Antimicrobial peptides in saliva, including caprotectin, beta-defensins, and histatins provide a first line of defense in the oral cavity. Histatin-5, a histidine-rich cationic peptide produced by the human salivary gland acinar cells, is fungicidal against Candida albicans at physiological concentrations. This peptide which is taken up by the yeast cell induces rapid cellular (potassium and magnesium) ion imbalance and cellular volume loss leading to the death of the yeast cell [2].
Secreted aspartyl protease, Sap9, is a glycosylphosphatidylinositol-anchored aspartic protease in the cell wall of C. albicans critical to the yeast's ability of adhere to and invade tissue. Neutrophils that are patrolling for yeast cells have been found to respond to this protease in preparation for their attack on yeast filaments [3]. C. albicans Sap9 is also capable of proteolytic cleavage of histatin-5, in an immune system avoidance technique which nullifies its anticandidal properties [4].
Epithelial cells line the cavities and surfaces of structures throughout the body. In the gastrointestinal tract they provide a selective filter which allows the uptake of necessary substances while passing others through as waste. They are the reason that the gastrointestinal tract from mouth to anus is actually considered to be "outside" of the body. One of their important roles here is to exclude harmful microbes, including yeast, from gaining access to the bloodstream by forming impenetrable cellular walls with extracellular proteins that serve as the mortar between the cells. Since they receive nourishment via diffusion of substances from the underlying connective tissue, and are at the boundary of absorption processes transferring nutrients in the other direction, they are also ideal locales for yeast colonization.
Another C. albicans secreted aspartyl protease, Sap5 [5], is able to target and degrade E-cadherin, a major protein in epithelial cell junctions [6]. This, in addition to the effect of acetaldehyde, which has already been shown to have a deleterious effect in this regard by inducing tyrosine phosphorylation [7], effectively provides invasive access to C. albicans beyond the intestinal barrier.
• See "Acetaldehyde + Tight Junctions" http://curezone.com/forums/fm.asp?i=1956265
Echinocandins such as caspofungin are antifungal drugs that target glucan synthase enzymes that C. albicans uses to build its cell walls.
However, when beta(1,3)-glucan levels are inadequate C. albicans can upregulate chitin biosynthesis to compensate, restoring the capacity for cell division, sustaining the viability of the cell, and abrogating morphological and growth defects associated with echinocandin treatment [8].
The recurrent theme illustrated here is that C. albicans does not idly succumb to the multi-faceted attempts of either the immune system or antifungal drugs designed to kill it or limit its access. The genetic machinery within the fungal cells provides ample opportunity for rapid adaptation to any and all such assaults upon its entrenchment within the human host. Add to this the eons of practice which this organism has had residing within the mammalian species and it is little wonder that it is such a formidable adversary.
It appears quite obvious that if it wanted to kill its host, it could; but that wouldn't be in its best interests. Since it is a parasitic fungus, it is dependent upon its host for its own survival. Extremely virulent strains of Candida that are too good at compromising the hosts' immune systems will soon find that their host-base has been eliminated.
Fungi are genetically motivated to insert themselves into the biochemical metabolism of their hosts and remain there. Whenever they can get their host to do something for them that they might be able to do themselves, they opt for offloading the task onto the host. As remarkable as it seems, in the case of Candida albicans, this applies to limiting its own pathogenicity as well.
Oxygenated derivatives of poly-unsaturated fatty acids play important roles in the regulation of development, wound healing and immune system responses. Resolvins, lipoxins, and prostaglandins promote or resolve inflammation so that a controlled response to a threat may occur without triggering chronic inflammation and inappropriate tissue damage.
Candida albicans is able to biosynthesize the anti-inflammatory lipid Resolvin E1 (RvE1) [9] to dampen the host immune response to its presence.
The local production of RvE1 by C. albicans can have both a deterrent and a stimulatory effect upon neutrophils, preventing their migration to sites of inflammation while still enhancing the killing functions associated with neutrophils, including phagocytosis, ROS (reactive oxygen species) synthesis and fungicidal activity. The particular aspect operative in a given situation depends upon fungal load with the net result being that RvE1 production by C. albicans may protect the budding forms of the fungus, while allowing the immune system to go after and curtail the tissue-invasive hyphal forms [10].
C. albicans is also capable of producing lipid metabolites that are functionally similar to host prostaglandins, inter-cellular signalling molecules. Production of authentic prostaglandin E2 (PGE2) from arachidonic acid was detected at 37C. Although the molecule is identical to that produced by its host, the generation pathway is unique to the yeast [11].
The prostaglandin PGE2 has already been mentioned in relation to the differential effects of acetaldehyde on PGE2 and PGF2-alpha involved in cellular growth and repair mechanisms:
• See "Acetaldehyde + Prostaglandins" http://curezone.com/forums/fm.asp?i=1951252
T helper 17 (Th17) cells play an important role in mucosal host defense through production of the signature cytokines interleukin-17 and 22. Pathogen-derived PGE2 can act directly on Th17 cells during differentiation to inhibit interleukin-17-dependent antimicrobial responses [12], thereby suppressing antifungal immunity.
Although resolvins and prostaglandins are both lipid-based molecules, resolvins in the body are formed from omega-3 polyunsaturated fatty acids (e.g. fish oils) while prostaglandins are derivatives of omega-6 arachidonic acid. One of the advantages of the Wondro Alternative Protocol:
• See "Wondro Alternative Protocol" http://curezone.com/forums/fm.asp?i=1947895
is that the unheated flax oil contains essential fatty acids such as linoleic (omega-6) and linolenic (omega-3) acid in their pristine form, something that can be utilized by the body to produce the longer unsaturated fatty acids required for resolvin and prostaglandin production. Since many of these substances act in tandem in stop and go signalling cascades, it is paramount that the body have the fatty acid resources to enable a balanced situational response, especially when microbes such as C. albicans may be skewing the signalling concentrations according to its own agenda.
The success of Dr. Johanna Budwig's anti-cancer diet [13], with its flaxseed oil and quark, in many intractable cases suggests that the essential fatty acids in cellular membranes that play an important role in inter-cellular prostaglandin action may be deficient in cancer-stricken individuals. Her observation that many cancer-treating drugs being evaluated at the time contained sulfhydryl groups led her to investigate unsaturated fatty acids in relation to cellular metabolism. In light of the investigation in this series, the sulfhydryl connection is relevant as well in relation to acetaldehyde scavenging and damage:
• See "Sulfur, Sulfur, Everywhere" http://curezone.com/forums/fm.asp?i=1945039
All factors including essential fatty acid deficiency, prostaglandin imbalance and acetaldehyde disruption play a role in contributing to the onset of yeast-induced cancer.
As well, since C. albicans is producing immunomodulating signal molecules (identical in every respect to those produced by the host itself) as an apparent technique for not only suppressing an immune response to its budding phase but also for self-limiting its own virulence, it must expect and rely upon a certain level of host pressure to maintain its colonization level within sustainable (i.e. non-fatal) limits. This may be why C. albicans is such a problem for patients where immunosuppression is a an infectious aspect (HIV [14]), or a deliberate part of therapy (transplants [15], steroid protocols [16]).
Unraveling the web that this organism spawns within a human host, even at supposedly harmless but nonetheless acetaldehyde-emitting [17] commensal levels, must take into account all of the action/reaction scenarios that are at its disposal.
[1] Fidel, Jr PL et al., "Mucosal Immunity to Candida albicans" in "Candida and Candidiasis", (Calderone/Clancy, eds), 2nd ed., 2012.
[2] Vylkova S et al., "Histatin 5 Initiates Osmotic Stress Response in Candida albicans via Activation of the Hog1 Mitogen-Activated Protein Kinase Pathway", Eukaryot Cell. 2007 October; 6(10): 1876–1888.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2043398
[3] Hornbach A et al., "The glycosylphosphatidylinositol-anchored protease Sap9 modulates the interaction of Candida albicans with human neutrophils.", Infect Immun. 2009 Dec;77(12):5216-24.
http://www.ncbi.nlm.nih.gov/pubmed/19805528
[4] Meiller TF et al., "A Novel Immune Evasion Strategy of Candida albicans: Proteolytic Cleavage of a Salivary Antimicrobial Peptide.", PLoS ONE 2009 4(4): e5039. doi:10.1371/journal.pone.0005039
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0005039
[5] Villar CC et al., "Mucosal tissue invasion by Candida albicans is associated with E-cadherin degradation, mediated by transcription factor Rim101p and protease Sap5p.", Infect Immun. 2007 May;75(5):2126-35.
http://www.ncbi.nlm.nih.gov/pubmed/17339363
[6] Frank CF et al., "Cleavage of E-cadherin: a mechanism for disruption of the intestinal epithelial barrier by Candida albicans.", Transl Res. 2007 Apr;149(4):211-22.
http://www.ncbi.nlm.nih.gov/pubmed/17383595
[7] Basuroy S et al., "Acetaldehyde disrupts tight junctions and adherens junctions in human colonic mucosa: protection by EGF and L-glutamine.", Am J Physiol Gastrointest Liver Physiol. 2005 Aug;289(2):G367-75. Epub 2005 Feb 17.
http://www.ncbi.nlm.nih.gov/pubmed/15718285
[8] Walker LA et al., "Stimulation of chitin synthesis rescues Candida albicans from echinocandins.", PLoS Pathog. 2008 Apr 4;4(4):e1000040.
http://www.ncbi.nlm.nih.gov/pubmed/18389063
[9] Arita M et al., "The contributions of aspirin and microbial oxygenase to the biosynthesis of anti-inflammatory resolvins: novel oxygenase products from omega-3 polyunsaturated fatty acids.", Biochem Biophys Res Commun. 2005 Dec 9;338(1):149-57.
http://www.ncbi.nlm.nih.gov/pubmed/16112645
[10] Haas-Stapleton EJ et al., "Candida albicans modulates host defense by biosynthesizing the pro-resolving mediator resolvin E1.", PLoS One. 2007 Dec 19;2(12):e1316.
http://www.ncbi.nlm.nih.gov/pubmed/18091990
[11] Erb-Downward JR et al., "Characterization of Prostaglandin E2 Production by Candida albicans", Infect. Immun. July 2007 vol. 75 no. 7 3498-3505.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1932954
[12] Valdez PA et al., "Prostaglandin E2 suppresses antifungal immunity by inhibiting interferon regulatory factor 4 function and interleukin-17 expression in T cells.", Immunity. 2012 Apr 20;36(4):668-79.
http://www.ncbi.nlm.nih.gov/pubmed/22464170
[13] Mannion C et al., "Components of an Anticancer Diet: Dietary Recommendations, Restrictions and Supplements of the Bill Henderson Protocol", Nutrients. 2011 January; 3(1): 1–26.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257729/#B13-nutrients-03-00001
[14] Samaranayake LP et al., "Oral candidiasis and human immunodeficiency virus infection.",
J Oral Pathol Med. 1989 Dec;18(10):554-64.
http://www.ncbi.nlm.nih.gov/pubmed/2695620
[15] Dongari-Bagtzogolou A et al., "Oral Candida infection and colonization in solid organ transplant recipients.", Oral Microbiol Immunol. 2009 Jun;24(3):249-54.
http://www.ncbi.nlm.nih.gov/pubmed/19416456
[16] Yang IA et al., "Inhaled corticosteroids for stable chronic obstructive pulmonary disease.", Cochrane Database Syst Rev. 2007 Apr 18;(2):CD002991.
http://www.ncbi.nlm.nih.gov/pubmed/17443520
[17] Gainza-Cirauqui ML et al., "Production of carcinogenic acetaldehyde by Candida albicans from patients with potentially malignant oral mucosal disorders.", J Oral Pathol Med. 2012 Aug 22.
http://www.ncbi.nlm.nih.gov/pubmed/22909057