Understanding the host immune response during cryptococcal meningitis (CM) is of critical
importance for the development of immunomodulatory therapies. We profiled the cerebrospinal
fluid (CSF) immune-response in ninety patients with HIV-associated CM, and examined
associations between immune phenotype and clinical outcome. CSF cytokine,
chemokine, and macrophage activation marker concentrations were assayed at disease
presentation, and associations between these parameters and microbiological and clinical
outcomes were examined using principal component analysis (PCA). PCA demonstrated a
co-correlated CSF cytokine and chemokine response consisting primarily of Th1, Th2, and
Th17-type cytokines. The presence of this CSF cytokine response was associated with evidence
of increased macrophage activation, more rapid clearance of Cryptococci from CSF,
and survival at 2 weeks. The key components of this protective immune-response were interleukin
(IL)-6 and interferon-γ, IL-4, IL-10 and IL-17 levels also made a modest positive
contribution to the PC1 score. A second component of co-correlated chemokines was identified
by PCA, consisting primarily of monocyte chemotactic protein-1 (MCP-1) and macrophage
inflammatory protein-1α (MIP-1α). High CSF chemokine concentrations were
associated with low peripheral CD4 cell counts and CSF lymphocyte counts and were predictive
of immune reconstitution inflammatory syndrome (IRIS). In conclusion CSF cytokine
and chemokine profiles predict risk of early mortality and IRIS in HIV-associated CM. We
speculate that the presence of even minimal Cryptococcus-specific Th1-type CD4+ T-cell
responses lead to increased recruitment of circulating lymphocytes and monocytes into the central nervous system (CNS), more effective activation of CNS macrophages and microglial
cells, and faster organism clearance; while high CNS chemokine levels may predispose
to over recruitment or inappropriate recruitment of immune cells to the CNS and IRIS
following peripheral immune reconstitution with ART. These results provide a rational basis
for future studies of immune modulation in CM, and demonstrate the potential of baseline
immune profiling to identify CM patients most at risk of mortality and subsequent IRIS.