Cryptococcus neoformans ex vivo capsule size is associated with intracranial pressure and host immune response in HIV-associated cryptococcal meningitis.
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 γ (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.
Department of Infection and Immunity, St George's University of London, London, United Kingdom.
Emma J
EJ
Robertson
Grace
G
Najjuka
Melissa A
MA
Rolfes
Andrew
A
Akampurira
Neena
N
Jain
Janani
J
Anantharanjit
Maximilian
M
von Hohenberg
Manlio
M
Tassieri
Allan
A
Carlsson
David B
DB
Meya
Thomas S
TS
Harrison
Bettina C
BC
Fries
David R
DR
Boulware
Tihana
T
Bicanic
D017088:AIDS-Related Opportunistic Infections / Q000134:cerebrospinal fluid / Q000276:immunology / Q000382:microbiology*; D000328:Adult; D000704:Analysis of Variance; D000935:Antifungal Agents / Q000494:pharmacology; D002555:Cerebrospinal Fluid / Q000166:cytology / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000166:cytology* / Q000276:immunology*; D016207:Cytokines; D005260:Female; D062607:Fungal Capsules / Q000737:chemistry / Q000276:immunology* / Q000382:microbiology; D006801:Humans; D007427:Intracranial Pressure / Q000276:immunology; D008297:Male; D016919:Meningitis, Cryptococcal / Q000134:cerebrospinal fluid / Q000276:immunology / Q000382:microbiology*; D010641:Phenotype; D011134:Polysaccharides / Q000737:chemistry / Q000302:isolation & purification; D014454:Uganda; D014783:Viscosity
D000935:Antifungal Agents; D016207:Cytokines; D011134:Polysaccharides; C027478:glucuronoxylomannan
CSF; Cryptococcus neoformans; HIV; cryptococcal meningitis; human; immune response; intracranial pressure; polysaccharide capsule