Cerebrospinal fluid cytokine-driven immune responses in HIV-negative cryptococcal meningitis

Cryptococcal meningitis (CM) is a central nervous system infection caused by Cryptococcus species. Although it is readily diagnosable, managing CM remains difficult due to high mortality rates and limited effectiveness of antifungal treatments. Cytokines play a central role in the immunopathogenesis of CM, yet their dynamics in HIV-negative patients remain incompletely characterized. We analyzed CSF cytokine profiles in 28 HIV-negative CM patients and 10 controls with non-CNS inflammatory diseases (NCID) using a 48-plex assay. We found that 39 cytokines increased significantly during infection, while 32 decreased after treatment. Among these, 10 cytokines showed the most pronounced differences. Principal component, correlation and logistic regression analyses were used to characterize these inflammatory cytokines, which exhibited strong positive loading scores on the first principal component and were positively correlated with CSF leukocyte counts. Additionally, monocyte chemotactic protein-3 (MCP-3), monokine induced by interferon gamma (MIG), macrophage inflammatory protein-1 alpha (MIP-1α), and interleukin-18 (IL-18) negatively correlated with the CSF/blood glucose ratio. These observations suggest that specific cytokine patterns are closely linked to central nervous system inflammation and metabolic alterations during CM. Our findings provide comprehensive insight into the immune landscape of HIV-negative CM patients, identify cytokines that may serve as markers of disease activity and treatment response, and could inform future studies exploring targeted immunomodulatory strategies.