Authors: Robertson EJ, Najjuka G, Rolfes MA, Akampurira A, Jain N, Anantharanjit J, von Hohenburg M, Tassieri M, Carlsson A, Meya DB, Harrison TS, Fries B, Boulware DR, Bicanic T.
Background. The Cryptococcus neoformans polysaccharide capsule is a well-characterised 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. 134 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(pre-treatment) 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-gamma(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.