Divergent neuroimmune signatures in the cerebrospinal fluid predict differential gender-specific survival among patients with HIV-associated cryptococcal meningitis

Abstract

IntroductionSurvival among people with HIV-associated cryptococcal meningitis (CM) remains low, particularly among women, despite the currently optimal use of antifungal drugs. Cryptococcus dissemination into the central nervous system [brain, spinal cord, and cerebrospinal fluid (CSF)] elicits the local production of cytokines, chemokines, and other biomarkers. However, no consistent diagnostic or prognostic neuroimmune signature is reported to underpin the risk of death or to identify mechanisms to improve treatment and survival. We hypothesized that distinct neuroimmune signatures in the CSF would distinguish survivors from people who died on antifungal treatment and who may benefit from tailored therapy.MethodsWe considered baseline clinical features, CSF cryptococcal fungal burden, and CSF neuroimmune signatures with survival at 18 weeks among 419 consenting adults by “gender” (168 women and 251 men by biological sex defined at birth).ResultsSurvival at 18 weeks was significantly lower among women than among men {47% vs. 59%, respectively; hazard ratio (HR) = 1.4 [95% confidence interval (CI), 1.0 to 1.9; p = 0.023]}. Unsupervised principal component analysis (PCA) demonstrated divergent neuroimmune signatures by gender, survival, and intragender-specific survival. Overall, women had lower levels of programmed death ligand 1, Interleukin (IL) (IL-11RA/IL-1F30, and IL-15 (IL-15) than men (all p < 0.028). Female survivors compared with those who died expressed significant elevations in levels of CCL11 and CXCL10 chemokines (both p = 0.001), as well as increased T helper 1, regulatory, and T helper 17 cytokines (all p < 0.041). In contrast, male survivors expressed lower levels of IL-15 and IL-8 compared with men who died (p < 0.044).ConclusionsSurvivors of both genders demonstrated a significant increase in the levels of immune regulatory IL-10. In conclusion, the lower survival among women with CM was accompanied by distinct differential gender-specific neuroimmune signatures. These female and male intragender-specific survival–associated neuroimmune signatures provide potential targets for interventions to advance therapy to improve the low survival among people with HIV-associated CM.

Molecular Diagnostics of Cryptococcus spp. and Immunomics of Cryptococcosis-Associated Immune Reconstitution Inflammatory Syndrome

“…A recent study revealed sex-specific neuroimmune signatures of fatal outcomes in patients who initiated antifungal therapies. Lower levels of CSF, CXCL10, CCL11, IL12p70, TNFα, CD40L, and IL17A are associated with high 18-week mortality in women; higher IL13 and IL15 levels are associated with mortality in men, and decreased levels of IL10 and IL13 with both sex groups [73].…”

Impact of Cerebrospinal Fluid Leukocyte Infiltration and Neuroimmmune Mediators on Survival with HIV-Associated Cryptococcal Meningitis

“…The baseline CSF cytokine and chemokine levels were measured using 1:2 dilutions with a human XL cytokine discovery kit per the manufacturer's instructions (R&D, Minneapolis, MN). The Luminex CSF data acquisition was performed at the University of Minnesota earlier explained [18,28]. Briefly, the Th1 cytokines regulated through T-bet and STAT1 transcription factors were TNF-α, IFN-γ, IL-2, and IL-12p70.…”

“…The CXCL10-interferon inducible protein 10 (IP-10) supports the recruitment of activated CXCR3 + T cells and Natural killer (NK) and NK T cells to mediate a Th1-induced immune response [17]. Women with low CSF levels of the CXCR3 + T cell chemoattractant chemokine, CXCL10 and Th17 T cell-activating cytokine, IL-17A were more likely to die on anti-fungal therapy [18]. These observations suggest immune-mediated evasion pressure by such factors that impair cryptococcal host recovery, as seen among patients with high fungal burden and diminished immune response.…”