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References
Table of Contents

Addendum

Introduction
Before beginning a discussion of the significance of the nature of fungal cell walls as related to the virulence of those fungi, it becomes necessary to define some basic biochemical terms.

One component of a fungal cell wall is a chemical known as a "glycoprotein." The prefix glyco- refers to polysaccharides or chains of sugars linked together in a highly specific manner. When polysaccharides (branched or unbranched) are attached to protein, the resultant combination is a glycoprotein.

The process of enzymatically attaching polysaccharides to protein is known as glycosylation. The sugar mannose is only one of many sugars that are incorporated into polysaccharides and glycoproteins. When a short-chain polysacccharide consists principally of mannose, it is known as an "oligomannoside". When an oligomannoside is attached to a protein, the process is known as "mannosylation".

When a surface has low affinity for water, it becomes a hydrophobic surface. Conversely, when a surface has high affinity for water (high wetability), it becomes a hydrophilic surface.

Candida albicans Surface Characteristics
It has been demonstrated with Candida albicans that outer chain mannosylation correlates with cell surface hydrophobicity (many mannose residues make the surface water repellant). Other studies show that the oligomannosides from hydrophobic cell walls are longer and in greater abundance than those from hydrophilic cell walls.¹³²

Hydrophobins
Hydrophobins are small, secreted fungal proteins that play a role in the growth and development of filamentous fungi. They are involved in the formation of aerial structures and in the binding of fungal threads (hyphae) to hydrophobic surfaces.¹³³

Candida albicans was used in an experiment to colonize and chronically infect laboratory mice. Results showed that yeast hydrophobic proteins are exposed on fungal cells present in invaded host tissues. The hydrophobicity of pathogenic strains of C. albicans has been correlated with virulence.¹³⁴

Cardiac Muscle Response to Cyclopiazonic Acid
As indicated above, cyclopiazonic acid (CPA) from Aspergillus and Penicillium has been shown to inhibit the uptake of calcium into the calcium storage chamber (sarcoplasmic reticulum) in skeletal and smooth muscles.

A study has been conducted to demonstrate the effect of CPA on cardiac muscle. In this study, CPA produced a marked prolongation of the contraction time period of the heart. It was proposed that this response was noted because of the known inhibition of calcium uptake into the sarcoplasmic reticulum.¹³⁵

PCR Test in Diagnostic Mycology
The Polymerase Chain Reaction (PCR) Test for the presence of Candida and Aspergillus has the ability to enhance the sensitivity and rapidity of conventional methods used in diagnosing fungal infection.¹³⁶

G-Test for Candida
Under culture conditions, Candida albicans releases a water-soluble polysaccharide consisting of a mannoprotein/beta-glucan complex and activated factor G. It has been shown that this complex is lethal when injected into mice. The G-test is suitable for detecting the onset and termination of deep-seated mycosis (fungal infection).¹³⁷

Aspergillus Binding to Lung Tissue
Aspergillus fumigatus is a soil fungus that causes invasive lung disease in those who cannot immunologically overcome it. A prerequisite to infection is the attachment of the fungal cell surface to host lung cells. Negatively charged carbohydrates on the conidial (spore) surface have been identified as the molecules responsible for attachment to extracellular matrix proteins. Furthermore, it has been shown that sialic acid on the terminal ends of polysaccharide chains are responsible for the negative surface charge and the binding affinity.

Sialic acid biosynthesis was found to be regulated by nutrient composition: the density of sialic acids on the bud (spore) surface grown in the minimum of nutrients was lower than the density seen when grown on rich, complex media. In addition, pathogenic Aspergillus species adhere to hostal tissue to a greater extent than non-pathogenic species. This discovery suggests that the ability (or lack thereof) of Aspergillus to bind to hostal lung tissue is dependent upon the diet of the host, a richer diet conducive to greater binding ability and invasiveness.¹³⁸

Adhesins are proteins found on the surface of fungal cells and assist in the binding of fungi to hostal cells. Some adhesins are sialic acid-binding and are capable of essentially crosslinking fungal cells to each other or other cells.¹³⁹

Fungal Cell Wall Composition
Cell walls of fungi are from 0.1– 0.5 µ in thickness and are built of microfibrils 20 nm in diameter. These fibrils are composed of chitin (70–80%) and a small amount of glucans, with the matrix composed of 1-3, beta-glucans, with the matrix composed of 1-3, beta, 1-6, glucan, glucomannan, galactomannan, and peptides. Another characteristic structure is the outermost layer (20 –50 nm in thickness) of the cell wall, consisting of hydrophobic protein rodlets. Chitin is the polymer comprising the outer shell of ants and lobsters and is very prevalent in nature.

During the transition from yeast (bud) to mycelial (thread) form, phosphatidylinositol and phosphatidylserine are reduced while phosphatidylcholine increases.¹⁴⁰

General Pain Mechanism (Excluding Substance P)
The physiology of pain involves a complex interaction of peripheral and central neuron system structures (CNS), extending from the skin, the viscera, and the musculoskeletal tissues to the cerebral cortex.

The general pain mechanism begins with the activation of the N-methyl-d-aspartate (NMDA) receptor by the neurotransmitter glutamate (glutamic acid, one of the amino acids). The NMDA receptor acts as a gate for the passage of sodium and potassium ions across the nerve membrane. The passage of these ions results in the intraneuronal elevation of calcium. This, in turn, stimulates the enzyme nitric oxide synthase (NOS) to synthesize nitric oxide (NO). Nitric oxide, being a gas, diffuses from the neuron and stimulates in neighboring neurons the formation of cyclic GMP (cGMP, cyclic guanosine monophosphate). The number of ion channels in target neurons regulated by cGMP determines whether NO may act excitatory or inhibitory in the generation of pain.

Recently, CHR (corticotropin-releasing hormone) has been found to act at all levels of the neuronal axis to produce analgesia (insensitivity to pain).¹⁴¹