation-mediated host Th17 response [28].
The beta-carboline norharmane is a known IDO inhibitor:
When acetaldehyde and tryptophan collide, they can undergo a non-enzymatic Pictet-Spengler condensation reaction to form 3-carboxy-1-methyl-1,2,3,4-tetrahydro-beta-carboline (3-MTBC) as described previously:
• See "Acetaldehyde + Tryptophan" http://curezone.com/forums/fm.asp?i=1963688
Is the beta-carboline 3-MTBC also an IDO inhibitor? If it is, then suddenly we have an evolutionary reason for C. albicans releasing acetaldehyde into its extracellular environment and the technique by which it scuttles the body's tryptophan starvation anti-microbial maneuver. Since acetaldehyde released anywhere can reach the bloodstream and be transported throughout the body [29], this also introduces the potential for systemic disruption of tryptophan metabolism at sites other than those being colonized by C. albicans. The consequences of this go far beyond the localized struggle between yeast and the immune system at mucosal sites!
The self versus non-self recognition process is crucial to any organism with immune system cells capable of inflicting lethal damage to other cells. IDO is one of the key players in this process [30]. Regulatory T cells (Tregs) are a subpopulation of T cells which modulate the immune system by dampening T cell activity after an infectious episode and maintaining tolerance to self-antigens. In other words, they are essential to prevent the body from attacking itself (autoimmunity). Tregs are especially important during pregnancy to prevent the mother's immune system from attacking the foetus, a common cause of miscarriage [31]. The tryptophan starvation pathway, mediated by the enzyme IDO which shunts tryptophan into kynurenine, is a critical step in the production of Tregs [32] which in turn quench the immune system post-infection to ensure that autoimmunity is not a deleterious consequence.
The dual role of IDO induction as both an antimicrobial effector and an immunosuppressor dampening T-cell activation and IFN-gamma production is something of a paradox unless tryptophan limitation is a more severe microbial deterrent than it is to T cells. Then under "ideal" conditions this allows IDO to act as an antimicrobial agent prior to its immunomodulatory effects. A similar incongruity appears with IDO in relation to its tumour-protective and tumour-destructive properties [33].
However, the commensal presence of C. albicans skews this precarious balancing act, with the potential impairment of the IDO tryptophan to kynurenine pathway necessary for Treg immunostabilization after infection not just manifesting when the body is actively targeting the yeast. The ongoing pulsed low-dosage acetaldehyde exposure resulting from the unique fermentation pathway of C. albicans means that the immune system is also continuously vulnerable. Hence, when an infectious agent, such as hepatitis C for example, results in immune system activation, then even after resolution of the viral infection, the inadequacy of the corresponding immune system downregulation phase means that the onset of an autoimmune condition, such as rheumatoid arthritis [34], is much more likely in individuals with a high background yeast load. The same argument applies not just to rheumatoid arthritis but to all of the conditions with an autoimmune component (e.g. encephalomyelitis [35], multiple sclerosis [36], diabetes [37], systemic lupus erythematosus [38]).
Furthermore, even when current yeast levels are low, since C. albicans appears to depend upon a certain amount of pressure from the host immune system to keep it in check, then any infectious assault which diverts immune system resources away from this containment will result in an increase in the yeast load and acetaldehyde emission levels -- something which sets the stage for problems in the future. Similarly, implementation of a steroidal immunosuppressive regimen may also allow yeast levels to increase with more acetaldehyde emission and more IDO inhibition. This would exacerbate the autoimmune condition and create a self-defeating loop of higher and higher dosage requirements attempting to quench the immune system irregularities, even with the potential off-label acetaldehyde scavenging abilities of steroids.
• See "Acetaldehyde + Prednisone" http://curezone.com/blogs/fm.asp?i=1991266
This model also validates the dramatic results documented in the historical Wondro testimonials pamphlet [39], where remission of arthritic conditions was a common theme. By functioning as an upstream scavenger of acetaldehyde emitted from yeast cells, the sulfurated fatty acids in the flax oil limited the contact of acetaldehyde with a plethora of vulnerable reaction points including, but not limited to, enzymatic pathways such as the IDO tryptophan to kynurenine shunt.
Invasive organisms such as C. albicans do not acquiesce to attempts from any level, whether an exogenous drug or an endogenous immune system tactic, to expunge them from their comfortable niche. Fungi, in particular, represent the reversion of certain primitive plant life to the prechlorophyll levels of parasitic bacteria. This means they have all of the advanced adaptive genetic machinery of a plant that is now directed at establishing and sustaining their parasitic presence within a suitable host.
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