# Cryptococcus: History, Epidemiology and Immune Evasion
## 6 Cell Wall  
The cell wall of _Cryptococcus_ spp., as in other species of fungus, provides protection against environmental stressors, such as ultraviolet radiation, dehydration and variations in pH, temperature and osmolarity [77; 78], in addition to mediating adhesion to host cells and protecting against free radicals and oxidant species produced by the cells of defense in the immune system [79; 80]. Contrary to what one might think, the cell wall of _Cryptococcus_ spp. is not a static barrier, but a dynamic structure that adapts to environmental conditions [81]. Its integrity is regulated by intracellular adapters that orchestrate its remodeling [82; 83] and its importance for the survival of the fungus in the host is made clear when the pathogenicity of mutant variants that lack cell wall integrity regulators is compromised [84]. Linked polysaccharides, plasma membrane-associated glycoproteins and pigments, such as melanin, comprise cell wall components, extending physically into the extracellular medium [77]. These polysaccharides that make up the cell wall of _Cryptococcus_ spp. are glycans, more specifically glucose polymers connected by \(\beta\)-(1-3), \(\beta\)-(1-6) and \(\alpha\)-(1-6) bonds [85], chitins, which are polymers of \(N\)-acetylglucosamine, and chitosans [86]. Unlike the glycans and glycoconjugates present in the polysaccharide capsule of _Cryptococcus_ spp., which are synthesized by glycosyltransferases in cytoplasmic organelles, cell wall polymers are produced by synthases present in the plasma membrane [87]. Synthases and deacetylases present at sites in the plasma membrane, producing chitin and chitosan, respectively, as the extracellular medium and other synthases form channels with activity of glycosyltransferases, allowing the passage of sugar nucleotides from the cytosol to the unreduced ends of glycans present in the cell wall [88]. Once in the extracellular medium, the glycans are arranged in layers of macrostructures, with the innermost part rich in electron density and composed of chitin, chitosan and \(\beta\)-glycans, the middle part rich in melanin and glycoproteins and the outermost part with lower electronic density being composed of \(\alpha\)- and \(\beta\)-glycans [89]. Glycans correspond to about 50 to 60% of the dry weight of the cell wall [76; 89]; \(\beta\)-(1-3)-glycans form long polysaccharide chains and are the most abundant component in fungal species acting as a skeleton of the cell wall. The \(\beta\)-(1-6)-glycans are the most abundant component in the cell wall of _C. neoformans_, forming smaller chains that link to glycosylphosphatidylinositol molecule anchors through glycosidic bonds, chitin molecules, chitosan, \(\beta\)-(1-3)-glycans and constituents of the polysaccharide capsule [90; 91]. However, the mechanism through which this arrangement occurs is still unknown, especially with regard to the percentage of the glycan composition in the cell wall of _C. gattii_. Furthermore, glycan degradation as a regulatory mechanism is not yet well characterized in _C. neoformans_ and _C. gattii_, despite the fact that \(\alpha\)-(1-3) and \(\beta\)-(1-3)-glycanase activity has already been identified in cell wall of _C. neoformans_[92]. Although glycans play an important role in the structure of the cell wall of _Cryptococcus_ spp., chitin polymers, \(\beta\)-(1-4)-\(N\)-acetylglucosamine, are responsible for the rigidity of the fungal cell wall, mainly due to its secondary structure, which is composed of antiparallel pleated beta-sheets stabilized by hydrogen bonds [90]. Interestingly, the percentage of chitin in the cell wall of fungi varies greatly according to their morphology, ranging from 1 to 2% in yeasts, reaching about 15% in filamentous fungi [93]. Other species of fungi have about 60% of their chitin converted into chitosan, \(\beta\)-(1-4)-\(N\)-glucosamine [94]. However, _C. neoformans_ has about three- to five-times more chitosan than chitin in its cell wall and, since chitosan has multiple positive charges, _C.