# Cryptococcus: History, Epidemiology and Immune Evasion
## 10 Cryptococcus Dissemination  
After its establishment in the lung tissue, the capsular and cell body growth of the fungus occurs, a mechanism that is closely associated with the impediment of phagocytosis and formation of titanized yeasts. Titan cells have been found in both _C. neoformans_ and _C. gatti_[185; 186]. These yeasts have a size greater than 20 \(\upmu\)m in cell body diameter and have a greater-than-normal capsular thickening, which gives the yeast greater external coverage with its structural virulence factors [187; 188]. A characteristic that the fungus has during infection is the tropism for the central nervous system [189], and associated with this, the titanization of the yeast is a morphological modification that is linked to favoring the spread to this region of the organism; however, _C. gatti_ is less likely to disseminate to the CNS as compared to _C. neoformans_, and _C. gatti_ is more likely to present as pneumonia [171; 190]. After the establishment of the yeast in the lungs, the fungus can spread to other organs in the organism, resulting in the progression to systemic cryptococosis [191] (Figure 2). This extrapulmonary spread favors the passage of the fungus to the central nervous system and can be mediated by the action of phagocytes present in the pulmonary alveoli, residing in the site of infection in the lungs [189]. There are several mechanisms proposed for this dissemination, the _\"Trojan Horse\"_ being one of the most observed [192]. In this dissemination, the yeast is internalized by resident phagocytes and migrates through transcytosis through the epithelial barrier; thus, the intact yeast inside the cell can migrate to the various tissues that the phagocyte finds in the body, including the central nervous system, going through the phagocyte by lytic or non-lytic extrusion, also called vomocytosis. Both _C. neoformans_ and _C. gatti_ have already presented this type of transport [193]. Yeast can be either phagocytosed or actively enter the cell body, by mechanisms not yet well elucidated [194] and, in addition, the cell can migrate through the pulmonary endothelium and blood-brain barrier by paracellular passage (between cells) and transcellular passage (through the cell) [195; 196] (Figure 2). Interestingly, even rare, transplacental migration can occur, with cases already well documented on this topic [197]. Although the transfer of yeast by the organism mediated by phagocytes is well described, there are other mechanisms by which _Cryptococcus_ spp. can cross physiological barriers, such as transcytosis by epithelial cells, already described as mediated by the binding of GXM with the CD14 receptor and palmitic acid from the yeast by binding to the pulmonary surfactant protein D, both mechanisms starting with the facilitation of cell adhesion [198; 199]. A similar mechanism has been associated with the binding of hyaluronic acid on CD44, also facilitating cell adhesion and the metalloproteinase Mpr1 engaging Annexin A2 in the transfer of yeast transcellularly across the blood-brain barrier [200; 201]. In addition to these mechanisms, _Cryptococcus_ yeast produces urease and induces the release of IL-33, which leads to the dissociation of tight junctions in the epithelium, facilitating paracellular passage [202; 203]. Urease, as well as other proteolytic enzymes and Plb1, are capable of destroying the epithelial cells in the blood-brain barrier, favoring the passage of yeast [204; 205] (Figure 2). Despite the mechanisms of dissemination of yeasts, dependent on their intrinsic factors, the dissemination of _Cryptococcus_ through immune cells is particularly important, mainly due to the subversion of cellular activity that the capsular constituents of yeast promote [189]. In this way, phagocytes have already been demonstrated important in the dissemination of the fungus to the central nervous system [206].