Capsule Structure Changes Associated with Cryptococcus neoformans Crossing of the Blood-Brain Barrier

Abstract

Cryptococcus neoformans is a yeast responsible for disseminated meningoencephalitis in patients with cellular immune defects. The major virulence factor is the polysaccharide capsule. We took advantage of a relevant murine model of disseminated meningoencephalitis to study the early events associated with blood-brain barrier (BBB) crossing. Mice were sacrificed at 1, 6, 24, and 48 hours post-intravenous inoculation, and classical histology, electron microscopy, and double immunofluorescence were used to study tissues and yeasts. Crossing of the BBB occurred early after inoculation, did not involve the choroid plexus but instead occurred at the level of the cortical capillaries, and caused early and severe damage to the structure of the microvessels. Seeding of the leptomeninges was not the primary event but occurred secondary to leakage of cortical pseudocysts. Organ invasion was associated with changes in cryptococcal capsule structure and cell size, which differed in terms of magnitude and kinetics, depending on both the organs involved, and potentially, on the bed structure of the local capillary. The rapid changes in capsule structure could contribute to inability of the host immune response to control cryptococcal infection in extrapulmonary spaces.

The Cryptococcal Enzyme Inositol Phosphosphingolipid-Phospholipase C Confers Resistance to the Antifungal Effects of Macrophages and Promotes Fungal Dissemination to the Central Nervous System

“…Previous studies have suggested that strains of C. neoformans that express larger polysaccharide capsules may have difficulty transversing the blood-brain barrier and establishing infection in the central nervous system (8,24). Perhaps by expressing a larger polysaccharide capsule to avoid the internalization by activated macrophages, the ⌬isc1 strain is hindering its own ability to disseminate to the brain in an immunocompetent host, such as the CBA/J mouse.…”

Unusual Galactofuranose Modification of a Capsule Polysaccharide in the Pathogenic Yeast Cryptococcus neoformans

“…C. neoformans is an extremely adaptable environmental yeast that can withstand a variety of harsh conditions (63)(64)(65) and is capable of living in close association with numerous organisms, including plants (66,67), birds (68,69), predatory amoebae (70), and mammals (71,72), notably humans (73,74). The cryptococcal capsule in particular is a dynamic structure whose morphology and architecture change with growth conditions (75)(76)(77) and the local environment (52,55). It may be that specific capsular features are only required in a subset of the diverse ecological niches inhabited by this yeast.…”

Características histomorfológicas e histoquímicas determinantes no diagnóstico da criptococose em animais de companhia

“…Estudos realizados em casos de criptococose humana e infecções experimentais em animais têm também demonstrado variações na espessura da cápsula, na parede e no diâmetro da célula das leveduras de acordo com o órgão analisado e o tempo de infecção (Feldmesser et al 2001, Del Poeta 2004, Charlier et al 2005, Xie et al 2012. Diversos autores têm sugerido que o espessamento da cápsula ocorre principalmente em leveduras maduras devido à adição de novos polissacarídeos e nanoproteínas à estrutura pré-existente (Charlier et al 2005, McFadden et al 2006. Apesar de haver variação na espessura da cápsula das leveduras nos casos de criptococose deste estudo, não foram observadas leveduras totalmente sem cápsula.…”