Phenotypic Switching ofCryptococcus neoformansCan Produce Variants That Elicit Increased Intracranial Pressure in a Rat Model of Cryptococcal Meningoencephalitis

Abstract

Increased intracranial pressure (ICP) plays an important role in the morbidity and mortality of cryptococcal meningoencephalitis. The microbial and host factors that contribute to the development of increased ICP are poorly understood. We found that phenotypic switch variants of Cryptococcus neoformans (smooth and mucoid) differed in their abilities to promote increased ICP in a rat model of cryptococcal meningitis. Rats infected with the mucoid variant developed increased ICP, whereas rats infected with the smooth parent did not. This trend correlated with a shorter survival time and a higher cerebrospinal fluid (CSF) fungal burden for mucoid variant-infected rats, although brain fungal burdens were comparable between mucoid variant-and smooth parent-infected rats. Magnetic resonance imaging revealed enhanced T2 signal intensity over the surfaces of the brains of mucoid variant-infected rats. In addition, more polysaccharide accumulated in the CSF and brains of mucoid variant-infected rats. The accumulation of glucorunoxylomannan was associated with elevated levels of MCP-1 (CCL2) and, accordingly, a more pronounced but ineffective monocytic inflammatory response in the meninges of mucoid variant-infected rats. In summary, these findings suggest that strainspecific characteristics can influence the development of increased ICP and indicate a manner in which phenotypic switching could influence the outcome of a central nervous system infection.Cryptococcus neoformans is an encapsulated yeast that causes disease primarily in patients with impaired immunity (13,38,42,45). Cryptococcosis usually presents as chronic meningoencephalitis that is difficult to eradicate, despite antifungal therapy (3, 45). Cryptococcal meningoencephalitis is associated with high morbidity and mortality, especially among immunocompromised hosts (26). Several laboratory indices and symptoms that predict poor outcome have been identified; these include altered mental status at presentation, markedly elevated cryptococcal antigen titers in cerebrospinal fluid (CSF) or blood, and fewer than 20 leukocytes/l in the CSF (11,26). In patients with AIDS, significant morbidity and mortality are often a result of increased intracranial pressure (ICP), which can persist even when the cryptococcal infection is controlled. In a large study, elevated ICP (Ͼ250 cm of H 2 O) was found in about 50% of patients with AIDS in whom this parameter was measured (12,26,41).To date there have been no conclusive studies in humans that relate elevated ICP in cryptococcal meningitis and mortality to the infecting strain of C. neoformans. The variability of the inflammatory responses to cryptococcal meningoencephalitis in patients with comparable levels of immunosuppression suggests that pathogen-related factors contribute to the pathogenesis of cryptococcal disease (33, 37). In animal models, differences in virulence among clinical strains have been described for pulmonary infections (2,17,19). In addition, the results of several studies have supported the concept th...

The Physical Properties of the Capsular Polysaccharides from Cryptococcus neoformans Suggest Features for Capsule Construction

“…The possibility that the viscosity of GXM had implications for pathogenesis was considered. Two aspects of cryptococcal infection where viscosity could be particularly relevant are the frequent lack of inflammatory cell infiltration in the lungs and the elevation of intracerebral pressure (46,47). The decrease in GXM solution viscosity as ionic strength increased establishes that GXM behaves in solution as a polyelectrolyte.…”

“…Thus, although GXM in water was viscous, GXM in serum or cerebrospinal fluid is not predicted to impart significant viscosity to the fluids. GXM levels in serum and cerebrospinal fluid measured in rodent models are usually less than 100 g/ml (46,48,49). At these concentrations viscosity should be low and unlikely to disrupt normal fluid dynamics in serum or central nervous system fluid.…”

Phenotypic Switching of Cryptococcus neoformans and Cryptococcus gattii

“…Near the time of death the inflammatory response increased and resulted in extensive destruction of alveolar membranes. In addition, the RC2-MC variant was able to promote increased intra-cranial pressure in a rat model of cryptococcal meningitis [38]. This finding was important because in human infection increased intra-cranial pressure is the leading cause of high morbidity and mortality [39].…”

Capsule Structural Heterogeneity and Antigenic Variation in Cryptococcus neoformans

“…6A and C). Identical structures were unexpected as the biophysical and immunomodulatory abilities of SM and MC GXM differed greatly and NMR-detectable changes in GXM repeat were reported in other switch variants with increased virulence (8,9,23).…”