Phagosome Extrusion and Host-Cell Survival after Cryptococcus neoformans Phagocytosis by Macrophages

Abstract

Cryptococcus neoformans (Cn) is an encapsulated yeast that is a facultative intracellular pathogen and a frequent cause of human disease. The interaction of Cn with alveolar macrophages is critical for containing the infection , but Cn can also replicate intracellularly and lyse macrophages . Cn has a unique intracellular pathogenic strategy that involves cytoplasmic accumulation of polysaccharide-containing vesicles and intracellular replication leading to the formation of spacious phagosomes in which multiple cryptococcal cells are present . The Cn intracellular pathogenic strategy in macrophages and amoebas is similar, leading to the proposal that it originated as a mechanism for survival against phagocytic predators in the environment . Here, we report that under certain conditions, including phagosomal maturation, possible actin depolymerization, and homotypic phagosome fusion, Cn can exit the macrophage host through an extrusion of the phagosome, while both the released pathogen and host remain alive and able to propagate. The phenomenon of "phagosomal extrusion" indicates the existence of a previously unrecognized mechanism whereby a fungal pathogen can escape the intracellular confines of mammalian macrophages to continue propagation and, possibly, dissemination.

The Interaction between Candida krusei and Murine Macrophages Results in Multiple Outcomes, Including Intracellular Survival and Escape from Killing

“…However, it could also reflect a mechanism developed by the immune system in which macrophages overloaded with yeast cells transfer part of the fungal burden to uninfected or less-infected macrophages. Some of these phenomena (macrophage fusion, yeast extrusion, and transfer between macrophages) have been described in other fungal pathogens (1,2,13,15,16), which suggests that these processes represent a universal strategy developed by the host cells to control the infection independently of the pathogen engulfed.…”

Role of microglia in fungal infections of the central nervous system

“…Peripheral macrophages have shown that opsonization by IgM and complement activation is important for efficient phagocytosis of cryptococci. 79 For example, increased survival of healthy mice and immunosuppressed mice infected with opsonized cryptococcal cells was observed compared to unopsonized yeast cells. 33,80,81 Within the brain, the capabilities of a monoclonal anti-capsular IgG enhance microglial cell phagocytosis of cryptococci.…”

The Facultative Intracellular Pathogen Candida glabrata Subverts Macrophage Cytokine Production and Phagolysosome Maturation

“…neoformans, by which fungal cells and macrophages remain alive even after the release of yeast cells (25,26): MDMs clearly burst when releasing C. glabrata cells. The process is therefore more comparable to cytolysis, an escape mechanism used by bacterial species such as Chlamydia or Leishmania spp.…”

“…Cr. neoformans can also escape macrophages via extrusion/expulsion (25,26). The formation of massive vacuoles by the fungus is followed by extrusion of the phagosomes and the release of the pathogen.…”