Mechanisms of Cryptococcus neoformans-Mediated Host Damage

Abstract

Cryptococcus neoformans is not usually considered a cytotoxic fungal pathogen but there is considerable evidence that this microbe can damage host cells and tissues. In this essay, we review the evidence that C. neoformans damages host cells and note that the mechanisms involved are diverse. We consider C. neoformans-mediated host damage at the molecular, cellular, tissue, and organism level. Direct mechanisms of cytotoxicity include lytic exocytosis, organelle dysfunction, phagolysosomal membrane damage, and cytoskeletal alterations. Cytotoxicity contributes to pathogenesis by interfering with immune effector cell function and disrupting endothelial barriers thus allowing dissemination. When C. neoformans-mediated and immune-mediated host damage is sufficient to affect homeostasis, cryptococcosis occurs at the organism level.

Keywords: Cryptococcus; cryptococcosis; cytotoxicity; damage; disease; macrophage.

Figure 1

Schematic representation of the different Cryptococcus neoformans-mediated cell host damages are various scales. Damage at the molecular level results from the secretion of various enzyme by C. neoformans (proteases, nuclease, urease, phospholipase) that degrade host molecules such as antibodies and/or modify cells membranes. C. neoformans ingestion is also able to trigger autophagy, apoptosis, and cell death in the host (mAb, monoclonal antibodies; Mp, macrophages). Damage at the cellular level involves modification of cellular compartments such as accumulation of polysaccharide vacuoles (1), inhibition of phagolysosomal maturation (2), phagolysosomal leakage (3), mitochondrial fission and depolarization (4), swelling and cytoskeleton abonomalities (5) or metabolic modification due to C. neoformans vesicles secretions (6), C. neoformans engulfment resulted also in non-lytic (7), or lytic (8) exocytosis. Damage at the tissue level consisted typical cryptococcal lesions in the brain parenchyma after intravenous inoculation of C. neoformans to outbred mice (sacrifice seven days after inoculation). No granuloma and accumulation of yeast masses without inflammatory cells can be observed engendering tissue disorganization. Coloration Alcian Blue (magnification 4×). Damage at the organism level combines to produce the clinical signs associated with cryptococcal diseases in humans with dissemination and neurological abnormalities as the most severe clinical presentation leading to death. Felines are also naturally susceptible to cryptococcosis with localized to disseminate infections. Mus musculus and Galleria mellonella are well established organisms for experimental models of infection that help understanding the pathophysiology of the disease and the biology of the yeast in relation to the host.