Background. The Cryptococcus neoformans polysaccharide capsule is a well-characterized virulence factor with immunomodulatory properties. The organism and/or shed capsule is postulated to raise intracranial pressure (ICP) in cryptococcal meningitis (CM) by mechanical obstruction of cerebrospinal fluid (CSF) outflow. Little is known regarding capsule phenotype in human cryptococcosis. We investigated the relationship of ex vivo CSF capsular phenotype with ICP and CSF immune response, as well as in vitro phenotype.Methods. In total, 134 human immunodeficiency virus (HIV)-infected Ugandan adults with CM had serial lumbar punctures with measurement of CSF opening pressures, quantitative cultures, ex vivo capsule size and shedding, viscosity, and CSF cytokines; 108 had complete data. Induced capsular size and shedding were measured in vitro for 48 C. neoformans isolates.Results. Cryptococcal strains producing larger ex vivo capsules in the baseline (pretreatment) CSF correlated with higher ICP (P =. 02), slower rate of fungal clearance (P =. 02), and paucity of CSF inflammation, including decreased CSF white blood cell (WBC) count (P <. 001), interleukin (IL)-4 (P =. 02), IL-6 (P =. 01), IL-7 (P =. 04), IL-8 (P =. 03), and interferon (P =. 03). CSF capsule shedding did not correlate with ICP. On multivariable analysis, capsule size remained independently associated with ICP. Ex vivo capsular size and shedding did not correlate with that of the same isolates grown in vitro.Conclusions. Cryptococcal capsule size ex vivo is an important contributor to virulence in human cryptococcal meningitis.
Bibliographical noteFunding Information:
Financial support. This work was suported by a Wellcome Trust Intermediate Fellowship to T. B., WT 089966. Research support for the clinical cohort and investigators was received from the US National Institutes of Health U01AI089244, R21NS065713, and K23AI073192. M. T. was supported by a research fellowship from the Royal Academy of Engineering/ EPSRC. B.C.F. and N. J. are supported by R21 A1087564, RO1 AI059681, and the Center for AIDS Research at the Albert Einstein College of Medicine and Montefiore Medical Center (NIH AI-51519). Potential conflict of interest. All authors: No reported conflicts.
- Cryptococcus neoformans
- cryptococcal meningitis
- immune response
- intracranial pressure
- polysaccharide capsule