Innate Immunity against Cryptococcus, from Recognition to Elimination

Abstract

Cryptococcus species, the etiological agents of cryptococcosis, are encapsulated fungal yeasts that predominantly cause disease in immunocompromised individuals, and are responsible for 15% of AIDS-related deaths worldwide. Exposure follows the inhalation of the yeast into the lung alveoli, making it incumbent upon the pattern recognition receptors (PRRs) of pulmonary phagocytes to recognize highly conserved pathogen-associated molecular patterns (PAMPS) of fungi. The main challenges impeding the ability of pulmonary phagocytes to effectively recognize Cryptococcus include the presence of the yeast's large polysaccharide capsule, as well as other cryptococcal virulence factors that mask fungal PAMPs and help Cryptococcus evade detection and subsequent activation of the immune system. This review will highlight key phagocyte cell populations and the arsenal of PRRs present on these cells, such as the Toll-like receptors (TLRs), C-type lectin receptors, NOD-like receptors (NLRs), and soluble receptors. Additionally, we will highlight critical cryptococcal PAMPs involved in the recognition of Cryptococcus. The question remains as to which PRR-ligand interaction is necessary for the recognition, phagocytosis, and subsequent killing of Cryptococcus.

Keywords: C-type lectin receptors (CLRs); Cryptococcus deneoformans; Cryptococcus gattii; Cryptococcus neoformans; NOD-like receptors (NLRs); Toll-like receptors (TLRs); host–pathogen interactions; innate immune response; pathogen-associated molecular patterns (PAMPs); pattern recognition receptors (PRRs).

Figure 1

TLRs and scavenger receptors required for cryptococcal PAMPs. Cryptococcus species contain a large polysaccharide capsule made up of GXM and GalXM. Extracellular receptors present in myeloid cells recognize GXM and GalXM via TLRs. TLR4 forms heterodimers with other extracellular receptors, including CD14, in order to detect capsular polysaccharides. TLR2, CD11b, and CD18 are also able to detect the capsule. Intracellular phagosomal TLR9 recognizes unmethylated CpG motifs of Cryptococcus. The NLR member NLRP3 is crucial for processing internalized cryptococci. Following the recognition of cryptococcal PAMPs, the adaptor molecule MyD88 is essential for the induction of pro-inflammatory mediators. Dashed lines represent various MyD88-dependent and independent signaling pathways required for pro-inflammatory mediator activation. ?? = unknown cryptococcal ligand for MARCO receptor.

Figure 2

Critical CLR members associated with fungal PAMPs. CLR members Dectin-1 and Dectin-3 have been described as being dispensable during cryptococcal infections and are not required for recognition of Cryptococcus (X) in murine studies. Dectin-2 deficiency resulted in mice being skewed towards a debilitating Th2-type response. Multiple CRD-containing CLRs, such as DC-SIGN and CD209, recognize mannosylated mannoproteins, and the mannose receptor (MR) recognizes mannose and chitin. These receptors induce pro-inflammatory mediators in a ITAM independent manner (gray dashed lines). The Mincle receptor is poorly characterized during cryptococcosis and Mincle’s cryptococcal ligand continues to be elucidated (??). CLR signal transduction can utilize the ITAM sequence present in FcγRs. ITAM activation phosphorylation activates Syk, which can then directly (solid blue line) or indirectly (dashed blue lines) activate the adaptor molecule complex comprised of CARD9, MALT1 and BCL10. This complex can directly induce pro-inflammatory mediators (solid blue line).