Abstract
Cryptococcus neoformans (Cn) is a basidiomycetous pathogenic yeast that is a frequent cause of meningoencephalitis in immunocompromised individuals. Cn is a facultative intracellular pathogen in mammals, insects and amoeba. Cn infection occurs after inhalation of spores or desiccated cells from the environment. After inhalation Cn localizes to the lungs where it can be phagocytosed by alveolar macrophages. Cn is surrounded by a polysaccharide capsule that helps the fungus survive in vivo by interfering with phagocytosis, quenching free radical bursts and shedding polysaccharides that negatively modulates the immune system. After phagocytosis, Cn resides within the phagosome that matures to become a phagolysosome, a process that results in the acidification of the phagolysosomal lumen. Cn replicates at a higher rate inside macrophages than in the extracellular environment, possibly as a result that the phagosomal pH is near that optimal for growth. Cn increases the phagolysosomal pH and modulates the dynamics of Rab GTPases interaction with the phagolysosome. Chemical manipulation of the phagolysosomal pH with drugs can result in direct and indirect killing of Cn and reduced non-lytic exocytosis. Phagolysosomal membrane damage after Cn infection occurs both in vivo and in vitro, and is required for Cn growth and survival. Macrophage treatment with IFN-γ reduces the phagolysosomal damage and increases intracellular killing of Cn. Studies on mice and humans show that treatment with IFN-γ can improve host control of the disease. However, the mechanism by which Cn mediates phagolysosomal membrane damage remains unknown but likely candidates are phospholipases and mechanical damage from an enlarging capsule. Here we review Cn intracellular interaction with a particular emphasis on phagosomal interactions and develop the notion that the extent of damage of the phagosomal membrane is a key determinant of the outcome of the Cn-macrophage interaction.
Highlights
Specialty section: This article was submitted to Fungi and Their Interactions, a section of the journal Frontiers in Microbiology
Cn is ubiquitous in the environment, inhabiting soils (Currie et al, 1994; Gugnani et al, 2005; Randhawa et al, 2008) and human infection occurs when aerosolized spores or desiccated fungal cells enter the lung via inhalation where Cn encounters the first line of defense: the alveolar macrophage (Feldmesser et al, 2000).Macrophages play a critical role in the pathogenesis of Cryptococcus neoformans: Tripping on Acid cryptococcosis, ranging from control of infection to possible roles in persistence, latency and extrapulmonary dissemination
Depletion of alveolar macrophage in rats and mice shows that the role of macrophages during Cn infection varies with the host species
Summary
Cryptococcus neoformans (Cn), a basidiomycetous pathogenic yeast, is a relatively frequent cause of meningoencephalitis in immunocompromised individuals (Horgan et al, 1990; Thinyane et al, 2015). This review will only focus on Cn, since most of the macrophage interaction studies have been done with Cn. Cn is an facultative intracellular pathogen in such diverse hosts as mammals, amoebae (Steenbergen et al, 2001) and insects (Tenor et al, 2015; Trevijano-Contador et al, 2015), and employs various virulence factors to subvert cellular defense mechanisms. The capsule functions in virulence through numerous mechanisms including preventing phagocytosis, quenching free radical bursts and interfering with immune responses (Bulmer and Sans, 1967; Zaragoza et al, 2008). Cn can persist in the host in a latent state inside macrophages and multinucleated giant cells in granulomas Cn in this latent state can emerge and cause disease if the host immune status change from immunocompetent to immunocompromised (Shibuya et al, 2005; Saha et al, 2007; Alanio et al, 2015). We will review the studies that explore the interactions of Cn in these diverse ranges of pH and phagosomal maturation
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