# Cryptococcus: History, Epidemiology and Immune Evasion
## 12 Immune Response against Cryptococcosis
### Immunomodulation  
Recognition of the molecular patterns associated with the fungus by immune cells is crucial for an efficient anti-cryptococcal response [227]. [PERSON] and colleagues described this aspect using TLR9-deficient mice. When its deficiency in a model of crypto-cocosis was caused by _C. gatttii_, it was associated with a lower Th1 and Th17 profile and a higher presence of titanized cells, characterizing a lack of disease control [185]. Mannose and \(\beta\)-glycan receptors also mediate the incorporation of _C. neoformans_ yeast by phagocytosis and production of cytokines with a pro-inflammatory profile, as in the production of TNF-\(\alpha\)[228]. Furthermore, complement receptors CR3 and CR4 are involved in the recognition of _C. neoformans_, mediating phagocytosis independently of antibody action, as previously seen when binding to GXM [137]. Receptors, such as dectin-1 and CD11b, are associated with a rapid interaction with _C. neoformans_ spores \(\beta\)-glycans, facilitating alveolar macrophage phagocytosis [229]. However, dectin-1 does not appear to be necessary for host defense against C. neoformans. This is most likely due to the blockade of \(\beta\)-glycan binding sites by GXM, since the spores that are non-encapsulated rapidly bind to the receptor exerting cellular activation, unlike encapsulated yeasts [230]. Receptors that alter the cytokine profile and mediate _C. neoformans_ yeast-cell adhesion are the SCARF1 and CD36 scavenger receptors, which increase IL-\(\beta\) and CXCL production [231], TLR2 and MyD88 adapter, which increase the production of TNF-\(\alpha\), IL-12 and IFN-\(\gamma\)[232] and mannose receptors that induce the proliferation of CD4\({}^{+}\) T lymphocytes [233]. In addition, non-encapsulated strains of _C. neoformans_ activate the inflammasome by NLRP3 and fungal capsular constituents appear to inhibit this process [234]. Likewise, inhibition in the production of IL-8 and CXCL has also been observed in endothelial cells in contact with _C. neoformans_ due to the presence of the polysaccharide capsule in the fungus [235]. The cytokine microenvironment is also compromised not only by the _Cryptooccus_ spp. intrinsic factors, as already observed, but by extrinsic ones. For instance, during infection caused by _C. gatttii_, the microbiota seem to be important for limiting the progression of the disease, with germ-free animals being more susceptible to this infection and with lower production  
Figure 3: Immune response against _Cryptococcus_ spp. and its capsular polysaccharides immunomodulatory effects.  
of IFN-\(\gamma\), IL -1\(\beta\) and IL-17, which leads to a lower infection control [236]. Interestingly, the production of IFN-\(\gamma\) appears to be more potent during macrophage phagocytosis induction of _C. neoformans_ and less responsive for the phagocytosis of _C. gattii_ yeasts, with _C. gattii_ also showing a reduced capacity for inducing IL-12 in vitro when compared to _C. neoformans_[237]. Within the _C. gattii_ species complex itself, there are differences in the in vitro cytokine induction potential, with the hypervirulent R265 variant _C. deuterorgattii_ showing the lowest inductions of pro-inflammatory cytokines, such as TNF-a, IL-1b and IL-6, which, in theory, suggests a greater escape from the pro-antifungal conditions of the inflammatory microenvironment during an infection [238].