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.
Highlights
Cryptococcus was first identified as a human pathogen as early as 1894, by Otto Busse
While Dectin-3 facilitates the recruitment of plasmacytoid dendritic cells (DCs) to the lungs during the protective immune response against pulmonary C. neoformans infection [94], Dectin-3 deficiency did not lead to increased susceptibility of mice to an experimental pulmonary infection of C. neoformans (Figure 2) [95]
Macrophages play a significant role in the regulation of the disease outcome, as they can be skewed towards a protective M1 classically activated phenotype, or an M2 alternatively activated phenotype that is associated with increased pathogenesis during cryptococcosis
Summary
Cryptococcus was first identified as a human pathogen as early as 1894, by Otto Busse Disease due to this fungal pathogen was rare, but Cryptococcus became known as a significant opportunistic fungal pathogen, causing life-threatening infections of the central nervous system (CNS) during the AIDS epidemic [1]. Cryptococcosis is an AIDS-defining illness, and remains the most fatal fungal disease among AIDS patients worldwide [6] Neal et al used a murine model of cryptococcal meningoencephalitis to demonstrate that disease exacerbation is due to the CD4+ T cell-mediated immune response, instead of the fungal burden in the CNS [9]. C. neoformans and C. gattii appear to skew the immune response towards a nonprotective Th2-type response, leading to its escape from the phagosome, proliferation within phagocytes, and aggravation of disease [15,16]. Cryptococcus, as well as how the yeast is able to evade detection by the host
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