Divergent Neuroimmune Signatures in the Cerebrospinal Fluid Predict Differential Gender-Specific Survival Among Patients With HIV-Associated Cryptococcal Meningitis

Abstract

Survival among people with HIV-associated cryptococcal meningitis (CM) remains low, exceptionally among women with the increased threat of death on current optimal use of antifungal drugs. Cryptococcus dissemination into the central nervous system (CNS) prompts a neuroimmune reaction to activate pathogen concomitant factors. However, no consistent diagnostic or prognostic immune-mediated signature is reported to underpin the risk of death or mechanism to improve treatment or survival. We theorized that the distinct neuroimmune cytokine or chemokine signatures in the cerebrospinal fluid (CSF), distinguish survivors from people who died on antifungal treatment, who may benefit from tailored therapy. We considered the baseline clinical disease features, cryptococcal microbiologic factors, and CSF neuroimmune modulated signatures among 419 consenting adults by gender (biological sex assigned at birth) (168 females and 251 males) by 18 weeks of survival on antifungal management. Survival at 18 weeks was inferior among females than males (47% vs. 59%; hazard ratio HR=1.4, 95% CI: 1.0 to 1.9, and p=0.023). Unsupervised principal component analysis (PCA) demonstrated the divergent neuroimmune signatures by gender, survival, and intragender-specific survival. Overall, females displayed lower levels of PD-L1, IL-1RA, and IL-15 than males (all p≤0.028). Female survivors compared with those who died, expressed significant fold elevations in levels of CSF (CCL11 - myeloid and CXCL10 - lymphoid chemokine (in both p=0.001), and CSF Th1, Th2, and Th17 cytokines. In contrast, male survivors expressed distinctly lower levels of CSF IL-15 and IL-8 compared with those who died. Survivors of either gender demonstrated a significant increase in the levels of immune regulatory element, IL-10. In the finale, we classified divergent neuroimmune key signatures in CSF by gender, survival, and intragender-specific survival among people with HIV-associated cryptococcal meningitis. These intragender-specific survival associated-neuroimmune signatures, suggests the discrete role of gender immune regulating mechanisms as the possible targets for interventions to advance therapy to improve survival among people with HIV-associated cryptococcal meningitis.

Keywords: CCL11/Eotaxin; CXCL10/IP-10; Cerebrospinal fluid; IL-5; Principal Component Analysis; cryptococcal meningitis; gender survival; neuroimmune signatures.

Figure 1.

The proportion of cases with HIV-associated CM by gender and of related survival by gender in 21 published case series. These studies include 38,485 cases with 5,834 reported deaths, which accounted for a 15.2% case fatality rate (see Supplementary Table 1 for details and references ^,,,,–. Bars show median values. 5 studies report survival by gender (4 references and this report; Supplemental Table 1).

Figure 2.

Survival among people with HIV-associated cryptococcal meningitis. The p-value <0.05 is statistically different.

Figure 3.

Projection of cytokine responses on Eigenvector correlation covariates on PC1 and PC 2 (axes) using unsupervised principal component analysis. Baseline cerebrospinal fluid (CSF) immune signature among participants who were diagnosed with HIV-associated CM showed distinct clusters by gender and by survival. PC - Principal component. Dots - show individual cytokines produced among participants projected on Eigenvector correlation covariates. Variables near the center (0; zero) are uncorrelated to the model and variables further away from the center (0; zero) are strongly correlated to the model. Variables among all cytokine projected on the variety of CSF cytokine patterns among participants by host survival (Figure 3A). The CSF secreted cytokines clustering by gender (Figure 3B). Cytokine clustering by female survival (Figure 3C). Cytokine clustering by men’s survival (Figure 3D).